Painting diagnosis

Earlier this month, Mayo Clinic pediatric neurologist Marc Patterson also made a painting diagnosis. In Andrew Wyeth’s 1948 painting ​Christina’s World, Patterson spotted the disease responsible for the awkward position of the picture's central figure, who was Wyeth's neighbor in rural Maine.

This figure, Christina Olson, suffered from a mysterious disease that gradually diminished her ability to walk. At the time, locals believed she had polio, but the disease was never definitely diagnosed before her death.

Olson was born in 1893, before the large-scale outbreaks of polio hit the U.S., writes to Christopher Wanjek at Live Science. As a three year old, she walked on the outer edges of her feet but her limbs gradually weakened, leaving her immobile in her 20s. She may have also lost some sensation in her limbs—when she fell asleep next to a stove in her 50s, she supposedly burned herself without noticing.

“All of these things to me speak against polio,” Patterson tells Wanjek. Polio symptoms tend to be worst at the beginning of the disease and improve over time, the opposite of Olson's experience. Instead, Patterson believes she suffered from Charcot-Marie-Tooth disease, a hereditary condition of the peripheral nerves that afflicts about 2.8 million people worldwide.

https://www.smithsonianmag.com/smart-news/doctor-will-frame-you-now-mds-diagnose-diseases-two-famous-paintings-180959227/

Courtesy of a colleague

It is one of the most famous paintings in American history: Christina's World, by Andrew Wyeth. The painting, which hangs in the Museum of Modern Art in New York, depicts a young woman in a field, gazing at a farmhouse on an idyllic summer day.

But this lovely image has a dark side.

The subject in the painting is Christina Olson, Wyeth's good friend and neighbor. For most of her life, she suffered from a mysterious disorder, which slowly took away her ability to walk, and eventually to use her hands. She died at the age of 74 after a difficult life, and her disease has never been diagnosed.

Until now.

After closely examining a range of evidence about her condition, Mayo Clinic child neurologist Marc Patterson has pinpointed a diagnosis. He thinks she likely had an early-onset form of Charcot-Marie-Tooth Disease, a group of inherited disorders that affect the peripheral nerves and can lead to significant problems with movement. He will deliver his diagnosis at the 23nd annual Historical Clinicopathological Conference, held Friday, May 6 at the University of Maryland School of Medicine. The conference is devoted to the diagnosis of disorders that afflicted historical figures; in the past, experts have focused on the diseases of luminaries such as Lenin, Darwin and Lincoln.

Dr. Patterson, a professor of neurology, pediatrics and medical genetics at the Mayo Clinic in Rochester, Minnesota, reviewed her medical history, and also considered Wyeth's art that portrayed her, including Christina's World.

"This was a fascinating case," he says. "This painting has long been a favorite of mine, and the question of Christina's ailment was an intriguing medical mystery. I think her case best fits the profile of this disease."

Also speaking at the conference will be Thomas B. Cole, associate editor for the Journal of the American Medical Association. Dr. Cole is an expert on art devoted to medical topics.

The conference was founded in 1995 by Philip A. Mackowiak, MD, Carolyn Frenkil and Selvin Passen History of Medicine Scholar-in-Residence at the University of Maryland School of Medicine. "This is a amazing piece of medical detective work," says Dr. Mackowiak. "It brings home the fact that medicine has learned enormous amounts in the past few decades."

https://www.sciencedaily.com/releases/2016/05/160506095700.htm

Patterson MC, Cole TB, Siegel E, Mackowiak PA. A Patient as Art: Andrew Wyeth's Portrayal of Christina Olson's Neurologic Disorder in Christina's World. J Child Neurol. 2017 Jun;32(7):647-649.

Abstract

In Christina's World, one of the most beloved works of American art, Andrew Wyeth painted Christina Olson crawling crablike across the field below her house, raised on emaciated arms, with a swollen knob for an elbow, and hands clenched and gnarled. The significance of these physical abnormalities, and the message Wyeth endeavored to convey via the portrait, are considered here in light of Christina's medical history and the disorder it most likely signifies.

From the article:

She began life as a small, blond-haired girl with a “silver giggle,” who seemed no different from other children. However, by the time she reached the age of 3, she was walking on the outsides of her feet with on odd gait. Even so, she was a bright, fiercely determined child, who stomped around ignoring her disability as it gradually worsened. By the time she was 13 years old, she stumbled and fell frequently, though with a mind wonderfully “bright, curious and hungry.”…

Her letters at that time, however, told a different story, one involving a series of “bad falls…

Christina’s balance soon worsened to the point that it was unsafe for her to look up without having a firm grip on something to steady her. Although she was still able to walk, her crablike gait forced her to use the entire width of the road when ambulating. Her mother made her kneepads to wear under her skirt as protection against her many falls. Her hands as yet unaffected were capable of the intricate work of a talented seamstress…

By the time she reached 26, Christina could walk only 3 or 4 steps without assistance, and her hands had become so misshapen and unsteady she had to use her elbows, knees, and wrists to do those things formerly done with her hands. Offers of help were gently but firmly refused. By the end of her fifth decade, she had lost the ability to stand and had to crawl to get where she wanted to go, though her mind continued to be as sharp as ever…

When she was 56, she developed a severe illness thought to have been pneumonia. One evening, while recuperating, she sat with one leg stretched out beneath a stove and fell asleep. When she awoke, the heat from the fire had seared the flesh from her withered leg. The third-degree burn healed slowly in response to repeated application of cod liver oil….

Having eliminated these possibilities, only one of the hereditary motor and sensory neuropathies remains as Christina’s probable diagnosis—one that presents in childhood and follows a slowly progressive course over the life of the patient—in short, “Charcot-Marie-Tooth disease.”

Update in Duchenne and Becker muscular dystrophy

Waldrop, Megan A., Flanigan, Kevin M.  Update in Duchenne and Becker muscular dystrophy, Current Opinion in Neurology: October 2019 - Volume 32 - Issue 5 - p 722-727 doi: 10.1097/WCO.0000000000000739

Abstract

Purpose of review

The purpose of this review is to highlight updates in the standard of care recommendations for DMD, and to describe approaches to and recent advances in genetic therapies for DMD.

Recent findings

Treatment of DMD patients with the corticosteroids prednisone or deflazacort remains the standard of care, and recent data shows that early treatment (as young as 5 months) with a weekend dosing regimen results in measurable improvement in motor outcomes. A mutation-specific therapy directed at restoring an open reading frame by skipping exon 51 is FDA-approved, and therapies directed at other exons are in trials. Gene replacement therapy shows significant promise in animal models, and trials are underway. Genome editing has received significant attention because of results in animal models, but challenges to implementation in humans remain.

Summary

The mainstay of treatment remains meeting well defined standards of care that have been shown to influence morbidity and mortality. These include use of systemic steroids, early nocturnal ventilatory support, appropriate cardiac care and prophylaxis, and wherever appropriate, scoliosis surgery. Early and accurate molecular diagnosis, along with appropriate and multidisciplinary care, provides the best opportunity for maximum benefit of both current standard and upcoming novel therapies for boys with DMD. Among the most promising of these is AAV-based gene replacement therapy, which is currently in clinical trials.

