If I have a heart attack tomorrow, why should I stay dead?

Can we come back from the dead? It depends, says a leading expert. Dr. Sam Parnia’s blockbuster book Lucid Dying chronicles decades of research that has led him and other experts to believe that our current methods of reviving those considered clinically dead are antiquated.

“Although for decades scientists believed the brain dies within 10 minutes of oxygen deprivation, recent scientific advances have proven this incorrect,” Parnia tells Newsmax. “Instead, after death, the oxygen-deprived brain and body go through a hibernation-like state for many hours longer. This means that for people who are otherwise healthy, such as those who are victims of accidents, shootings, or sudden cardiac arrests, death should be understood as a medically treatable event ─ like a stroke — for many hours after it has taken place.”

Parnia, associate professor of medicine at New York University’s Langone Medical Center, has been studying end-of-life phenomena for over 30 years and reveals his eye-opening research in his new book.

He questions when life ends, and when death begins, adding that while we’ve made major breakthroughs in the fields of treatment for cancer, cardiovascular disease and other ailments, our progress in treating death has been stagnant.

“What we believe about death is fundamentally wrong,” says Parina. It is not the end, he says, but a “reversible state.”

According to Yahoo.com, Parnia says that seeing a flatline on an electrocardiogram (EKG) ─ a measure of the electrical impulses of the heart ─ is not necessarily a death sentence. Recent evidence backs this up.

Researchers at Yale University successfully revived decapitated pig brains up to 14 hours post-mortem in 2019. In 2022, Yale scientists showed how a modified heart and lung machine combined with drugs restored organs in pigs. “It is just a matter of time,” suggests Parnia, that these results can be translated to humans.

There are also stories about how people have been revived after their hearts stopped for hours because they were in freezing temperatures that somehow preserved the organ. Thanks to a machine called an ECMO (extracorporeal membrane oxygenation), which serves as an artificial heart and lung, these patients survived. Parnia says that cooling the body is highly protective.

In a study published last year, researchers found that in patients who survived cardiac arrest, nearly 40% had brain activity that returned to normal, or nearly normal, even an hour into CPR. An electroencephalogram (EEG) captured the brain activity with electrodes, according to NYU Langone Health. These patients later had clear memories of experiencing death and while unconscious, had brain patterns linked to thought and memory.

“This is the first large study to show that these recollections and brain wave changes may be signs of universal, shared elements of so-called near-death experiences,” said Parnia, who was senior author of that study.

The expert says that we need to revise our thinking and methods of reviving patients. CPR, introduced in 1959, has a paltry 10% success rate and many hospitals now have ECMO machines that are far superior. He acknowledges that not every patient can be brought back from the dead. People with multiple organ failure are unlikely candidates. But others, like himself at age 52, do not have to stay dead.

“I tell everyone, look, I’m going to have a cardiac arrest soon. And I am appalled at the treatment I’m going to get. If I have a heart attack tomorrow, why should I stay dead? That’s not necessary anymore. I have little doubt that, in the future, people who would be declared dead today will routinely be brought back to life.”

https://www.newsmax.com/health/health-news/death-reversible-revive/2024/08/28/id/1178199/

Parnia S. Death and consciousness--an overview of the mental and cognitive experience of death. Ann N Y Acad Sci. 2014 Nov;1330:75-93. doi: 10.1111/nyas.12582. PMID: 25418460.

Abstract

Advances in resuscitation science have indicated that, contrary to perception, death by cardiorespiratory criteria can no longer be considered a specific moment but rather a potentially reversible process that occurs after any severe illness or accident causes the heart, lungs, and brain to stop functioning. The resultant loss of vital signs of life (and life processes) is used to declare a specific time of death by physicians globally. When medical attempts are made to reverse this process, it is commonly referred to as cardiac arrest; however, when these attempts do not succeed or when attempts are not made, it is called death by cardiorespiratory criteria. Thus, biologically speaking, cardiac arrest and death by cardiorespiratory criteria are synonymous. While resuscitation science has provided novel opportunities to reverse death by cardiorespiratory criteria and treat the potentially devastating consequences of the resultant postresuscitation syndrome, it has also inadvertently provided intriguing insights into the likely mental and cognitive experience of death. Recollections reported by millions of people in relation to death, so-called out-of-body experiences (OBEs) or near-death experiences (NDEs), are often-discussed phenomena that are frequently considered hallucinatory or illusory in nature; however, objective studies on these experiences are limited. To date, many consistent themes corresponding to the likely experience of death have emerged, and studies have indicated that the scientifically imprecise terms of NDE and OBE may not be sufficient to describe the actual experience of death. While much remains to be discovered, the recalled experience surrounding death merits a genuine scientific investigation without prejudice.

Parnia S, Keshavarz Shirazi T, Patel J, Tran L, Sinha N, O'Neill C, Roellke E, Mengotto A, Findlay S, McBrine M, Spiegel R, Tarpey T, Huppert E, Jaffe I, Gonzales AM, Xu J, Koopman E, Perkins GD, Vuylsteke A, Bloom BM, Jarman H, Nam Tong H, Chan L, Lyaker M, Thomas M, Velchev V, Cairns CB, Sharma R, Kulstad E, Scherer E, O'Keeffe T, Foroozesh M, Abe O, Ogedegbe C, Girgis A, Pradhan D, Deakin CD. AWAreness during REsuscitation - II: A multi-center study of consciousness and awareness in cardiac arrest. Resuscitation. 2023 Oct;191:109903. doi: 10.1016/j.resuscitation.2023.109903. Epub 2023 Jul 7. PMID: 37423492.

Abstract

Introduction: Cognitive activity and awareness during cardiac arrest (CA) are reported but ill understood. This first of a kind study examined consciousness and its underlying electrocortical biomarkers during cardiopulmonary resuscitation (CPR).

Methods: In a prospective 25-site in-hospital study, we incorporated a) independent audiovisual testing of awareness, including explicit and implicit learning using a computer and headphones, with b) continuous real-time electroencephalography(EEG) and cerebral oxygenation(rSO2) monitoring into CPR during in-hospital CA (IHCA). Survivors underwent interviews to examine for recall of awareness and cognitive experiences. A complementary cross-sectional community CA study provided added insights regarding survivors' experiences.

Results: Of 567 IHCA, 53(9.3%) survived, 28 of these (52.8%) completed interviews, and 11(39.3%) reported CA memories/perceptions suggestive of consciousness. Four categories of experiences emerged: 1) emergence from coma during CPR (CPR-induced consciousness [CPRIC]) 2/28(7.1%), or 2) in the post-resuscitation period 2/28(7.1%), 3) dream-like experiences 3/28(10.7%), 4) transcendent recalled experience of death (RED) 6/28(21.4%). In the cross-sectional arm, 126 community CA survivors' experiences reinforced these categories and identified another: delusions (misattribution of medical events). Low survival limited the ability to examine for implicit learning. Nobody identified the visual image, 1/28(3.5%) identified the auditory stimulus. Despite marked cerebral ischemia (Mean rSO2 = 43%) normal EEG activity (delta, theta and alpha) consistent with consciousness emerged as long as 35-60 minutes into CPR.

Conclusions: Consciousness. awareness and cognitive processes may occur during CA. The emergence of normal EEG may reflect a resumption of a network-level of cognitive activity, and a biomarker of consciousness, lucidity and RED (authentic "near-death" experiences).

West RL, Otto Q, Drennan IR, Rudd S, Böttiger BW, Parnia S, Soar J. CPR-related cognitive activity, consciousness, awareness and recall, and its management: A scoping review. Resusc Plus. 2022 May 9;10:100241. doi: 10.1016/j.resplu.2022.100241. PMID: 35586308; PMCID: PMC9108988.

Abstract

Background: There are increasing numbers of reports of cognitive activity, consciousness, awareness and recall related to cardiopulmonary resuscitation (CPR) and interventions such as the use of sedative and analgesic drugs during CPR.

Objectives: This scoping review aims to describe the available evidence concerning CPR-related cognitive activity, consciousness, awareness and recall and interventions such as the use of sedative and analgesic drugs during CPR.

Methods: A literature search was conducted of Medline, Embase and CINAHL from inception to 21 October 2021. We included case studies, observational studies, review studies and grey literature.

Results: We identified 8 observational studies including 40,317 patients and 464 rescuers, and 26 case reports including 33 patients. The reported prevalence of CPR-induced consciousness was between 0.23% to 0.9% of resuscitation attempts, with 48-59% of experienced professional rescuers surveyed estimated to have observed CPR-induced consciousness. CPR-induced consciousness is associated with professional rescuer CPR, witnessed arrest, a shockable rhythm, increased return of spontaneous circulation (ROSC), and survival to hospital discharge when compared to patients without CPR-induced consciousness. Few studies of sedation for CPR-induced consciousness were identified. Although local protocols for treating CPR-induced consciousness exist, there is no widely accepted guidance.

Conclusions: CPR-related cognitive activity, consciousness, awareness and recall is uncommon but increasingly reported by professional rescuers. The data available was heterogeneous in nature and not suitable for progression to a systematic review process. Although local treatment protocols exist for management of CPR-induced consciousness, there are no widely accepted treatment guidelines. More studies are required to investigate the management of CPR-induced consciousness.