__________________________________________________________________________

From the article

The standard therapy for DMD is oral corticosteroids. Although patients were first treated with prednisone in 1974, it was not until shortly after discovery of the protein, that several studies were conducted evaluating daily prednisone for use in DMD and a benefit in terms of functional improvements were seen. However, because of concerns about side effects, prednisone was not widely used and management of the disease varied widely nationally and internationally. Over time, practice parameters were developed, but it was not until 2010 that the first international guidance for the care and management of DMD was published. This consensus guidance has recently been updated, and the interested reader is referred to these detailed recommendations. In this review, we will highlight some of these current standard of care recommendations for DMD, and promising upcoming therapies for the dystrophinopathies…

Current recommendations include initiation before substantial physical decline, typically by the age of 5, using daily dosing of either prednisone 0.75 mg/kg/day or deflazacort 0.9 mg/kg/day [22]. As earlier treatment may result in larger benefit in regards to loss of ambulation, many clinicians elect to initiate weekend dosing around age 3 years, using 5 or 10 mg/kg of prednisone per week dividing into two doses delivered on each Saturday and Sunday…

A recent article of interest addressed therapy with allogenic cardiosphere-derived cells (CDCs), to which have been attributed antifibrotic, anti-inflammatory, and regenerative properties via secretion of growth factors and mRNAs. A potential therapeutic benefit was suggested by a small (n = 25), open-label randomized trial of direct infusion of 75 million cells into the coronary arteries of patients, in which cardiac MRI suggested diminished fibrotic burden and improved regional myocardial function at 6 and 12 months; a subsequent randomized blinded trial is underway….

Corticosteroids, in addition to the interventions mentioned above, have greatly improved respiratory function via increased skeletal muscle strength and subsequent less severe scoliosis, which can directly impact ventilatory function. Although nocturnal ventilatory support has long been known to have an impact on morbidity and mortality, the coincident correction of spinal scoliosis in appropriate patients can increase survival by nearly a decade…

Muscle biopsy still has a place in the diagnosis of dystrophinopathies. Importantly, up to 7% of dystrophinopathy patients may have mutations that are undetectable by genomic DNA analysis, and many have deep intronic mutations that result in the inclusion of intronic sequence as pseudoexons that require analysis of muscle-derived mRNA to identify. Muscle biopsy also remains useful in assessing dystrophin protein expression in patients where the observed phenotype does not correlate with the phenotype predicted by the application of the ‘reading-frame rule.’ The most common category of these mutations consists of predicted nonsense, out-of-frame mutations (as identified from blood) that actually affect mRNA splicing and resulting in significant amounts of in-frame transcript and sufficient protein expression to alter the clinical course…

A major rationale for accurate genetic diagnosis is to make use of a growing number of mutation-specific therapies. In general, these are directed toward restoring an open-reading frame. The first of these is the antisense phosphorodiamidate morpholino oligomer (PMO) eteplirsen, directed toward altering splicing of the dystrophin mRNA to exclude exon 51. This therapy is applicable to multiple mutations; as examples, deletions of exons 45–50, 48–50, 50, or 52 (among others) are all predicted to have reading frames restored by exon 51 skipping, and are thus, amenable to eteplirsen treatment. Although treatment restores a relatively small amount of dystrophin, the antisense PMO showed improved ambulation and respiratory effects, and more favorable results than a trial of a competing 2’O-Me phosphorothioate antisense oligonucleotide. Following its Food and Drug Administration (FDA) approval, eteplirsen is in widespread clinical use; further treatment trials with morpholinos directed to other exons (casimersen for exon 45, and golidersen for exon 53) are underway. Cocktails of PMOs may ultimately be combined to generate a therapy that addresses skipping larger regions, such as exons 45–55, which would be therapeutic for up to 63% of patients. Another mutation-specific therapeutic approach is nonsense suppression, such as with the drug ataluren, although that drug failed to show a convincing benefit in a randomized placebo controlled trial and is not marketed in the United States…

Among the most promising experimental therapies is gene replacement using adenoassociated viral (AAV) vectors. AAV is not associated with human disease, and AAV genomes are essentially nonintegrating into chromosomes, factors that provide a margin of safety for considering therapeutic development. Different AAV serotypes have differential tropism to human tissues, and utilization of muscle tropic AAVs in combination with appropriate promoters has allowed the development of vectors designed for treatment of muscle diseases. The power of AAV gene replacement has recently been demonstrated by the remarkable results achieved in patients with spinal muscular atrophy type 1 (SMA1) treated with an AAV9 vector carrying the full-length SMN cDNA. The extraordinary survival benefit resulting from this treatment led to FDA approval of this viral therapy under the trade name Zolgensma in May 2019…

There is great excitement around the possibility that in the near future there will be novel therapies that may significantly alter the course of DMD, and the impact of these therapies will be maximized by the development of newborn screening strategies that result in presymptomatic diagnosis.  Nevertheless, the mainstay of treatment remains meeting well defined standards of care that have been shown to influence morbidity and mortality. These include use of systemic steroids, early nocturnal ventilatory support, appropriate cardiac care and prophylaxis, and wherever appropriate, scoliosis surgery. Nevertheless, the promise of novel therapies is significant. Importantly, the prospect of gene-directed therapies, including viral gene replacement, supports the need for early diagnosis and treatment, the rationale for which is increasingly well documented. Early and accurate molecular diagnosis, along with appropriate and multidisciplinary care, will provide the best opportunity for maximum benefit of novel therapies in each boy with DMD.

A challenge to viral gene replacement for DMD is that unlike the case with the SMN cDNA, the full-length DMD cDNA is too large, at approximately 11.5 kilobases (kb), to fit into an AAV genome, which has a maximum packaging capacity of around 5 kb. As a result, several groups have designed microdystrophin genes, essentially based upon the reading-frame rule; these encode miniaturized DMD constructs that encode protein products in which critical functional domains are included – generally, critical N-terminal and C-terminal-binding domains, with differing inclusion of other regions. A full discussion of the differences among these is beyond the scope of this article, but the interested reader is referred to a recent detailed review.  Three such competing microdystrophin trials are underway at present (sponsored by Pfizer, Sarepta Therapeutics, and Solid Therapeutics), with unpublished (to date) reports of early promising results. The ultimate durability of such therapy remains to be seen, as does the ultimate beneficial effect of the engineered microdystrophins, as no natural mutations as seen in BMD exist to inform expectations. Nevertheless, preclinical data for each construct is promising, and the results of each trial are eagerly awaited.

An alternate approach to viral gene therapy is the delivery of surrogate genes that can substitute for dystrophin function. One such example is the GALGT2 gene, which encodes an O-mannosyltransferase responsible for the terminal glycosylation of dystroglycan at the neuromuscular and myotendinous junctions, where utrophin replaces dystrophin in the dystroglycan-associated protein complex. Expression of exogenous GALGT2 via a viral vector results in expression of the glycosylated dystroglycan epitope and localization of utrophin across the entire myofiber, resulting in improvement in mouse models, and a pilot trial of gene delivery in humans is underway. Another promising approach delivers noncoding small nuclear RNAs (U7snRNA) with antisense sequences directed toward exon definition elements; these RNAs can induce highly efficient exon skipping, with promising results in animal models and planning for near-term trials underway…