Keywords: ALS, Advanced life support; Awareness; CPR, Cardiorespiratory resuscitation; Cardiac arrest; Cardiopulmonary resuscitation; Consciousness; ED, Emergency Department; EMS, Emergency medical service; GCS, Glasgow coma scale; ICU, Intensive care unit; IHCA, In-hospital cardiac arrest; ILCOR, International Liaison Committee on Resuscitation; Near death experience; OHCA, Out-of-hospital cardiac arrest; OR, Odds Ratio; PTSD, Post-traumatic stress disorder; Post-traumatic stress disorder; ROSC, Return of spontaneous circulation; VF, Ventricular fibrillation; VT, Ventricular tachycardia; pVT, pulseless ventricular tachycardia.

Parnia S, Post SG, Lee MT, Lyubomirsky S, Aufderheide TP, Deakin CD, Greyson B, Long J, Gonzales AM, Huppert EL, Dickinson A, Mayer S, Locicero B, Levin J, Bossis A, Worthington E, Fenwick P, Shirazi TK. Guidelines and standards for the study of death and recalled experiences of death--a multidisciplinary consensus statement and proposed future directions. Ann N Y Acad Sci. 2022 May;1511(1):5-21. doi: 10.1111/nyas.14740. Epub 2022 Feb 18. PMID: 35181885.

Abstract

An inadvertent consequence of advances in stem cell research, neuroscience, and resuscitation science has been to enable scientific insights regarding what happens to the human brain in relation to death. The scientific exploration of death is in large part possible due to the recognition that brain cells are more resilient to the effects of anoxia than assumed. Hence, brain cells become irreversibly damaged and "die" over hours to days postmortem. Resuscitation science has enabled life to be restored to millions of people after their hearts had stopped. These survivors have described a unique set of recollections in relation to death that appear universal. We review the literature, with a focus on death, the recalled experiences in relation to cardiac arrest, post-intensive care syndrome, and related phenomena that provide insights into potential mechanisms, ethical implications, and methodologic considerations for systematic investigation. We also identify issues and controversies related to the study of consciousness and the recalled experience of cardiac arrest and death in subjects who have been in a coma, with a view to standardize and facilitate future research.

Keywords: cardiac arrest; cardiopulmonary resuscitation-induced consciousness (CPRIC); death; death by brain death criteria; external visual awareness (EVA); near-death experiences (NDEs); out-of-body experiences (OBEs); post-intensive care syndrome (PICS); recalled experience of death (RED) coma; resuscitation.

SPTAN1 monoallelic variant associated disorders

Inspired by a patient

Morsy H, Benkirane M, Cali E, Rocca C, Zhelcheska K, Cipriani V, Galanaki E, Maroofian R, Efthymiou S, Murphy D, O'Driscoll M, Suri M, Banka S, Clayton-Smith J, Wright T, Redman M, Bassetti JA, Nizon M, Cogne B, Jamra RA, Bartolomaeus T, Heruth M, Krey I, Gburek-Augustat J, Wieczorek D, Gattermann F, Mcentagart M, Goldenberg A, Guyant-Marechal L, Garcia-Moreno H, Giunti P, Chabrol B, Bacrot S, Buissonnière R, Magry V, Gowda VK, Srinivasan VM, Melegh B, Szabó A, Sümegi K, Cossée M, Ziff M, Butterfield R, Hunt D, Bird-Lieberman G, Hanna M, Koenig M, Stankewich M, Vandrovcova J, Houlden H; Genomics England Research Consortium. Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia. Genet Med. 2023 Jan;25(1):76-89. doi: 10.1016/j.gim.2022.09.013. Epub 2022 Nov 4. PMID: 36331550; PMCID: PMC10620943.

Abstract

Purpose: Nonerythrocytic αII-spectrin (SPTAN1) variants have been previously associated with intellectual disability and epilepsy. We conducted this study to delineate the phenotypic spectrum of SPTAN1 variants.

Methods: We carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Functional studies were performed on fibroblasts from 2 patients.

Results: Statistically significant enrichment of rare (minor allele frequency < 1 × 10-5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 × 10-5). We identified 31 individuals carrying SPTAN1 heterozygous variants or deletions. A total of 10 patients presented with pure or complex HSP/HA. The remaining 21 patients had developmental delay and seizures. Irregular αII-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants.

Conclusion: We found that SPTAN1 is a genetic cause of neurodevelopmental disorder, which we classified into 3 distinct subgroups. The first comprises developmental epileptic encephalopathy. The second group exhibits milder phenotypes of developmental delay with or without seizures. The final group accounts for patients with pure or complex HSP/HA.

Syrbe S, Harms FL, Parrini E, Montomoli M, Mütze U, Helbig KL, Polster T, Albrecht B, Bernbeck U, van Binsbergen E, Biskup S, Burglen L, Denecke J, Heron B, Heyne HO, Hoffmann GF, Hornemann F, Matsushige T, Matsuura R, Kato M, Korenke GC, Kuechler A, Lämmer C, Merkenschlager A, Mignot C, Ruf S, Nakashima M, Saitsu H, Stamberger H, Pisano T, Tohyama J, Weckhuysen S, Werckx W, Wickert J, Mari F, Verbeek NE, Møller RS, Koeleman B, Matsumoto N, Dobyns WB, Battaglia D, Lemke JR, Kutsche K, Guerrini R. Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy. Brain. 2017 Sep 1;140(9):2322-2336. doi: 10.1093/brain/awx195. PMID: 29050398; PMCID: PMC6248409.

Abstract

De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte αII spectrin, have been associated with severe West syndrome with hypomyelination and pontocerebellar atrophy. We aimed at comprehensively delineating the phenotypic spectrum associated with SPTAN1 mutations. Using different molecular genetic techniques, we identified 20 patients with a pathogenic or likely pathogenic SPTAN1 variant and reviewed their clinical, genetic and imaging data. SPTAN1 de novo alterations included seven unique missense variants and nine in-frame deletions/duplications of which 12 were novel. The recurrent three-amino acid duplication p.(Asp2303_Leu2305dup) occurred in five patients. Our patient cohort exhibited a broad spectrum of neurodevelopmental phenotypes, comprising six patients with mild to moderate intellectual disability, with or without epilepsy and behavioural disorders, and 14 patients with infantile epileptic encephalopathy, of which 13 had severe neurodevelopmental impairment and four died in early childhood. Imaging studies suggested that the severity of neurological impairment and epilepsy correlates with that of structural abnormalities as well as the mutation type and location. Out of seven patients harbouring mutations outside the α/β spectrin heterodimerization domain, four had normal brain imaging and three exhibited moderately progressive brain and/or cerebellar atrophy. Twelve of 13 patients with mutations located within the spectrin heterodimer contact site exhibited severe and progressive brain, brainstem and cerebellar atrophy, with hypomyelination in most. We used fibroblasts from five patients to study spectrin aggregate formation by Triton-X extraction and immunocytochemistry followed by fluorescence microscopy. αII/βII aggregates and αII spectrin in the insoluble protein fraction were observed in fibroblasts derived from patients with the mutations p.(Glu2207del), p.(Asp2303_Leu2305dup) and p.(Arg2308_Met2309dup), all falling in the nucleation site of the α/β spectrin heterodimer region. Molecular modelling of the seven SPTAN1 amino acid changes provided preliminary evidence for structural alterations of the A-, B- and/or C-helices within each of the mutated spectrin repeats. We conclude that SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the α/β heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the α20 repeat is important for α/β spectrin heterodimer formation and/or αII spectrin function.

Van de Vondel L, De Winter J, Beijer D, Coarelli G, Wayand M, Palvadeau R, Pauly MG, Klein K, Rautenberg M, Guillot-Noël L, Deconinck T, Vural A, Ertan S, Dogu O, Uysal H, Brankovic V, Herzog R, Brice A, Durr A, Klebe S, Stock F, Bischoff AT, Rattay TW, Sobrido MJ, De Michele G, De Jonghe P, Klopstock T, Lohmann K, Zanni G, Santorelli FM, Timmerman V, Haack TB, Züchner S; PREPARE Consortium; Schüle R, Stevanin G, Synofzik M, Basak AN, Baets J. De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia. Mov Disord. 2022 Jun;37(6):1175-1186. doi: 10.1002/mds.28959. Epub 2022 Feb 12. PMID: 35150594; PMCID: PMC9232883.

Abstract

Background: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy.

Objectives: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia.

Methods: We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants.

Results: We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat.

Conclusions: We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism.

Van de Vondel L, De Winter J, Beijer D, Coarelli G, Wayand M, Palvadeau R, Pauly MG, Klein K, Rautenberg M, Guillot-Noël L, Deconinck T, Vural A, Ertan S, Dogu O, Uysal H, Brankovic V, Herzog R, Brice A, Durr A, Klebe S, Stock F, Bischoff AT, Rattay TW, Sobrido MJ, De Michele G, De Jonghe P, Klopstock T, Lohmann K, Zanni G, Santorelli FM, Timmerman V, Haack TB, Züchner S; PREPARE Consortium; Schüle R, Stevanin G, Synofzik M, Basak AN, Baets J. De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia. Mov Disord. 2022 Jun;37(6):1175-1186. doi: 10.1002/mds.28959. Epub 2022 Feb 12. PMID: 35150594; PMCID: PMC9232883.