Recent advances in genome editing at the DMD locus in model systems have raised interest in the prospect of somatic editing as a therapeutic approach. Most such approaches have utilized CRISPR/Cas9 systems, with guide RNAs (gRNAs) directing endonuclease activity to induce excision of one or more exons in order to restore an open reading frame. CRISPR/Cas9 editing has shown promising results in both mouse and canine models. Such an approach can theoretically extend to excision of the entire region of exon 45 to exon 55, with the previously stated goal of treating the largest number of DMD patients. However promising, multiple challenges remain prior to clinical trials. There are concerns regarding germline alteration, off-target effects, and immune responses to the bacterial Cas9 proteins used in many strategies. Depending upon the Cas9 used, packaging of the Cas9 gene along with the necessary gRNAs into a single AAV vector may not be possible, suggesting a need for dual vectors, and overall efficiency of editing remains a challenge. Despite enthusiasm of the patient community, genome editing therapy will likely require significant further preclinical studies…

There is great excitement around the possibility that in the near future there will be novel therapies that may significantly alter the course of DMD, and the impact of these therapies will be maximized by the development of newborn screening strategies that result in presymptomatic diagnosis . Nevertheless, the mainstay of treatment remains meeting well defined standards of care that have been shown to influence morbidity and mortality. These include use of systemic steroids, early nocturnal ventilatory support, appropriate cardiac care and prophylaxis, and wherever appropriate, scoliosis surgery. Nevertheless, the promise of novel therapies is significant. Importantly, the prospect of gene-directed therapies, including viral gene replacement, supports the need for early diagnosis and treatment, the rationale for which is increasingly well documented. Early and accurate molecular diagnosis, along with appropriate and multidisciplinary care, will provide the best opportunity for maximum benefit of novel therapies in each boy with DMD.

Finding the strength to let go of my son

I would describe myself as many things; as a wife, a mother, a daughter, a Jewish woman, a teacher, a friend, a thinker, a dreamer, a believer. But tonight, as I write this, I am only a mother of one: my eldest son, my firstborn, my miracle child, the one who wasn’t supposed to survive.

If I were to tell you about him, it would be to tell you of his soulful eyes and his winning smile. I would tell you of his gentle nature, his beautiful, shining presence and his innocent need to hug every person he meets as though he really means it, putting our polite social conventions to shame.

But if you were to ask others, they would describe only his outward appearance. A thirteen year old boy in a wheelchair who is unable to talk, to walk or even to feed himself. These are the facts about my son, but it paints only a fraction of the full picture. The medical files that we have on him fill an entire shelf, and on his diagnoses alone I could fill an entire paragraph.

He is the oldest child of our family, a beloved big brother to all his siblings. As I watch the way they all treat him with love and respect, the way they accept and appreciate him exactly as he is, I am in awe.

Yet, I see this family shifting and the future is coming sooner than I expected. I know a change will come soon. It is something we all go through eventually, but will be especially difficult for those of us with children who can never be independent.

One day, I am going to have to let him go.

Just like all my other children that will leave my home, so will he. But unlike my other children, he won’t be leaving of his own accord. I will have to place him gently in the arms of another and say “Please help me carry this child – I cannot do it on my own anymore.”

My heart is broken.

This Pesach we are experiencing a taste of this future. For the first time in his life, our son Doniel, will be spending a few days in a care home. We found a wonderful Jewish respite home that can take our son for those few days we are unable to care for him at home.

I can’t sleep.

I have made lists, filled out forms, spoken to all the staff at the home to explain to them every detail about him, but I still lie here unable to sleep. What if they don’t remember all the things I told them? What if he doesn’t like their food? What if he feels lonely or lost? But mostly I wonder whether he will feel unloved by those of us who love him the most.

How do you explain to a child who doesn’t understand that one day he will live a life separate from yours? How do you let that child know that, wherever they are in the world, their home is always going to be in your heart and mind? That they are branded on your soul for eternity, as you offer their name up in your prayers every day, morning, afternoon and evening.

As I stand in my kitchen cooking for Pesach, I think about the month of Nissan and the birth of the Jewish People. I imagine us walking out of Egypt as a group of people broken and lost, but still with a small flame of hope inside us. We knew, even then, that we weren’t just walking away from all that was holding us back, but that we were walking towards our greatest selves.

This seder night, I will reflect on the freedom that we were given on this day, thousands of years ago. The freedom to walk towards G-d, place ourselves gently in His arms, and ask Him to carry us, because we cannot do it on our own anymore.

https://hevria.com/estih/finding-strength-let-go-son/

Courtesy of my daughter.

Migraine in children under 6 years of age

Francesca Marchese, Luciana Rocchitelli, Luca Maria Messina, Rosaria Nardello, Giuseppe Donato Mangano, Francesca Vanadia, Salvatore Mangano, Filippo Brighina, Vincenzo Raieli.  Migraine in children under 6 years of age: A long-term follow-up study. European Journal of Pediatric Neurology.  Published:April 16, 2020DOI:https://doi.org/10.1016/j.ejpn.2020.04.005

Highlights

•

The prevalence of autonomic cranial symptoms and familiarity suggest the persistence of migraine in adulthood.

•

The migraine persistence facilitates the sensitization of neural centers associated to pain leading to increased allodynia.

•

Several clinical feature of migraine syndrome may change during the follow-up.

•

The prevalence of autonomic cranial symptoms and the familiarity of migraine suggest the persistence of migraine in adulthood, while the active persistence of the disorder may facilitate the strengthening of the sensitizing neural centers associated with pain leading to increased allodynia.

Abstract

Background

Early starting of migraine seems predictive for less favorable outcome in later ages, however follow-up investigations are very few and all with short-term prospective period. We report here the longest follow-up study in a population of children presenting with migraine under the age of 6.

Methods

We followed-up 74 children under 6 years of age, referred for headache to our department between 1997 and 2003. The study was carried out between October 2016 and March 2018. Headache diagnoses were made according to the IHS criteria.

Results

23/74 patients, 31% of the original cohort, were found at follow-up in a period ranging between 15 to 21 years after the first visit. Seven of them were headache free. The remaining 16 patients had migraine. In the migraine group, the localization of pain changed in 75% of the subjects, 11/16 (68.7%) had allodynia and 9/16 (56.25%) had cranial autonomic symptoms.

Conclusions

Our results suggest that the onset of migraine at very young age represents unfavorable prognostic factor for persistence of the disease at later ages. Some clinical features may change during clinical course, and the active persistence of the disorder may lead to an increase in allodynia.

Courtesy of:  https://www.mdlinx.com/journal-summaries/migraine-migraine/2020/04/23/7666199?spec=neurology

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. JAMA Psychiatry. Published online April 01, 2020. doi:10.1001/jamapsychiatry.2020.0306

Key Points

Question  Is preeclampsia linked to the neurodevelopment of offspring beyond its established association with cerebral palsy?

Findings  In this population-based birth cohort of 980 560 participants based on the Norwegian Medical Birth Registry, preeclampsia in term pregnancies was associated with an increased risk of cerebral palsy, autism, attention-deficit/hyperactivity disorder, epilepsy, and intellectual disability in offspring.

Meaning  After excluding the possible role of preterm delivery, preeclampsia in term pregnancies was associated with an increased risk of neurodevelopmental disorders among offspring.

Abstract

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:  https://www.medpagetoday.com/psychiatry/generalpsychiatry/85756

High association of MOG-IgG antibodies in children with bilateral optic neuritis

Wendel EM, Baumann M, Barisic N, et al.  High association of MOG-IgG antibodies in children with bilateral optic neuritis. European Journal of Paediatric Neurology —April 17, 2020

Abstract

Background

Bilateral optic neuritis (bilON) is a rare clinical presentation often thought to be associated with relapsing disorders such as neuromyelitis optica spectrum disorders (NMOSD) or multiple sclerosis (MS).