Abstract

Background: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy.

Objectives: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia.

Methods: We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants.

Results: We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat.

Conclusions: We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society.

BCAP31 mutations

Inspired by a patient

Whalen S, Shaw M, Mignot C, Héron D, Bastaraud SC, Walti CC, Liebelt J, Elmslie F, Yap P, Hurst J, Forsythe E, Kirmse B, Ozmore J, Spinelli AM, Calabrese O, de Villemeur TB, Tabet AC, Levy J, Guet A, Kossorotoff M, Kamien B, Morton J, McCabe A, Brischoux-Boucher E, Raas-Rothschild A, Pini A, Carroll R, Hartley JN; Care4Rare Canada Consortium; Frosk P, Slavotinek A, Truxal K, Jennifer C, Dheedene A, Cui H, Kumar V, Thomson G, Riccardi F, Gecz J, Villard L. Further delineation of BCAP31-linked intellectual disability: description of 17 new families with LoF and missense variants. Eur J Hum Genet. 2021 Sep;29(9):1405-1417. doi: 10.1038/s41431-021-00821-0. Epub 2021 Feb 18. PMID: 33603160; PMCID: PMC8440520.

Abstract

The BCAP31 gene, located at Xq28, encodes BAP31, which plays a role in ER-to-Golgi anterograde transport. To date, BCAP31 pathogenic variants have been reported in 12 male cases from seven families (six loss of function (LoF) and one missense). Patients had severe intellectual disability (ID), dystonia, deafness, and central hypomyelination, delineating a so-called deafness, dystonia and cerebral hypomyelination syndrome (DDCH). Female carriers are mostly asymptomatic but may present with deafness. BCAP31 is flanked by the SLC6A8 and ABCD1 genes. Contiguous deletions of BCAP31 and ABCD1 and/or SLC6A8 have been described in 12 patients. Patients with deletions including BCAP31 and SLC6A8 have the same phenotype as BCAP31 patients. Patients with deletions of BCAP31 and ABCD1 have contiguous ABCD1 and DXS1375E/BCAP31 deletion syndrome (CADDS), and demonstrate a more severe neurological phenotype with cholestatic liver disease and early death. We report 17 novel families, 14 with intragenic BCAP31 variants (LoF and missense) and three with a deletion of BCAP31 and adjacent genes (comprising two CADDS patients, one male and one symptomatic female). Our study confirms the phenotype reported in males with intragenic LoF variants and shows that males with missense variants exhibit a milder phenotype. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation. We further demonstrate that carrier females (n = 10) may have a phenotype comprising LD, ID, and/or deafness. The male with CADDS had a severe neurological phenotype, but no cholestatic liver disease, and the symptomatic female had moderate ID and cholestatic liver disease.

Cacciagli P, Sutera-Sardo J, Borges-Correia A, Roux JC, Dorboz I, Desvignes JP, Badens C, Delepine M, Lathrop M, Cau P, Lévy N, Girard N, Sarda P, Boespflug-Tanguy O, Villard L. Mutations in BCAP31 cause a severe X-linked phenotype with deafness, dystonia, and central hypomyelination and disorganize the Golgi apparatus. Am J Hum Genet. 2013 Sep 5;93(3):579-86. doi: 10.1016/j.ajhg.2013.07.023. PMID: 24011989; PMCID: PMC3769969.

Abstract

BAP31 is one of the most abundant endoplasmic reticulum (ER) membrane proteins. It is a chaperone protein involved in several pathways, including ER-associated degradation, export of ER proteins to the Golgi apparatus, and programmed cell death. BAP31 is encoded by BCAP31, located in human Xq28 and highly expressed in neurons. We identified loss-of-function mutations in BCAP31 in seven individuals from three families. These persons suffered from motor and intellectual disabilities, dystonia, sensorineural deafness, and white-matter changes, which together define an X-linked syndrome. In the primary fibroblasts of affected individuals, we found that BCAP31 deficiency altered ER morphology and caused a disorganization of the Golgi apparatus in a significant proportion of cells. Contrary to what has been described with transient-RNA-interference experiments, we demonstrate that constitutive BCAP31 deficiency does not activate the unfolded protein response or cell-death effectors. Rather, our data demonstrate that the lack of BAP31 disturbs ER metabolism and impacts the Golgi apparatus, highlighting an important role for BAP31 in ER-to-Golgi crosstalk. These findings provide a molecular basis for a Mendelian syndrome and link intracellular protein trafficking to severe congenital brain dysfunction and deafness.

Louie RJ, Collins DL, Friez MJ, Skinner C, Schwartz CE, Stevenson RE. Schimke XLID syndrome results from a deletion in BCAP31. Am J Med Genet A. 2020 Sep;182(9):2168-2174. doi: 10.1002/ajmg.a.61755. Epub 2020 Jul 18. PMID: 32681719.

Abstract

A family with three affected males and a second family with a single affected male with intellectual disability, microcephaly, ophthalmoplegia, deafness, and Involuntary limb movements were reported by Schimke and Associates in 1984. The affected males with Schimke X-linked intellectual disability (XLID) syndrome (OMIM# 312840) had a similar facial appearance with deep-set eyes, downslanting palpebral fissures, hypotelorism, narrow nose and alae nasi, cupped ears and spacing of the teeth. Two mothers had mild hearing loss but no other manifestations of the disorder. The authors considered the disorder to be distinctive and likely X-linked. Whole genome sequencing in the single affected male available and the three carrier females from one of the families with Schimke XLID syndrome identified a 2 bp deletion in the BCAP31 gene. During the past decade, pathogenic alterations of the BCAP31 gene have been associated with deafness, dystonia, and central hypomyelination, an XLID condition given the eponym DDCH syndrome. A comparison of clinical findings in Schimke XLID syndrome and DDCH syndrome shows them to be the same clinical entity. The BCAP31 protein functions in endoplasmic reticulum-associated degradation to promote ubiquitination and destruction of misfolded proteins.

Rinaldi B, Van Hoof E, Corveleyn A, Van Cauter A, de Ravel T. BCAP31-related syndrome: The first de novo report. Eur J Med Genet. 2020 Feb;63(2):103732. doi: 10.1016/j.ejmg.2019.103732. Epub 2019 Jul 19. PMID: 31330203.

Abstract

Pathogenic variants in the BCAP31 gene have recently been associated with a severe congenital neurological phenotype, named DDCH after its key features: deafness, dystonia and central hypomyelination. BCAP31 is located at the Xq28 chromosomal region and only male individuals are currently known to be affected, the pathogenic variant being usually transmitted by healthy mothers. Here, we describe a three-year-old male child referred for severe developmental delay, failure to thrive, hearing loss and dyskinetic movements. After a conventional diagnostic workflow, including a normal array-CGH, a tentative diagnosis of dyskinetic cerebral palsy was retained. Clinical exome sequencing in the trio identified a small intragenic deletion in exon 8 of BCAP31, c.709_721del (p.Val237Trpfs*69), originated de novo and not previously reported. Based on the ACMG variant classification, this variant is predicted to be 'likely pathogenic'. Given the consistent phenotypical overlap with the subjects already ascertained with DDCH, we considered this variant to be clinically relevant for this child and causative of his condition.

Frontal horn cysts in normal neonates

Inspired by a patient

Nakamura N, Miyazaki C, Hasegawa Y, Onodera M, Sugiura M, Kubo K, Nakajima T, Hattori S, Terae S. [Neonatal cystic structure adjacent to frontal horn--MRI features]. Nihon Igaku Hoshasen Gakkai Zasshi. 2005 Oct;65(4):368-72. Japanese. PMID: 16334388.

Abstract

Purpose: To evaluate the incidence and features of cystic structures adjacent to the frontal horns of neonates using MRI, and to assess the clinical features of the neonates.

Materials and methods: Between April 2001 and January 2005, MRI examinations were performed at our hospital in 352 neonates and infants whose postconceptional age was less than 48 weeks. We retrospectively evaluated the MRI findings and the clinical records.

Results: Seventeen babies (8 males and 9 females) showed cystic structures adjacent to frontal horns, hemilaterally or bilaterally. The incidence of the cysts was 4.8% in total, and was 1.4% (1/74), 9.2% (6/65), and 4.7% (10/213)in term infants, preterm infants born at 33-36 weeks of gestational age, and at less than 32 weeks, respectively. The cysts ranged from 1 to 8 mm in diameter, and were located in the white matter adjacent to ventricular walls and in the portion cephalad to the frontal horns. The cysts resolved in 5 cases (with follow-up ranging from 3 months to 2 years of age), causing slight dilatation of the frontal horn. Developmental disturbances were not observed in patients without other abnormalities.