Objective

To characterize the clinical, radiological phenotype and antibody status of children presenting with bilON.

Material and methods

Retrospective multicenter study on children with bilON age <18 years with a first episode aquired demyelinating syndrome (ADS), cMRI, AQP4- and serum MOG-antibody status and follow-up data were collected.

Results

30 patients (f:m = 15:15, median age 8.0y) with bilON met the inclusion criteria. 22/30 (73%) were MOG-positive (median: 1:1280, range: 1:160–1:1520). No patient showed AQP4-abs. 4/30 patients (13%), all with high MOG-abs titers, had recurrent episodes. No patient developed MS. Improvement after IVMP was observed in most patients (26/30; 87%). Outcome was favorable with no sequelae in 22/30 patients. Serial MOG-abs titers tested in 15/22 patients decreased to a median of 1:160 (range: 0–1:640) over a period of 31 months (range: 2–141 months) in 14/15 (93%) patients. MR imaging showed a predominantly anterior affection of the visual system in seropositive patients with bilateral intraorbital lesions in 68% (15/22), compared to 25% in MOG-negative patients (2/8).

Conclusion

Pediatric bilON is associated with high MOG-abs titers in combination with anterior involvement of the visual system. Despite severe loss of vision, the majority of patients shows distinct recovery after IVMP.

Courtesy of:  https://www.mdlinx.com/journal-summaries/optic-neuritis-optic-neuritis/2020/04/17/7657714?spec=neurology

Osteogenesis imperfecta

https://www.youtube.com/watch?v=h4jKY9d4yc4

Recommendations for preventing and treating pediatric migraine

Preventive Pharmacotherapy

Current therapy options from low to high confidence for prevention are listed in Table I.

  

Amitriptyline (1 mg/kg/d) combined with cognitive behavioral therapy (CBT) carries the highest confidence of efficacy. This combination has been shown to decrease frequency of migraine or headache days and headache frequency by at least 50%. However, this difference has not been shown in amitriptyline in combination with headache education alone.

Acute Medication 

In a randomized trial published in 2013, researchers assessed amitriptyline as well as CBT for chronic migraine compared to amitriptyline plus headache education in children and adolescents. The primary endpoint was headache days and the secondary was PedMIDAS score at 20 weeks. Clinical significance was defined as a > 50% reduction in headache days and PedMIDAS score < 20 points. Headache days were reduced significantly by 11.5 days for the amitriptyline plus CBT group vs 6.8 days in the headache education plus amitriptyline group. Scores of the PedMIDAS decreased by 52.7 points versus 38.6 points which was significant in favor of amitriptyline plus CBT…

The only category that holds medication in high confidence is the outcome of being pain-free at 2 hours, including sumatriptan/naproxen oral tablet 10/60 mg, 30/180 mg, 85/500 mg, and zolmitriptan nasal spray 5 mg.1

A trial was published in 2012 comparing the efficacy and safety of all three doses of sumatriptan/naproxen combination therapy. This study included patients ages 12 to 17 years with two to eight migraine attacks per month for 6 months that typically lasted more than 3 hours when untreated. The primary endpoint was being pain-free at 2 hours. Rates of pain-free status were significantly higher in all three treatment groups compared to placebo. A post-hoc analysis found no differences among the three dosing regimens. Two-hour photophobia-free and phonophobia-free status were significant in the 85/500 mg group compared to placebo. Additionally, pain-free status was sustained to 24 hours in the 85/500 mg group.6 In the triptan class, while it is safe to take these medications during the aura preceding a migraine, it may be more effective when taken at the start of pain.1 Table II summarizes the acute treatment options recommended in the new guidelines. Generally, triptans are avoided as first-line options until non-prescription options (ie, acetaminophen, ibuprofen) have failed. For consideration of triptans, the safety profile should be weighed against the clinical benefits of use.

https://www.practicalpainmanagement.com/pain/headache/ask-pharmd-what-are-recommendations-preventing-treating-pediatric-migraine

Seizures during treatment of childhood acute lymphoblastic leukemia

European Journal of Paediatric Neurology — Anastasopoulou S, Heyman M, Eriksson MA, et al. Seizures during treatment of childhood acute lymphoblastic leukemia: A population-based cohort study.  European Journal of Paediatric Neurology  April 20, 2020

Given that seizures are common in children with acute lymphoblastic leukemia (ALL), researchers analyzed the frequency, timing, etiology and risk factors of seizures in ALL individuals. Participants in the study were children aged 1–17.9 years at diagnosis of B-cell-precursor and T cell ALL who were treated according to the Nordic Society of Pediatric Haematology and Oncology ALL2008 protocol between 2008 and 2015. Data reported that seizures occurred in 81/1464 (5.5%) individuals. Results revealed that the cumulative incidence of seizures was 1.7% for one months and 5.3% for one year. Findings suggested that seizures are relatively common in ALL patients and most commonly occur in patients with posterior reversible encephalopathy syndrome, sinus venous thrombosis, or as an isolated symptom. Older children are at a higher risk of seizures.

Courtesy of:  https://www.mdlinx.com/journal-summaries/leukemia-seizure-disorders-acute-lymphoblastic-leukemia/2020/04/20/7662055/?spec=neurology

Leukoencephalopathy with calcifications and cysts treated with bevacizumab

Fay AJ, King AA, Shimony JS, Crow YJ, Brunstrom-Hernandez JE. Treatment of  Leukoencephalopathy With Calcifications and Cysts With Bevacizumab. Pediatr Neurol. 2017;71:56–59. doi:10.1016/j.pediatrneurol.2017.03.008

Abstract

Background: Leukoencephalopathy with calcifications and cysts is a rare, autosomal recessive cerebral microangiopathy that causes progressive white matter disease, calcifications, and cysts within the brain. It is typically associated with slowly progressive psychomotor regression, seizures, and movement disorders. Although leukoencephalopathy with calcifications and cysts affects only the central nervous system, it demonstrates remarkable neuropathologic and radiologic overlap with Coats plus, a disorder of small vessels of the brain, eyes, gastrointestinal tract, and bone. Coats disease without extraocular involvement, a genetically distinct disorder from Coats plus, is characterized by retinal telangiectasias and exudative retinopathy, accompanied by neovascularization. Inhibition of vascular endothelial growth factor (VEGF) signaling with the monoclonal anti-VEGF antibody bevacizumab can improve retinal edema and exudates in Coats disease. Given these observations, we reasoned that VEGF inhibition might also be effective in treating leukoencephalopathy with calcifications and cysts and Coats plus, neither of which has any known therapy.

Methods: We treated an 18-year-old man with leukoencephalopathy with calcifications and cysts using biweekly infusions of the VEGF inhibitor bevacizumab for more than one year and performed clinical examinations and brain imaging at three month intervals.

Results: After treatment for more than one year, the patient showed improved bradykinesia and range of motion, and brain magnetic resonance imaging demonstrated a marked reduction in cyst volume and white matter lesions.

Conclusions: Further studies in a cohort of patients are warranted to investigate the efficacy of VEGF inhibition as a treatment for leukoencephalopathy with calcifications and cysts.

Can a parent refuse the brain death examination?