Conclusion: Cystic structures near the frontal horns in neonates are detected by MRI at a rate of 4.8%. They will resolve spontaneously without causing developmental abnormalities.

Chang CL, Chiu NC, Ho CS, Li ST. Frontal horn cysts in normal neonates. Brain Dev. 2006 Aug;28(7):426-30. doi: 10.1016/j.braindev.2006.01.002. Epub 2006 Feb 28. PMID: 16503391; PMCID: PMC7125929.

Abstract

Frontal horn cysts (FHCs) are elliptical, smooth, thin-walled cysts adjacent to the tip of the anterior horns of the lateral ventricles. Among 3,545 terms or near term healthy babies who underwent cranial ultrasound examination in our hospital over a 2-year 5-month period, 18 were found to have FHCs (17 typical and one atypical; seven bilateral and 11 unilateral, of which seven were on the left and four on the right). The female to male ratio was 2:1. The incidence of FHCs in normal term babies was thus 0.5%. Six children had resolution of the cyst within 1 month, and 6 more had resolution on repeat scan from 2 to 11 months of age. Four children did not have subsequent ultrasonography to document resolution, but they had normal growth and development. Two were lost to follow up. The infant with an atypical FHC had an enlarged left frontal horn cyst with a midline shift on follow up, but he had normal development. Our study suggests that FHC may be a normal physiologic variant or a benign pathologic condition that can be expected to resolve spontaneously within a few months. It is reasonable to follow typical FHC by cranial ultrasound examinations at 1 or 2 and 6 months of age. In the case of an atypical cyst, more frequent follow up and further image studies like CT or MRI are necessary.

Dr. Ann Tilton

I also received my MD from the University of Texas Medical Branch in Galveston.

Ann Tilton, MD, FAAN, received the AAN President's Award at this year's AAN Annual Meeting in April. Here, she discusses the events and people who shaped her career—and what mentorship means to her.

As a child growing up in Texas, Ann Tilton, MD, FAAN, recalls precisely the moment when her friend asked her what she wanted to be when she grew up. She responded without hesitation from the top of a tree they had climbed: I want to be a doctor.

Dr. Tilton has more than achieved her childhood aspirations in her more than 40 years of work as a successful child neurologist conducting groundbreaking research and running a rehabilitation unit. She received the AAN President's Award this past April at the AAN Annual Meeting in Denver for her exemplary career and volunteer work on behalf of the field of neurology.

A former president of the Child Neurology Foundation and the Child Neurology Society and former vice president of the AAN Board of Directors, Dr. Tilton said she was “floored” when AAN President Carlayne E. Jackson, MD, FAAN, called her over the winter to inform her of the award.

“I walked up and told my husband, ‘This isn't real,’” said Dr. Tilton, a professor of neurology and pediatrics and chief of the child neurology section at Louisiana State University Health Sciences Center and member of the Neurology Today editorial board, adding, “It was just the most wonderful experience.”

One could say the same of her career. After graduating early from her undergraduate program at Texas A&M University—Kingsville with a degree in biology/chemistry and before starting medical school, Dr. Tilton spent time doing environmental impact studies as well as benchtop research, something she continued during residency. This gave her some more insight into what she might want to do—and not do—with her career.

“It became apparent even early on [while] I was talking to my rabbits and mung beans that I needed to talk to people,” she said with a laugh.

Dr. Tilton stayed in the Lonestar State for medical school, graduating from the University of Texas Medical Branch in Galveston, and then headed to the University of Texas Southwestern in Dallas for her residency.

Neurology wasn't Dr. Tilton's initial choice, though. “I flipped a coin—medicine or pediatrics—and went for best two out of three, and pediatrics won,” she said.

She enjoyed pediatrics, but a visit to a neurology clinic at a Dallas hospital grabbed her more and changed the course of her career.

“Behind every door was a diagnosis I'd never seen,” Dr. Tilton recalled. “I said, ‘I'm home. This is what I need to do.’ ... And I loved neuroscience. The unknown, the diagnostic—all of those things were fun.”

She combined her newfound fascination of the brain with her interest in treating children to become a child neurologist. After finishing residency, Dr. Tilton stayed on at the school for a couple years as a faculty member, an experience she described as “the ultimate super fellowship.”

“When you start out, you're the low person on the totem pole, and whatever they needed, I did,” she said. “I did all kind of things, [and] it was absolutely remarkable. ... I did neuromuscular clinics, set up the EEG lab, all of these things.”

Eventually, Dr. Tilton moved to Louisiana, where her husband, a cardiologist, grew up. They settled in New Orleans and raised two daughters and two sons as Dr. Tilton embraced her work at Louisiana State University.

Finding Mentors

“Mentors can come from many places, some unexpected,” she said, which for her included an orthopedist, who she said was “always looking to the future of care” and encouraged her to explore the use of botulinum toxins to treat patients.

“This was very early in its use, and there were few injectors, no guidebooks, and the beginning of clinical studies,” Dr. Tilton said. “I saw it as a challenge with great potential, so I accepted the challenge and decided to develop the program. That discussion and interest went on to define my research and clinical practice.”

As a mentor herself today, Dr. Tilton believes it is important for leaders to recommend junior members for positions. But they also must do their job well and enjoy it, she added.

Asked to run the Rehabilitation Center at Children's Hospital of New Orleans, Dr. Tilton said her career began to evolve as she ended up caring for lots of children with cerebral palsy. That condition and disabilities became her focus, and she's watched treatments bound forward, from botulinum toxin injections to intrathecal baclofen pumps and other interventions.

“It was just a wonderful ride,” she said. “The families, they have joy in things that people from the outside have no idea.”

Dr. Tilton also found time to give back to her field, serving as a member and vice chair of the ACGME Neurology Residency Review Committee and past chair of the American Board of Psychiatry and Neurology. She also held numerous roles with the AAN, including secretary/treasurer of the AAN Institute, vice president of the AAN Board of Directors, chair of the Meeting Management Committee, and mentor in AAN leadership programs, earning the academy's Leading in Excellence Through Mentorship award in 2022.

She has seen more women enter medicine since she graduated from medical school, and she tries hard to mentor them. This can be as simple as taking a walk with them and being available to listen and chat, encouraging them to “be authentic and truthful to yourself,” she said, adding that she makes sure to include, promote, encourage, and advocate for other women.

“It's incredibly important that women support women and people recognize the difficulties of being the primary caregiver and nurturer and nurturing in different places,” Dr. Tilton said.

Finding Challenges and Opportunities

Working with wonderful colleagues has been a highlight of her career, she said, but the job also has had its challenges, like knowing she can't change the course of disease for some patients and the extreme costs of the new treatments for neuromuscular diseases.

Dr. Tilton also continues to conduct clinical research—she has some work in movement disorders ready to begin—in addition to seeing patients and running the rehabilitation unit.

One patient whose story has stuck with her had an unusual disorder, dopa-responsive dystonia, which left him non-verbal and using a wheelchair but cognitively normal. Thanks to an available medicine, however, he soon was walking and talking and eventually went to college.

During elementary school, a classmate died of myasthenia gravis, a devastating incident that left Dr. Tilton questioning how such a thing could happen. Thanks to advances in treatment, however, such a death would not occur today, she noted. Mandatory newborn screenings for diseases like Duchenne muscular dystrophy and gene therapy for spinal muscular atrophy also have changed the game for child neurology—and transformed the lives of those patients.

While Dr. Tilton has no plans to retire just yet, the grandmother of two toddlers has some ideas for how she may spend her career after medicine.

“So much of your career is what's next, what's next?’” said Dr. Tilton. “I've taken some coaching courses. I hope to do career coaching and follow up on things I have postponed and have not done. I'm exploring art, sculpture, new travel, and of course always hunting for a long-lost talent.”

https://journals.lww.com/neurotodayonline/fulltext/2024/08150/aan_president_awardee_ann_tilton_on_career.9.aspx/?cid=eTOC+Issues.2024-neurotodayonline

AI reliably diagnoses Marfan syndrome from a simple facial photograph.

AI Accurately Diagnoses a Genetic Condition From Facial Photographs

August 12, 2024

by Sean McCabe

A Yale School of Medicine team reports in a new study, published in the journal Heliyon, that an artificial intelligence (AI) model was able to reliably diagnose people living with Marfan syndrome from a simple facial photograph.

Marfan syndrome is a genetic disorder, affecting about 1 in 3,000 people, which impacts the body's connective tissues. "Patients living with Marfan Syndrome are usually very tall and thin," said John Elefteriades, MD, professor of surgery at Yale School of Medicine and senior author of the study. "They have long faces and are prone to spine and joint issues. However, many are not diagnosed."

Marfan syndrome increases the risk for aortic dissection, where the aorta splits suddenly after becoming enlarged. "It is often lethal, and when the patient survives, urgent surgery is needed," Elefteriades said. "Being able to identify individuals from a photograph with AI will enhance diagnosis and enable protective therapies."

In their pilot study, researchers assembled 672 facial photographs of people with and without Marfan syndrome. A Convolutional Neural Network was trained on 80% of the photographs, then asked to identify the other 20% as Marfan or non-Marfan faces. The model successfully distinguished between Marfan and non-Marfan faces with 98.5% accuracy.

Researchers say they plan to make the tool available online in the future. "We are planning to extend this work beyond this initial pilot project," said Elefteriades. "We anticipate that many individuals may self-test once we put the test online."

"Yale School of Medicine faculty and students are leading the way in developing novel applications of AI to recognize and diagnose diseases, including rare diseases, earlier when we can have the greatest impact," said Nancy J. Brown, MD, dean of Yale School of Medicine.

Sandip Mukherjee, Mohammad A. Zafar, and Bulat Ziganshin were also authors on the study. Danny Saksenberg of Emerge, who also has an appointment at Yale, conducted the AI analysis.

https://medicine.yale.edu/news-article/ai-accurately-diagnoses-a-genetic-condition-from-facial-photographs/#:

Saksenberg D, Mukherjee S, Zafar MA, Ziganshin B, Elefteriades JA. Pilot study exploring artificial intelligence for facial-image-based diagnosis of Marfan syndrome. Heliyon. 2024 Jun 28;10(13):e33858. doi: 10.1016/j.heliyon.2024.e33858. PMID: 39055814; PMCID: PMC11269824.

Highlights
•
We explore Artificial Intelligence for detection of Marfan Disease (MFS) from simple facial images.
•
AI proves extremely effective at detection of MFS.
•
Overall accuracy is 98.5 % (0 false positives, 2 % false negatives).
•
Clinical usefulness is anticipated.

Abstract

Background

Marfan Syndrome (MFS), a genetic disorder impacting connective tissue, manifests in a wide array of phenotypes which can affect numerous bodily systems, especially the thoracic aorta. The syndrome often presents distinct facial features that potentially allow for diagnostic clinical recognition. Herein, we explore the potential of Artificial Intelligence (AI) in diagnosing Marfan syndrome from ordinary facial images, as assessed by overall accuracy, F1 score, and area under the ROC curve.

Methods

This study explores the utilization of Convolutional Neural Networks (CNN) for MFS identification through facial images, offering a novel, non-invasive, automated, and computerized diagnostic approach. The research examines the accuracy of Neural Networks in the diagnosis of Marfan Disease from ordinary on-line facial images. The model was trained on 80 % of 672 facial images (182 Marfan and 490 control). The other 20 % of images were used as the test set.

Results

Overall accuracy was 98.5 % (0 % false positive, 2 % false negative). F1 score was 97 % for Marfan facies and 99 % for non-Marfan facies. Area under the ROC curve was 100 %.

Conclusion

An Artificial Intelligence (AI) program was able to distinguish Marfan from non-Marfan facial images (from ordinary on-line photographs) with an extremely high degree of accuracy. Clinical usefulness of this program is anticipated. However, due to the limited and preliminary nature of this work, this should be viewed as only a pilot study.

Chiropractic for crying

A newborn in Columbus, Ohio, has a brand new demeanor ever since being treated by a chiropractor, her parents say.

Lily Freeman, just 2 months old, wasn’t a happy baby, her father, Joseph Freeman, told Fox News Digital.

When his daughter was born, her umbilical cord was wrapped around her neck twice.

About a week after the birth, Freeman and his wife, Stephanie Murdock, noticed that the baby exhibited extreme fussiness, grimacing, clenched fists, and stiff arms and legs.

Murdock, who was breastfeeding, went on a strict diet, cutting out all dairy and eggs, hoping to spark some change.

"When she was placed on her back, she would cry uncontrollably," Freeman said. "The only thing that worked was holding her upright. We knew something was wrong."

The couple took their baby to four different doctors, who concluded that since she was gaining weight and was healthy, she probably had colic — which would improve in three to four months.

"As her parents, we could not just sit back and wait it out," Freeman said. "We knew she had invisible pain."

The couple posted on social media, searching for answers from fellow parents. Many recommended they see a chiropractor.

"We had no previous knowledge that chiropractors treated children," Freeman said. "We were extremely skeptical because Lily was only 2 weeks old."

Freeman and Murdock took their baby to see Dr. Josh Russell at Ability Chiropractic in Hillard, Ohio. The doctor explained to them that the birthing process can be "traumatic" for mother and child.

In an interview with Fox News Digital, Russell said that he and his colleague, Dr. Tyler Morman, often treat babies with colicky behavior.

They typically perform a "thorough exam" and investigate the child’s history, including the details of the pregnancy, labor and delivery.

"The whole premise of chiropractics is to help the nervous system function the way that it should," he said.

"When you have a lack of mobility within the spine and tightness in musculature … that interferes with the nervous system's communication to send signals to the rest of the body."

When evaluating a baby, the movements of the spinal joints will help determine where adjustments are needed, Russell said.

When adjusting, the doctor said the appropriate pressure is what might be used to check "a peach or a tomato for ripeness."

"It’s a sustained pressure, holding a specific area that needs to move better," he said. "Once that nervous system interference is gone, we see huge changes."

Freeman, the baby's mom, told Fox News Digital after the second chiropractic visit, he and Murdock noticed a "huge change" in their little one's mobility and demeanor.

"She started smiling for the first time since she was born," he said. "We could place her on her back without her uncontrollably crying."

He added, "She was able to sleep without waking up every 20 minutes in pain. It was a beautiful thing to witness Lily transform into a totally different baby."

Some claim practice is ‘overwhelmingly safe'

Russell said he sees family members ranging in age from one day old to 99 years old.

Babies, toddlers and kids who may be having trouble with eating, sleeping or bowel movements could find great benefit from an adjustment, according to the chiropractor.

For toddlers, Russell claims that chiropractic care can also help with hyperactivity.

Regarding parents’ worries that an adjustment could hurt their baby, he stated that the practice is "overwhelmingly safe."

"I haven't had any adverse reactions to chiropractic care," he said.

"Our protocol … is a thorough exam, very light adjustments. It's really nothing crazy."

Freeman encouraged other parents to "do their research" and consult with a chiropractor before undergoing treatment.

"Knowledge is power, and we had to advocate for Lily," he said. "You have to be the voice for the voiceless."

Dr. Lora Tanis, a New Jersey chiropractor who is also the president of the Council on Chiropractic Pediatrics, also weighed in, telling Fox News Digital that she "definitely recommends" chiropractic care for babies.

"Often there are mechanical forces or circumstances that would warrant a spinal evaluation for a baby, and therefore, having a baby evaluated early can potentially avoid future problems," she said in an email.

Chiropractors are trained to perform "age-appropriate exams prior to determining if the child is a candidate for chiropractic care," Tanis added.

Babies who suffer from neuromusculoskeletal conditions will show signs of "greater comfort" following a visit to the chiropractor, she said.

"Many parents report that their baby cries less and sleeps more soundly after chiropractic care."

"Adjustments performed on children are very gentle, precise and appropriate for their age," Tanis said.

She encouraged parents to seek chiropractic help for children if they notice abnormal posture or head position, decreased motion of extremities, irritability with movement, or trauma.

Experts warn of risks

Not all experts agree that chiropractic adjustments are safe for newborns.

An observational study published in Pediatrics, the journal of the American Academy of Pediatrics (AAP), concluded that "serious adverse events may be associated with pediatric spinal manipulation."

Beth C. Natt, M.D., system medical director of pediatrics at Atlantic Health System in New Jersey, echoed those concerns.

"I do not recommend chiropractic care for babies," she told Fox News Digital.

"Although watching a newborn baby get ‘adjusted’ might be a popular video clip on TikTok, the reality is that the American Academy of Pediatrics (AAP) and other reputable medical organizations do not recommend chiropractic care for infants due to safety and efficacy concerns."

"Infants are wired to adapt to their environment without external interventions like chiropractic care."

Claims that chiropractic care can treat conditions like colic, reflux and sleep disturbances are "not supported by rigorous scientific studies," according to Natt.

Although some believe that infants need to be "realigned" after childbirth, Natt disagreed.

"The infant’s body undergoes these natural adjustments and development after birth, and infants are wired to adapt to their environment without external interventions like chiropractic care," she said.

Infants have "delicate and developing bones and joints," the doctor noted, which makes them "more s

"There have been documented cases of serious injuries, including fractures and spinal cord injuries, after chiropractic care in infants," Natt warned.

The doctor recommended parents speak with their pediatricians about their concerns before seeing a chiropractor.

The pediatrician can perform an assessment of the infant and determine whether other, less risky therapies are better for the infant, she said.

Natt added, "At the end of the day, we are all aligned — we want to ensure that we care for the health, safety and comfort of our patients."

Fox News Digital reached out to the AAP requesting comment.

https://www.foxnews.com/health/ohio-baby-smiling-chiropractic-adjustments-parents-say-safe

Vohra S, Johnston BC, Cramer K, Humphreys K. Adverse events associated with pediatric spinal manipulation: a systematic review. Pediatrics. 2007 Jan;119(1):e275-83. doi: 10.1542/peds.2006-1392. Epub 2006 Dec 18. Erratum in: Pediatrics. 2007 Apr;119(4):867. Erratum in: Pediatrics. 2007 Jul;120(1):251. PMID: 17178922.