Brittany M. Lee, Amy Trowbridge, Macallagh McEvoy, Aaron Wightman, Stephanie A. Kraft and Jonna D. Clark.  Can a Parent Refuse the Brain Death Examination? Pediatrics April 2020, 145 (4) e20192340; DOI: https://doi.org/10.1542/peds.2019-2340

https://pediatrics.aappublications.org/content/145/4/e20192340

Abstract

The American Academy of Neurology believes that doctors have the right to do tests to evaluate whether a patient is brain dead even if the family does not consent. They argue that physicians have “both the moral authority and professional responsibility” to do such evaluations, just as they have the authority and responsibility to declare someone dead by circulatory criteria. Not everyone agrees. Truog and Tasker argue that apnea testing to confirm brain death has risks and that, for some families, those risks may outweigh the benefits. So, what should doctors do when caring for a patient whom they believe to be brain dead but whose parents refuse to allow testing to confirm that the patient meets neurologic criteria for death? In this article, we analyze the issues that arise when parents refuse such testing.

From the article:

The American Academy of Neurology does not believe that obtaining informed consent before performing a brain death evaluation is necessary. Instead, they argue that physicians have “both the moral authority and professional responsibility” to do such evaluations, just as they have the authority and responsibility to declare death by circulatory criteria. Not everyone agrees,  nor do experts agree on how exactly such evaluations should be performed.  So, what should doctors do when caring for a patient whom they believe has died but whose parents refuse to allow testing to confirm death by neurologic criteria (DNC)? In this article, experts from intensive care, bioethics, and palliative care analyze the issues that arise when parents refuse formal testing to declare death by neurologic criteria (“brain death”).

Most neurologists (78%) and pediatric neurologists and intensivists (72%) do not feel consent is necessary before testing for DNC.  But the law varies from state to state. One Virginia court ruled that parental consent was not necessary to perform testing, whereas courts in Kansas and Montana ruled in favor of a consent requirement.  In Montana, the court found that testing for DNC is a “medical procedure with significant repercussions” that patients (or their surrogates) have a fundamental right to consent to or refuse, also noting that the state legislature’s silence regarding the consent requirement could not be interpreted as permission to proceed without consent.   Recently, Nevada became the first state to revise its Determination of Death Act to expressly indicate that determination of death is “a clinical decision that does not require…consent.”  In sum, states are split regarding the legality of physician testing for DNC without consent.

The requirement to obtain informed consent before performing medical interventions stems from the ethical principle of respect for persons. In limited situations, consent may be assumed, including for emergent care or specific, routine physical examinations or tests (such as blood counts or radiographic imaging), when a patient provides general consent for care within an inpatient visit. In these situations, proceeding without express consent is supported by duties of beneficence because it is assumed to be in the patient’s interest to receive care in an emergency or undergo diagnostic testing to aid in treatment or prognostication. Clinical testing for DNC, however, often takes place in a controlled environment, and reasonable people may disagree about whether determining a patient has died is in that person’s interest. As Truog and Tasker have argued, if we cannot assume that a patient would want a procedure, we are obligated to seek informed consent.

If parents refuse testing for DNC, their child is presumed to be alive, and the ethical justification for overruling their refusal is unclear. The formal clinical test provides no direct medical benefit to the child, only the possibility of a legal determination of death, resulting in permissible unilateral withdrawal of mechanical support. Therefore, individualistic standards, such as the best interest standard or harm principle, do not justify overruling a refusal because it is neither clear that testing to declare DNC is in a child’s best interest nor that a profoundly impaired child whose death has not been confirmed is harmed by continued existence compared with the alternative.

There are a number of bases for claims that parental consent is not necessary. One is that continued provision of mechanical support reflects futile or medically inappropriate care. We believe that mechanical support is not futile if the patient remains legally alive and the family’s goal of treatment is continued life. Another justification for testing without consent is a professional responsibility to provide appropriate care based on an accurate diagnosis. However, this responsibility does not permit physicians to overrule parental refusals of diagnostic tests unless the refusal results in clear, preventable, and imminent harm to the child. Finally, others may argue that permitting refusal of formal DNC testing may overwhelm limited intensive care resources with individuals who likely meet the definition of DNC, potentially limiting access to care for others.  Although these are legitimate concerns, they are not supported by reported experience in states or countries with limited acceptance of brain death.  Even if parental refusal of formal DNC testing did result in waste of limited resources, policies about who should be assessed and how their surrogates should be approached, including whether consent is required, should be developed at the state or national level rather than applied in an ad hoc manner at the bedside.

This analysis suggests that there is no ethical justification for physicians to unilaterally perform testing for DNC against parental wishes. In some states, as noted, doctors have the legal right to perform such testing. However, having a legal right does not mean that it is ethical. Physicians should respect parents’ refusals and attempt to understand the reasoning for refusal. The pursuant discussions may reveal that the family has an underlying concern about the diagnosis of brain death itself, some degree of mistrust in the process, or perhaps a need for more time to come to terms with their child’s prognosis. In any case, the process of informed consent may serve a broader function beyond merely obtaining permission to proceed with formal testing for DNC. E.C.’s case and others like it underscore the importance of considering consent as a mutual, dialectic process that builds on and contributes to the patient-family-doctor relationship. Although these cases are tragic and challenging for all involved, optimal communication, empathy, and time may lead to resolution…

For additional support during a time-limited trial before testing, eliciting the expertise of consulting services, including the bioethics consult and palliative care teams, may be beneficial. Chaplains may help align with a family’s faith and use religious guidance to support families. Social workers may provide counseling, help facilitate visitation from other family members and friends, and ensure that the family has their basic needs met to optimize their decision-making capacity. In addition, eliciting support from those whom the family trusts, including community or spiritual leaders external to the institution, may be important. Often, with time and the inclusion of consultants, trust may grow, and the family may come to feel honored and supported in these tragic circumstances.

Even so, some families may continue to refuse testing. To address these situations, hospitals should allow for accommodation of families when necessary.  This approach may require additional interventions, including tracheostomy and gastrostomy tube placement, transfer to a different location, and additional support for the health care team. Those are worth the effort to demonstrate sincere respect, maintain trust, and provide the compassionate care that all children and families deserve…

A palliative approach includes multiple assessments that could guide how best to approach the process of brain death examination for a particular family. Exploring the family’s understanding of their child’s disease and prognosis may uncover knowledge gaps or concerns that should be explored further. It is critical to understand how a family’s faith, culture, and personal belief system impact their comprehension of “brain death” and the child’s needs. Understanding the values of a particular family as they relate to medical care in general, and brain death specifically, creates the opportunity for providers to develop a thoughtful medical approach. It is also essential to explore a family’s previous experience with serious illness to allow for a deeper understanding and insight into their emotional process and how they have navigated past traumas. The foundation created by these assessments can inform a thoughtful approach for communication and decision-making around testing for DNC.

Collaboration and relationship building are critical. Although medical teams may be limited by the constraints of their institutional work structure, in cases such as this, continuity matters. A consistent care team allows one to build rapport and a trusting relationship. When this is not possible, we must provide a meaningful summary to colleagues of the emotional work and complex communication that has occurred as well as use the interdisciplinary approach to bridge the issue of continuity as much as possible for families.

Finally, providers should consider the importance of time. Critically ill children depend on the rapid assessments, decisions, and interventions of the PICU team for survival. Rapid decision-making is the norm. This case highlights the importance of recognizing when it is time to slow down. Although examination for DNC may not be viewed as a decision from the physician perspective, many families recognize the timing of examination as a decision point. Allowing time for parents to process and ready themselves is sensible and may be necessary to absorb the diagnosis. A 2013 report from The Hastings Center asserts that requests for a delay in the declaration of death or in the discontinuation of interventions are reasonable and should be accommodated if possible as a way to help loved ones with grief and bereavement.

Although no amount of time takes away a family’s pain and grief, using an interdisciplinary approach centered on the unique needs of a family may strengthen the partnership between parents and medical teams to allow for space to move through the challenges of brain death examination.

Time, continuity of relationships, and an interdisciplinary approach can improve trust and collaboration such that both parties are able to hear and appreciate each other’s perspectives. With this approach, the relationship with the family is reframed from one that is focused on moving through examination and declaration of death to one that accounts for the needs of the individual family based on their lived experience…

The concept of brain death has undergone a surprising trajectory in the public mind. When first proposed, it was widely accepted. By 1990, every state in the United States recognized brain death as an appropriate legal criterion for declaring a person dead. But the concept seems to be generating more controversy over time and moving from the pages of medical journals into the mainstream press. In 2018, a feature article in The New Yorker magazine raised questions about whether people who meet legal standards for brain death are in fact dead.

The current controversies reflect both shifts in values and technological advances in intensive care. When brain death was first conceptualized, patients who met neurologic criteria would quickly progress to circulatory death. That is no longer true. In some cases, their hearts and other organs continue to function normally. As Shewmon points out, patients who meet criteria for brain death can assimilate nutrients; fight infection and foreign bodies; maintain homeostasis; eliminate, detoxify, and recycle cell waste throughout the body; maintain body temperature; grow proportionately; heal wounds; exhibit cardiovascular and hormonal stress responses to unanesthetized surgical incision; gestate fetuses; and undergo puberty. Given the contentiousness of the concept of brain death, it seems ethically appropriate to honor parents’ refusals of formal testing. To force such testing will ultimately erode people’s trust in doctors, bioethicists, policy makers, and the legal system. As noted, most parents eventually accept testing and a diagnosis of brain death. Accommodating the rare exceptions is a price worth paying to maintain public trust.

COVID 19 and the central nervous system

Contents:

1. What Defines a Brain Pathogen

2. Why SARS-CoV-2 Can Be a Brain Pathogen

3. Neurological Manifestations of SARS-CoV-2

   - 25th Feb: Neurological signs

   - 3rd Mar: Histopathological examinations

   - 4th Mar: Encephalitis case

   - 21st Mar: Encephalopathy case

   - 28th Mar: Recurrent seizures case

   - 31st Mar: Hemorrhagic necrotizing encephalopathy case

   - 1st Apr: Guillain-Barré syndrome case

   - 3rd Apr: Meningitis/encephalitis case

   - 8th Apr: Smell loss without nasal obstruction case

   - 10th Apr: Encephalitis case

4. How SARS-CoV-2 Can Invade the Brain

5. What Actions Are Needed

6. Why Things Aren’t So Straightforward

7. Is it the Immune System or Virus?

Excerpts:

Why SARS-CoV-2 Can Be a Brain Pathogen

Weeks before clinical cases of SARS-CoV-2 brain infections were reported, Chinese and Pakistani researchers have already argued why the virus is capable of invading the brain:

Reason 1: SARS-Cov-2 is a type of coronavirus and most previous coronaviruses like SARS and MERS are known to infect the brain. It’s unlikely that SARS-CoV-2 is an outlier coronavirus.

Reason 2: SARS-CoV-2 enters a cell via the ACE2 receptor. Though this receptor is mainly expressed in the lungs, the brain has it as well.

Reason 3: Previously known coronaviruses infect the brainstem, which receives neurons from the lungs and respiratory tract. A damaged cardiorespiratory function of the brainstem likely underlies some cases of respiratory failure in COVID-19 victims.

Reason 4: COVID-19 patients show neurological symptoms such as confusion, nausea, headache, and loss of smell and taste. The last hints at a possible damaged olfactory system in the brain — and other coronaviruses are known to infect the olfactory bulb…

How SARS-CoV-2 Can Invade the Brain

Abdul Mannan Baig, MD and senior instructor at the Aga Khan University in Pakistan, is one of the earliest researchers to raise awareness about the neuroinvasive capacity of SARS-CoV-2.

In a recent paper published on 7th April, he outlined a few possible pathways by which SARS-CoV-2 can infiltrate the brain. “The hematogenous route appears to be the likely pathway for SARS-CoV-2 to reach the brain, but other routes to the CNS like across the cribriform plate of the ethmoid bone in proximity to the olfactory bulb should be taken into consideration in cases of early-phase COVID-19-affected patients who exhibit loss of smell and taste accompanied with neurological signs and symptoms,” Dr. Baig wrote.

Hematogenous means bloodstream wherein SARS-CoV-2 may enter the systemic circulation from the lungs and then reach and cross the blood-brain-barrier. The cribriform plate is where olfactory nerves of the nose cross and connect into the brain (i.e., the olfactory bulb of the limbic system); this route directly bypasses the blood-brain-barrier…

Why Things Aren’t So Straightforward

An important note is that most viruses do not normally cause brain diseases as their primary symptom. Herpes simplex virus, for example, causes cold sores but also encephalitis in some cases. Likewise for COVID-19 as respiratory disease, but can be a brain disease — causing meningitis, seizures, encephalitis, and encephalopathy — in rare instances.

In other words, viruses can infect the brain, but they may not cause brain diseases. Either because the brain immune system prevents it or the virus remains non-infective in the brain. In the latter case, the virus becomes latent (or sleeps) in the brain owing to the control of the immune system. As follows, when the immune system is suppressed, viruses have the chance to reactivate and re-cause diseases— more details here:  https://medium.com/microbial-instincts/first-case-of-covid-19-encephalitis-7b305fcfe9a8

Is it the Immune System or Virus?

Some scientists have even considered that brain diseases can be an “indirect result” of COVID-19. “It is also important to mention here that the neurological signs and symptoms observed in the COVID-19 cases could be a manifestation of hypoxia, respiratory, and metabolic acidosis at an advanced stage of the disease,” Dr. Baig himself argued against his propositions.

As mentioned above, Dr. Geraci also believed that the COVID-19-associated encephalopathy is due to the “cytokine storm” wherein the immune system damages the brain as collateral damage of fighting SARS-CoV-2. While this may be true, evidence of SARS-CoV-2 genes being found in the cerebrospinal fluid cannot be discounted.

“Although inflammation is critical for CNS pathogen clearance, lasting effects of immune molecules and pathogen by-products may represent an underlying mechanism of neurologic dysfunction,” explains Robyn Klein, MD and professor in the Departments of Medicine, Pathology & Immunology, and Neuroscience of Washington University. This means that an overdriven immune system and SARS-CoV-2 in the brain could both contribute additively to the development of brain diseases.

https://medium.com/microbial-instincts/neurology-and-covid-19-everything-researchers-know-so-far-f7e0607e2071

Charlotte Figi

Charlotte Figi, the Colorado Springs girl who, as a gleeful and fragile child, launched a movement that led to sweeping changes in marijuana laws across the globe, has died from complications possibly related to the new coronavirus.

She was 13.

Charlotte’s death was announced by a family friend Tuesday night on the Facebook page of her mother, Paige Figi.

“Charlotte is no longer suffering. She is seizure-free forever. Thank you so much for all of your love,” read the post, which also asked the public to respect Figi’s family’s privacy.