ABSTRACT

BACKGROUND. Spinal manipulation is a noninvasive manual procedure applied to specific body tissues with therapeutic intent. Although spinal manipulation is commonly used in children, there is limited understanding of the pediatric risk estimates.

OBJECTIVE. Our goal was to systematically identify and synthesize available data on adverse events associated with pediatric spinal manipulation.

METHODS. A comprehensive search was performed of 8 major electronic databases (eg, Medline, AMED, MANTIS) from inception to June 2004 irrespective of language. Reports were included if they (1) were a primary investigation of spinal manipulation (eg, observation studies, controlled trials, surveys), (2) included a study population of children who were aged 18 years or younger, and (3) reported data on adverse events. Data were summarized to demonstrate the nature and severity of adverse events that may result rather than their incidence.

RESULTS. Thirteen studies (2 randomized trials, 11 observational reports) were identified for inclusion. We identified 14 cases of direct adverse events involving neurologic or musculoskeletal events. Nine cases involved serious adverse events (eg, subarachnoidal hemorrhage, paraplegia), 2 involved moderately adverse events that required medical attention (eg, severe headache), and 3 involved minor adverse events (eg, midback soreness). Another 20 cases of indirect adverse events involved delayed diagnosis (eg, diabetes, neuroblastoma) and/or inappropriate provision of spinal manipulation for serious medical conditions (ie, meningitis, rhabdomyosarcoma).

CONCLUSIONS. Serious adverse events may be associated with pediatric spinal manipulation; neither causation nor incidence rates can be inferred from observational data. Conduct of a prospective population-based active surveillance study is required to properly assess the possibility of rare, yet serious, adverse events as a result of spinal manipulation on pediatric patients.

Serial biomarker measurements to predict recovery in concussion

A study of 81 Australian football players with sports-related concussion suggests that serial biomarker measurements could help identify cases with heightened and prolonged increases in serum glial fibrillary acidic protein and neurofilament light levels, guiding return-to-play decisions based on patients' recovery. Researchers say that the next important step is demonstrating how and when the two proteins should be measured as return-to-play biomarkers.

How long does it take adult athletes' brains to fully recover after a concussion? Can blood biomarkers better estimate return-to-play readiness? A new study published online June 7 in JAMA Network Open provides some insight on these questions and others, as it found that biomarkers of neurobiological recovery could be detected after a sports-related concussion (SRC) and that they persisted over time in subsets of individuals—inviting important consideration for many sports neurologists and their patients.

Looking at 81 Australian football players who had experienced SRC, as well as 56 controls who had not, the study aimed to evaluate levels of serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) at eight time points after injury—24 hours and one, two, four, six, eight, 12, and 26 weeks—as well as to measure cognitive performance, symptoms, and return-to-training times.

“In this cohort study, a subset of SRC cases, particularly those with loss of consciousness, showed heightened and prolonged increases in GFAP and NfL levels that persisted for at least four weeks,” wrote lead author Stuart McDonald, PhD, a senior research fellow in the department of neuroscience at the faculty of medicine at Monash University in Melbourne, Australia, and his colleagues. “These findings suggest that serial biomarker measurement could identify such cases, guiding return-to-play decisions based on neurobiologic recovery.”

Key Findings

The average age of participants was about 23 years for those with concussion and 25 for those without. A majority of both groups were male and White.

The SRC group exhibited higher GFAP levels at 24 hours and four weeks, and higher levels of NfL from one to 12 weeks, compared with the controls. Importantly, participants with SRC who also had loss of consciousness (comprising one-third of all SRC cases) showed higher GFAP at 24 hours, one week, two weeks, and four weeks, as well as higher NfL from one week to 12 weeks compared with SRC participants without loss of consciousness.

The investigators also found that participants in the subgroup with extreme and prolonged increases in GFAP and those with extreme/moderate NfL increases took longer to return to training than those in the moderate GFAP and minimal or no change NfL subgroups. Participants who took longer to return to training also showed higher rates of loss of consciousness; and after stratification by this factor, those with loss of consciousness exhibited larger and more persistent differences in GFAP and NfL.

“The unique thing about this study is not the measure but how many times and how consistently we did it—eight times over six months for 137 athletes,” Dr. McDonald said in a news release accompanying the study. “We demonstrated that blood levels of GFAP are elevated in the vast majority of athletes with concussion at 24 hours, and we are working to have this much-needed diagnostic test approved for use in the next few years.”

However, the authors acknowledged several key limitations—including the disproportionate percentage of men in the analysis as well as the younger ages of participants, meaning these data cannot provide insights into biological sex and age. The sample size was also relatively small, they wrote.

In the future, “our vision is for serial measures of these proteins to be integrated into clinical care, guiding return-to-play decisions based on both symptom and neurobiological recovery,” said Dr. McDonald. “The next important step is demonstrating how and when we should measure these two proteins as return-to-play biomarkers. Our findings take us closer to this becoming a reality.”

Expert Commentary

The current study design was both straightforward and thorough, said Joshua Kamins, MD, associate clinical professor of neurology and associate director of the Steve Tisch BrainSPORT Program at David Geffen School of Medicine at UCLA. Notably, “the authors were able to analyze very acute levels (within 24 hours) and also to track these values out to distant time points, weeks from the initial injury,” and these measures were able to both identify concussive injuries as well as predict subjects with delayed recovery.

Just a few years ago, Dr. Kamins said he would not have believed blood-based biomarkers had a function beyond determining if an injury is more severe than a concussion. Now, “we are seeing that these biomarkers may serve an important function in the near future, by diagnosing and prognosing mild traumatic brain injury/concussion.”

Biomarkers for concussion could achieve two potential goals, he explained: improving the diagnosis of concussion and improving prognosis of concussion, which has a “relatively heterogeneous rate of recovery.”

This first goal can be difficult, he said, “because although imperfect, our history and examination tools—if used in combination—can achieve a sensitivity of greater than 80 percent (JE Resch, et al, 2016). Moreover, taking a history and exam is both quick and free.”

However, for the second goal, “although most adults are symptom-free in fewer than 14 days, 20 to 30 percent of patients have symptoms beyond one month, often lasting months to years. If easy-to-perform tests are able to predict prolonged recovery at day one, or at various time points during the acute window, we would know to whom to direct more aggressive treatment and how to guide our patients.”

The present study adds to a growing body of biomarker literature that should offer hope that we are moving toward the reality of “reliable and useful blood-based biomarkers,” he said.

Still, these tests must be considered experimental at this time. “In particular, caution should be used when interpreting elevated biomarkers outside of the acute window,” Dr. Kamins said. The study's main limitations were well addressed by the authors—”most significantly, the smaller sample size limited the amount of statistical inference that could be made.”

“The challenge with mild traumatic brain injury is that it currently has no established biomarker. If this study is reproducible and well validated, there is the potential for it to offer us a blood biomarker that could help with return-to-play decisions,” said Teena Shetty, MD, MPhil, FAAN, a neurologist and the founder and director of the concussion program in neurology at the Hospital for Special Surgery in New York City.

One main point of interest from this paper, she said, is that some patients who pass currently established post-concussion assessments of full recovery may still be neurobiologically vulnerable even if clinicians are not able to detect this on provocative vestibular, balance, or exertion testing. “This paper suggests that neurobiologic effects may persist even after we clear individuals who are asymptomatic and otherwise pass tests of physical therapy and exertion,” Dr. Shetty said.

The interpretation of loss of consciousness for neurologists who treat concussion already has had a historic evolution, she continued. “Twenty years ago, neurologists believed that loss of consciousness represented a more severe concussion, but that theory has since been reconsidered, with loss of consciousness considered less of a prognostic indicator than initially thought.”

If validated, these findings “may see some providers return to the more conservative return-to-play guidelines that we have moved away from,” Dr. Shetty said. While this paper doesn't disagree with previous research, it may suggest a role for tracking these biomarkers along with the loss of consciousness.

“As someone who sees concussion patients, this paper leads me to want to strengthen the basis for my own return-to-play decisions and also to consider this phenomenon of neurobiologic recovery and how we can better understand and stratify this,” Dr. Shetty said. “At what point can we measure GFAP and NfL? What levels should we concerned about? How do we correlate this to recovery?”

It also points to the fact that we need to better define what neurobiologic recovery means for these patients and if this correlates with patients having a longer recovery time, she said.

This idea of neurobiologic recovery is germane “in part because we know these individuals are more susceptible to a second injury,” Dr. Shetty said. “If that's the concern, how do we determine that the brain has returned to normal using these biomarkers? How do we know that this is enough of a measure and these individuals won't still be at elevated risk?”

Mild traumatic brain injury is challenging because it is a functional injury rather than a structural one, so it can be difficult to validate biomarkers, she explained, adding that returning to exercise continues to offer clear advantages, notwithstanding their potential risks. Given this study, “it's really important to look at increased return-to-play time and cognitive performance and that trajectory and to understand this better,” she added.

Future studies of these biomarkers also would need to look a broader range of ages, different types of athletes, and more women, Dr. Shetty said.