Paige Figi had posted in recent weeks on Facebook about a serious illness that sickened all the members of her family with fever, coughing and breathing difficulties and sent Charlotte to the hospital.

In an update Wednesday to the Facebook post announcing Charlotte’s death, Paige Figi said the family did not initially meet the criteria for testing for COVID-19, the disease caused by the coronavirus, so they self-treated at home, as instructed. Charlotte’s symptoms worsened, and she was admitted to the hospital on April 3, where she was tested for COVID-19.

The test result came back negative — though the coronavirus test has been beset with false negatives. Figi wrote that Charlotte was treated on a floor designated for COVID-19 patients, “using all of the medical protocols set in place.”

She was discharged from the hospital on Sunday, after her condition seemed to improve. She suffered a seizure Tuesday morning resulting in respiratory failure and cardiac arrest, however, and she was taken back to the hospital, where she was treated “as a likely COVID-19 case.” Figi said seizures commonly occur along with illnesses in children like Charlotte with Dravet syndrome.

“Her fighting spirit held out as long as it could and she eventually passed in our arms peacefully,” Paige Figi wrote.

Early Wednesday, the Realm of Caring Foundation, an organization co-founded by Paige Figi, wrote on Facebook that Charlotte’s death was due to complications from COVID-19. But the organization later amended the post to remove the reference to the coronavirus.

If her death is verified by public health officials as related to COVID-19, Charlotte would be the youngest victim of the pandemic in Colorado so far. A spokeswoman for El Paso County Public Health said Wednesday that the department cannot comment about individual cases. But she said the county, at least yet, does not have any confirmed pediatric deaths from COVID-19.

“Your work is done Charlotte, the world is changed, and you can now rest knowing that you leave the world a better place,” the Realm of Caring Foundation wrote on Instagram.

Dravet syndrome is a rare and debilitating form of epilepsy that first appears when children are young. From the time she was just 3 months old, Charlotte suffered hundreds of small and large seizures a day. Pharmaceutical treatments proved ineffective, and, by the age of 5, Charlotte struggled to walk and talk and required a feeding tube.

After hearing about a family in California that treated their child’s seizures with oil made from cannabis, Paige Figi began to research the possibility and soon connected with a Colorado Springs medical marijuana dispensary owner named Joel Stanley, who, along with his brothers, had helped developed a strain of cannabis rich in cannabidiol, or CBD, a non-psychoactive compound.

https://coloradosun.com/2020/04/08/charlotte-figi-cbd-coronavirus/

Courtesy of a colleague

Relapsing-remitting clinical course expands the phenotype of Aicardi-Goutières syndrome

Lambe J, Murphy OC, Mu W, Sondergaard Schatz K, Barañano KW, Venkatesan A. Relapsing-remitting clinical course expands the phenotype of Aicardi-Goutières syndrome. Ann Clin Transl Neurol. 2020;7(2):254–258. doi:10.1002/acn3.50979

Abstract

Aicardi-Goutières syndrome (AGS) is a rare and likely underdiagnosed genetic leukoencephalopathy, typically presenting in infancy with encephalopathy and characteristic neuroimaging features, with residual static neurological deficits. We describe a patient who, following an initial presentation at the age of 12 months in keeping with AGS, exhibited a highly atypical relapsing course of neurological symptoms in adulthood with essentially normal neuroimaging. Whole-exome sequencing confirmed a pathogenic RNASEH2B gene variant consistent with AGS. This case highlights the expanding phenotypes associated with AGS and the potential role of whole-exome sequencing in facilitating an increase in the rate of diagnosis.

Courtesy of a colleague

Gilani A, Adang LA, Vanderver A, Collins A, Kleinschmidt-DeMasters BK. Neuropathological Findings in a Case of IFIH1-Related Aicardi-Goutières Syndrome. Pediatr Dev Pathol. 2019;22(6):566–570. doi:10.1177/1093526619837797

Abstract

Aicardi-Goutières syndrome (AGS) is a rare syndrome characterized by calcification, diffuse demyelination, and variable degree of brain atrophy. The syndrome is genetically heterogeneous with mutations in 7 genes, including TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1 (interferon-induced helicase c domain-containing protein 1) associated with the syndrome, so far. These mutations lead to the overproduction of α-interferon within the central nervous system. Mutations in IFIH1 have been recently described in a subset of AGS, with only 1 previous report of neuropathological findings. We report neuropathological findings in a second case of AGS with a known mutation in IFIH1 gene. The patient is a 16-year-old adolescent boy with early-onset symptoms that progressed to profound loss of cognitive and motor functions. The patient experienced sudden cardiopulmonary arrest at the age of 16 years. At autopsy, the cause of death was determined to be pulmonary thromboembolism. Neuropathological examination revealed microcephaly (brain weight: 916 g) with relatively mild brain atrophy on gross examination. Microscopic examination revealed multifocal calcifications limited to small to medium central nervous system arteries (no evidence of calcification in other organs), involving bilateral cerebral cortex, basal ganglia, thalamus, and cerebellum. Ultrastructural examination showed Calcospherules limited to the vessel walls and the perivasulcar area without evidence of neuronal ferrugination or tubuloreticular bodies. The extent of calcifications was variable across different brain regions, resembling findings in previously reported cases and correlated with the extent of IFIH1 protein expression (data derived from Allen Brain Institute). AGS is a rare cause of brain calcifications that can closely mimic congenital and neonatal infections such as Rubella and similar infections.

Jaxon Strong

Jaxon Buell, the boy who was nicknamed “Jaxon Strong” for his determination to live after he was born with an extreme brain malformation, has died. He was 5.

The child passed away "very peacefully and comfortably" on April 1 in North Carolina, his parents said.

His story and striking photos — showing what his family described as "bright blue eyes, awesome hair and amazing smile" — made worldwide headlines, and TODAY featured the family’s account of what it was like to care for Jaxon in 2015 and 2016.

Jaxon Buell was born with part of his brain missing"Jaxon was truly special, filled with strength, sweetness, and an amazing spirit, and he will be missed," his dad said.Courtesy Buell family

"He passed away in my arms and surrounded by his parents and family who were loving on him and providing comfort and endless hours of snuggles throughout his final days," Brandon Buell, 35, his father, told TODAY in an email.

"Ultimately, Jaxon passed away from his body and organs shutting down, as is common with children like him. This had absolutely nothing to do with the COVID-19 virus, but was something we always knew from the beginning would likely happen. We just didn't know when."

Jaxon recently entered into hospice care at home after showing signs of slowing down in the past year or so, and the family was preparing to say goodbye, his dad added.

"Jaxon's legacy is about his strength and his amazing sweet spirit. He truly made me, his mom, his family, and all who learned of his story better," he said.

Jaxon was "thriving and getting a little better each and every day," his dad told TODAY in 2015.Jaxon was "thriving and getting a little better each and every day," his dad told TODAY in 2015.

Jaxon was born on Aug. 27, 2014, in Orlando, Florida, with microhydranencephaly, a developmental abnormality that affects the brain. It left him with 80 percent of his brain missing, with the cerebellum — the region that controls movement, coordination and balance — most affected. Doctors believed his brain stopped forming a few weeks after he was conceived, Brandon Buell said.

There were no concerns about the pregnancy until the second ultrasound at week 17, when the ultrasound tech became quiet as she got to Jaxon’s head region, his father recalled. A flurry of tests and potential diagnoses followed.