“These biomarkers could theoretically challenge current decisions and influence clinical management if they are validated, but further study must be pursued,” Dr. Shetty told Neurology Today. Generally, she said, “looking at a combination of neurophysiologic imaging and blood markers would be more valuable and more accurate.”

It is not yet clear how to interpret persistently elevated biomarker levels, and these findings should not alter decision-making at this time, Dr. Kamins said. “However, I look forward to a future when we can utilize blood tests to aid in the objective diagnosis of brain injury and provide reliable information to our patients about the expected duration of their recovery.”

https://journals.lww.com/neurotodayonline/fulltext/2024/07180/elevated_blood_biomarkers_may_predict_recovery.3.aspx

O’Brien WT, Spitz G, Xie B, et al. Biomarkers of Neurobiologic Recovery in Adults With Sport-Related Concussion. JAMA Netw Open. 2024;7(6):e2415983. doi:10.1001/jamanetworkopen.2024.15983

Key Points

Question Do distinct trajectory subgroups exist in the serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) following sport-related concussion?

Findings In this cohort study of 81 individuals with sport-related concussion, in a subset of cases, increases in GFAP and NfL levels were substantial and persisted for at least 4 weeks. Individuals in these extreme biomarker subgroups were more likely to have experienced loss of consciousness (LOC) and longer to return to training times.

Meaning The findings of this study suggest the utility of serial measurements of GFAP and NfL to track neurobiologic recovery, with the association between LOC and extended biomarker elevations supporting the use of LOC for informing more conservative return-to-play timelines.

Abstract

Importance Sport-related concussion (SRC), a form of mild traumatic brain injury, is a prevalent occurrence in collision sports. There are no well-established approaches for tracking neurobiologic recovery after SRC.

Objective To examine the levels of serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in Australian football athletes who experience SRC.

Design, Setting, and Participants A cohort study recruiting from April 10, 2021, to September 17, 2022, was conducted through the Victorian Amateur Football Association, Melbourne, Australia. Participants included adult Australian football players with or without SRC. Data analysis was performed from May 26, 2023, to March 27, 2024.

Exposure Sport-related concussion, defined as at least 1 observable sign and/or 2 or more symptoms.

Main Outcomes and Measures Primary outcomes were serum GFAP and NfL levels at 24 hours, and 1, 2, 4, 6, 8, 12, and 26 weeks. Secondary outcomes were symptoms, cognitive performance, and return to training times.

Results Eighty-one individuals with SRC (median age, 22.8 [IQR, 21.3-26.0] years; 89% male) and 56 control individuals (median age, 24.6 [IQR, 22.4-27.3] years; 96% male) completed a total of 945 of 1057 eligible testing sessions. Compared with control participants, those with SRC exhibited higher GFAP levels at 24 hours (mean difference [MD] in natural log, pg/mL, 0.66 [95% CI, 0.50-0.82]) and 4 weeks (MD, 0.17 [95% CI, 0.02-0.32]), and NfL from 1 to 12 weeks (1-week MD, 0.31 [95% CI, 0.12-0.51]; 2-week MD, 0.38 [95% CI, 0.19-0.58]; 4-week MD, 0.31 [95% CI, 0.12-0.51]; 6-week MD, 0.27 [95% CI, 0.07-0.47]; 8-week MD, 0.36 [95% CI, 0.15-0.56]; and 12-week MD, 0.25 [95% CI, 0.04-0.46]). Growth mixture modeling identified 2 GFAP subgroups: extreme prolonged (16%) and moderate transient (84%). For NfL, 3 subgroups were identified: extreme prolonged (7%), moderate prolonged (15%), and minimal or no change (78%). Individuals with SRC who reported loss of consciousness (LOC) (33% of SRC cases) had higher GFAP at 24 hours (MD, 1.01 [95% CI, 0.77-1.24]), 1 week (MD, 0.27 [95% CI, 0.06-0.49]), 2 weeks (MD, 0.21 [95% CI, 0.004-0.42]) and 4 weeks (MD, 0.34 [95% CI, 0.13-0.55]), and higher NfL from 1 week to 12 weeks (1-week MD, 0.73 [95% CI, 0.42-1.03]; 2-week MD, 0.91 [95% CI, 0.61-1.21]; 4-week MD, 0.90 [95% CI, 0.59-1.20]; 6-week MD, 0.81 [95% CI, 0.50-1.13]; 8-week MD, 0.73 [95% CI, 0.42-1.04]; and 12-week MD, 0.54 [95% CI, 0.22-0.85]) compared with SRC participants without LOC. Return to training times were longer in the GFAP extreme compared with moderate subgroup (incident rate ratio [IRR], 1.99 [95% CI, 1.69-2.34]; NfL extreme (IRR, 3.24 [95% CI, 2.63-3.97]) and moderate (IRR, 1.43 [95% CI, 1.18-1.72]) subgroups compared with the minimal subgroup, and for individuals with LOC compared with those without LOC (IRR, 1.65 [95% CI, 1.41-1.93]).

Conclusions and Relevance In this cohort study, a subset of SRC cases, particularly those with LOC, showed heightened and prolonged increases in GFAP and NfL levels, that persisted for at least 4 weeks. These findings suggest that serial biomarker measurement could identify such cases, guiding return to play decisions based on neurobiologic recovery. While further investigation is warranted, the association between prolonged biomarker elevations and LOC may support the use of more conservative return to play timelines for athletes with this clinical feature.

Angelman syndrome and walking

Colin Farrell broke down when his son James learned to walk after his Angelman syndrome diagnosis.

The actor, 48, detailed the “profound” moment to People, which occurred just ahead of James’ 4th birthday.

The little one’s occupational therapist told Farrell they had “something to show” him, the Oscar nominee said in his cover story interview, published Wednesday.

“I knew they were working on walking. And I stood over there, and she let him go, and he just came to [me],” he told the outlet, getting emotional.

“It was so profound. It was magic,” Farrell recalled of the “overwhelmingly beautiful” milestone.

“I’ll never forget just the face of determination on him as he walked toward me,” the “Total Recall” star continued. “He took, like, six steps, and I burst into tears.”

“I’ll never forget just the face of determination on him,” Farrell recalled.

The “Total Recall” star shares James with ex Kim Bordenave.

Farrell, who shared rare details about his and ex Kim Bordenave’s 21-year-old son to promote his new foundation, said James was initially diagnosed with cerebral palsy when he was 1 as it shares “a lot of the same characteristics” with Angelman syndrome.

The toddler was “really checked out” at the time due to not sitting up or crawling.

James received his correct diagnosis for the rare neurogenetic disorder at age 2, with Farrell gushing that his eldest child has “worked so hard all his life.”

The Golden Globe nominee became a dad in 2003 when James was born, followed by son Henry, 14, with Alicja Bachleda-Curuś six years later.

In May 2021, Farrell and Bordenave filed for conservatorship of James.

“Once your child turns 21, they’re kind of on their own,” he said on Wednesday. “All the safeguards that are put in place … go away so you’re left with a young adult who should be an integrated part of our modern society and more often than not is left behind.”

He said James has “worked so hard all his life.”

The “True Detective” alum created the Colin Farrell Foundation to combat this.

“[I] for years wanted to do something in the realm of providing greater opportunities for families who have a child with special needs, to receive the support that they deserve, basically the assistance in all areas of life,” he said.

Farrell added that James and individuals like him have “earned the right to have a greater degree of individuality and autonomy on life and a greater degree of community.”

https://pagesix.com/2024/08/08/parents/colin-farrell-details-son-taking-first-steps-after-angelman-syndrome-diagnosis/

Multisystem inflammatory syndrome as a sequela of SARS-CoV-2 infection

Scientists Get to the Bottom of COVID’s Worst Pediatric Complication

Study reveals a mechanism behind multisystem inflammatory syndrome in children (MIS-C).

By Levi Gadye

Early in the pandemic, some children fought off COVID with few, if any, symptoms, only to go into organ failure a few weeks later.

Most recovered after aggressive treatment, but their sudden illness, dubbed multisystem inflammatory syndrome in children (MIS-C), remained a mystery.

Now, a team of scientists from UC San Francisco, Chan Zuckerberg Biohub San Francisco, St. Jude Children’s Research Hospital and Boston Children’s Hospital has discovered what led to many of these cases, with a study that has implications for other autoimmune diseases.

The researchers found that the children’s immune systems had latched onto a part of the coronavirus that closely resembles a protein found in the heart, lungs, kidneys, brain, skin, eyes and GI tract, and launched a catastrophic attack on their own tissues.

The study, published Aug. 7 in Nature, offers one of the clearest connections yet linking viral infection and subsequent autoimmune disease.

“Thanks to our world-class team we’ve found an answer for how children get this mysterious disease,” said Aaron Bodansky, MD, a critical care fellow in UCSF’s Department of Pediatrics and lead author of the paper. “We hope this kind of approach can help break new ground in understanding similar diseases of immune dysregulation that have stumped us for decades, like multiple sclerosis or type 1 diabetes.”