Doctors weren’t sure he’d be born alive, but Jaxon let out a faint cry when has was delivered via C-section at 37 weeks. The baby boy was very undersized and his head was not fully developed, but he was beautiful, his father said.

Jaxon stayed in the neonatal intensive care unit for three and a half weeks. He had a strong heartbeat and was breathing well.

 “Doctors told us, ‘There’s really nothing we can do for him. Take him home and make him comfortable,’” Brandon Buell said in 2015.

“It sounds crazy, but he didn’t need that much extra care.”

The family had to learn to how use a feeding tube, and deal with seizures and periods of extreme fussiness. Still, Jaxon was happy and comfortable — not on life support or struggling, his father said. The child’s vision was fuzzy, but his hearing was good and he liked to smile, he noted.

The family was told Jaxon would not make it to his first birthday, but he passed that milestone and beyond.

As the boy got older, he progressed in small but significant ways when it came to interacting with his toys and in therapy, his dad said. He originally did not have voluntary movements, but after turning 2, the family said it was overjoyed that Jaxon would pucker his lips to give kisses, and reach for his parents or his toys.

Still, his unique challenges meant no one knew what the next day would bring for him, his dad told TODAY in 2016.

“There’s a miracle behind Jaxon’s story. We want to let other families know that even when there’s a dark situation, every life should be celebrated, valued and cherished,” Brandon Buell said.

https://www.today.com/parents/jaxon-buell-jaxon-strong-boy-born-part-brain-missing-dies-t177668

Courtesy of my daughter

See:  http://childnervoussystem.blogspot.com/2017/05/microhydranencephaly.html

Hydroxychloroquine and azithromycin as a treatment of COVID-19 2

Molina JM, Delaugerre C, Goff JL, Mela-Lima B, Ponscarme D, Goldwirt L, de Castro N. No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection. Medecine et Maladies Infectieuses (2020),doi:https://doi.org/10.1016/j.medmal.2020.03.006

The COVID-19 epidemic is the worst worldwide pandemic in a century with more than 500,000

cases and 25,000 deaths so far. In France, more than 30,000 cases have been reported up to

March 27, and nearly 2,000 have died.

Pending the availability of a vaccine, there is a critical need to identify effective treatments

and a number of clinical trials have been implemented worldwide.

Chloroquine analogs have been shown to inhibit the acidification of endosomes and to exhibit

in vitro a non specific antiviral activity at high micromolar concentration against a broad range

of emerging virus (HIV, dengue, hepatitis C, chikungunya, influenza, Ebola, SARS and MERS

viruses) and more recently COVID-19 (1-2).

In France, following the results of a clinical study in Marseille, there is considerable interest

for the use of hydroxychloroquine to treat COVID-19 disease, and the French Ministry of

Health recently allowed the use of hydroxychloroquine to treat COVID-19 disease pending the

results of ongoing clinical trials (3).

In their study, Gautret et al. reported a 100% viral clearance in nasopharyngeal swabs in 6

patients after 5 and 6 days of the combination of hydroxychloroquine and azithromycin (3).

This rate of viral clearance was lower with hydroxychloroquine alone (57.1%) and was only

12.5% in patients who did not receive hydroxychloroquine (p< 0.001).

Such a rapid and full viral clearance was quite unexpected and we wished to assess in a

prospective study virologic and clinical outcomes of 11 consecutive patients hospitalized in

our department who received hydroxychloroquine (600 mg/d for 10 days) and azithromycin

(500 mg Day 1 and 250 mg days 2 to 5) using the same dosing regimen reported by Gautret et

al. (3).

There were 7 men and 4 women with a mean age of 58.7 years (range: 20-77), 8 had significant

comorbidities associated with poor outcomes (obesity: 2; solid cancer: 3; hematological

cancer: 2; HIV-infection: 1).

At the time of treatment initiation, 10/11 had fever and received nasal oxygen therapy. Within

5 days, one patient died, two were transferred to the ICU. In one patient, hydroxychloroquine

and azithromycin were discontinued after 4 days because of a prolongation of the QT interval

from 405 ms before treatment to 460 and 470 ms under the combination. Mean through

blood concentration of hydroxychloroquine was 678 ng/mL (range: 381-891) at days 3-7 after

treatment initiation.

Repeated nasopharyngeal swabs in 10 patients (not done in the patient who died) using a

qualitative PCR assay (nucleic acid extraction using Nuclisens Easy Mag®, Biomerieux and

amplification with RealStar SARS CoV-2®, Altona), were still positive for SARS-CoV2 RNA in

8/10 patients (80%, 95% confidence interval: 49-94) at days 5 to 6 after treatment initiation.

These virologic results stand in contrast with those reported by Gautret et al. and cast doubts

about the strong antiviral efficacy of this combination. Furthermore, in their report Gautret et

al also reported one death and three transfers to the ICU among the 26 patients who received

hydroxychloroquine, also underlining the poor clinical outcome with this combination.

In addition, a recent study from China in individuals with COVID-19 found no difference in the

rate of virologic clearance at 7 days with or without 5 days of hydroxychloroquine, and no

difference in clinical outcomes (duration of hospitalization, temperature normalization,

radiological progression) (4). These results are consistent with the lack of virologic or clinical

benefit of chloroquine in a number of viral infections where it was assessed for treatment or

prophylaxis with sometimes a deleterious effect on viral replication (5-8).

In summary, despite a reported antiviral activity of chloroquine against COVID-19 in vitro, we

found no evidence of a strong antiviral activity or clinical benefit of the combination of

hydroxychloroquine and azithromycin for the treatment of our hospitalized patients with

severe COVID-19. Ongoing randomized clinical trials with hydroxychloroquine should provide

a definitive answer regarding the alleged efficacy of this combination and will assess its safety.

1. Wang  M,  Cao  R,  Zhang  L,  et  al. Remdesivir  and  chloroquine  effectively  inhibit  the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell research 2020; 30:269-71.  2. Al-Bari  AA.  Targeting  endosomal  acidification  by  chloroquine  analogs  as  a  promising strategy  for  the  treatment  of  emerging  viral  diseases.  Pharmacology  research  and perspectives. 2017;5:e00293 3. Gautret  P,  Lagier  JC,  Parola  P,  et  al. Hydroxychloroquine  and  azithromycin  as  a treatment   of   COVID-19:   results   of   an   open-label   non-randomized   clinical   trial. International Journal of Antimicrobial Agents 2020 (ahead of print).   4. Chen J, Liu D, Lui L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 COVID-19). Journal of Zhejiang University 2020; 03-03  5. Roques P, Thiberville SD, Dupuis-Maguiraga L et al. Paradoxical effect of chloroquine treatment in enhancing Chikungunya virus infection. Viruses, 2018:10:268 6. Tricou V, Minh NN, Van TP et al. A randomized controlled trial of chloroquine for the treatment  of  dengue  in  Vietnamese  adults.  PLos  Neglected  tropical  diseases  2010; 4:e785.  7. Paton  NI,  Lee  L,  Xu  Y,  et  al. Chloroquine  for  influenza  prevention:  a  randomised, double-blind, placebo-controlled trial. Lancet Infectious Diseases, 2011; 11:677-83  8. Paton  NI,  Goodall  RL,  Dunn  DT,  et  al. Effects  of  hydroxychloroquine  on  immune activation   and   disease   progression   among HIV-infected   patients   not   receiving antiretroviral therapy: a randomized controlled trial. JAMA. 2012;308 (4):353-61.