As the novel coronavirus spread among millions of people, MIS-C cases mounted, affecting about 1 in 2,000 children under 18 with COVID.

Adrienne Randolph, MD, MSc, a critical care pediatrician at Boston Children’s Hospital and co-senior author of the paper, tracked these cases and collected patient samples through a national network of pediatric ICUs she had founded called Overcoming COVID-19.

“Every time COVID peaked in an area, about 30 days later, there’d be a peak of these kids presenting with what looked like septic shock in our network of ICUs, except they were negative for all kinds of infection,” Randolph said. “If we hadn’t intervened and supported them, they could have died.”

Reported MIS-C case ranges, on or before May 3, 2021States with no cases reported: Maine, Vermont. States with 1 through 24 cases reported: Alaska, Delaware, Hawaii, Kansas, Montana, Nebraska, New Hampshire, New Mexico, North Dakota, Oklahoma, Rhode Island, South Dakota, West Virginia, Wyoming. States with 25 through 49 cases reported: Arkansas, Idaho, Iowa, Kentucky, Mississippi, Oregon, Washington, Washington D.C. States with 50 through 99 cases reported: Alabama, Colorado, Connecticut, Indiana, Minnesota, Missouri, Nevada, Ohio, Texas, Utah, Virginia, Wisconsin. States with 100 through 149 cases reported: Arizona, Georgia, Louisiana, Maryland, Massachusetts, Michigan, New Jersey, New York, North Carolina, Pennsylvania, South Carolina, Tennessee. States with 150 through 199 cases reported: Florida, Illinois. States with 300 or more cases reported: Califorinia.

Treating children with MIS-C at UCSF, Bodansky noticed that it resembled Kawasaki disease and other rare pediatric inflammatory diseases that he had long sought to better understand.

Co-senior author Mark Anderson, MD, PhD, who directs the Diabetes Center at UCSF and is a CZ Biohub SF Investigator, suggested Bodansky try a tool that he and Joe DeRisi, PhD, president of Chan Zuckerberg Biohub San Francisco, were using, called Phage Immunoprecipitation Sequencing (PhIP-Seq), to see if it could uncover the cause of MIS-C.

PhIP-Seq screens blood for autoantibodies, or antibodies that mistakenly attack the human body rather than an outside threat, such as a virus. DeRisi, corresponding author and professor of biophysics and biochemistry at UCSF, had already used PhIP-Seq to understand severe neurological symptoms, as well as the link between viral infections and multiple sclerosis.

“We thought, could there be some sort of trigger with the immune system that leads to MIS-C?” Anderson recalled. “Thanks to Overcoming COVID-19, which our pediatric ICU was part of, we realized there might be enough samples to do PhIP-Seq on kids that had MIS-C and compare their antibodies with kids that had gotten COVID but did not get MIS-C.”

It opens the door to understanding why so many of these post-infectious, horribly inflammatory autoimmune events occur.”

With the approval of the Centers for Disease Control and Prevention (CDC), Randolph sent samples from 199 children with MIS-C to UCSF, along with 45 samples from children who had not developed MIS-C after COVID.

PhIP-Seq revealed that one third of the MIS-C cases had autoantibodies for an obscure human protein, called SNX8, which is present in certain immune cells that reside throughout the body. For some reason, the immune system was making antibodies targeting itself.

The scientists spent months hunting for a link between these autoantibodies and SARS-CoV-2. Then, late one night while looking at SNX8 on his computer screen with Bodansky, DeRisi had a flash of insight. What if the human protein resembled a portion of SARS-CoV-2’s N protein?

“We ran an analysis here on my computer – I did it myself – and it matched!” DeRisi recalled. “It was the same thing. It blew our minds."

Next, the team screened the MIS-C kids’ antibodies against proteins from the virus. The antibodies were targeting the very part of the N protein that matched SNX8. But antibodies from the healthy kids targeted other parts of the N protein that did not resemble a human protein.

The match between the autoantibodies, SNX8 and the N protein was a clear sign of an autoimmune overreaction.

But there was a hitch: antibodies can only go after threats that are floating in the blood. SNX8 is hidden inside of cells and would be invisible to them.

Anderson and Bodansky suspected that killer T cells, which screen the contents of human cells and destroy infected ones, were involved in this case of mistaken molecular identity.

Joe Sabatino, MD, PhD, UCSF professor of neurology and co-author of the paper, found that some T cells from the MIS-C patients seemed to target SNX8.

To prove that these T cells were truly attacking both targets, Paul Thomas, PhD, professor of host-microbe interactions at St. Jude, and his team carefully screened T cells from some of the MIS-C patients for matches with human SNX8 and the viral N protein.

Usually, doing an experiment like this is like trying to find a needle in a haystack. The body has so many different kinds of T cells that they need to be grown, or expanded, in the lab to find the rare culprit.

“Just taking these T-cells from patients directly, without any expansion, we found clusters of T cells that were specific for these two different target proteins,” said Thomas, who is a co-senior author of the paper. “It gives us an overwhelming amount of confidence that this response, associated with the autoantibody profile, is naturally elicited in a subset of these patients.”

Most children who had MIS-C have fully recovered, and major ICUs now only see a few new cases each year, mostly in unvaccinated children.

By tracing the disease from virus to autoantibody to T cell, the findings point to a new way of investigating – and hopefully one day treating – autoimmune disease more generally.

“This paper is special because it actually finds the smoking gun – what made these kids so sick,” DeRisi said. “It opens the door to understanding why so many of these post-infectious, horribly inflammatory autoimmune events occur.”

https://www.ucsf.edu/news/2024/08/428176/scientists-get-bottom-covids-worst-pediatric-complication

Bodansky, A., Mettelman, R.C., Sabatino, J.J. et al. Molecular mimicry in multisystem inflammatory syndrome in children. Nature (2024). https://doi.org/10.1038/s41586-024-07722-4

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.

Insomnia

25-Year-Old with Neurological Disease Doesn't Sleep: 'Can’t See Myself Making It More Than a Year'

The undiagnosed disease is connected to severe muscle pain and affects the heart, according to the user, who shared their story on Reddit

A 25-year-old Reddit user shared the worsening conditions of their undiagnosed neurological disorder, which they said impacts sleep to the point where they don't think they'll survive much longer

In a Reddit post with more than 11,000 upvotes, they noted it’s similar to Fatal Familial Insomnia, but shared that doctors haven't been able to diagnose the condition — apart from the fact that it stems from ongoing spinal issues

The user said they had given up hope — but comments and suggestions in the thread “motivated me” to find help

A 25-year-old with a rare, undiagnosed neurological disease that keeps them from sleeping shared, “I don’t know how long I have, but can’t see myself making it more than a year.“

In a post on Reddit’s popular AMA — Ask Me Anything — subreddit, user BPD-Recovery shared their journey with this undiagnosed disease, which they said they've been told is similar to Fatal Familial insomnia.

As the Cleveland Clinic explains, Fatal Familial insomnia “is a rare genetic condition that causes sleeping difficulties (insomnia), memory loss (dementia) and involuntary muscle twitching. This condition gets worse over time and it’s life-threatening.”

As BPD-Recovery shared, the issues all stem from their spine.

“I have had severe muscular pain since 16. Initially started like carpal tunnel. Muscles progressively get worse over time. In time, discovered all musc. Issues were coming from left shoulder,” the user wrote in the post, which had 11,000 upvotes and more than 1,600 comments.

“Now, I cannot breathe normally due to muscle tension," they continued. "My torso is now lightly twisted away from my problem side, My spine causes my sleeplessness. When my back was better, and I could release it, my sleep would immediately resume.”

The Redditor shared that two years ago, “my spine completely locked up, and I have not experienced normal sleep since.”

The user said that when they sleep, they will “Wake up. Extremely exhausted. Can barely move. Energy comes barely online around 3 p.m. Energy comes fully online around 7 p.m. Feel great then.”

Although they shared that their symptoms are similar to Fatal Familial Insomnia, they said “There is no name for my condition. I have progressively deteriorated over 2 years. It began with hallucinations, irritability, extreme mood swings, exhaustion, etc.”

“In the last 4 months it’s began affecting my heart," the user further noted. "My nervous system is f-----. I have severe dysautonomia, which means my heart and blood pressure go from super low to super high erratically. I’ve been in and out of emergency rooms for borderline heart attacks about 7 times in the past 3 months.”

They shared that they're struggling with cognition, saying “I have also had to bring ppl to talk to doctors because I was so delirious. I have been too tired to speak on hundreds of occasions.”

“I regularly zone out and stare at walls. I forget what I did 30 seconds prior. I literally microsleep while awake,” they shared. “I have strained pasta onto my countertop, hit a parked car in my driveway, called people the wrong names, forgot basic words, said 'oh hey don’t do xyz' as I was doing it.”

Although the Redditor noted that “gabapentin (a neurosuppresant) helps marginally,” they admitted that “I am f------ terrified of dying. The cardiac issues are recent and I think I’m on my last leg.”

The thread was full of commenters who suggested new treatment options — from calling specialists to trying new therapies— which may have given the user hope.

“I kind of gave up due to extreme despair from years of medical gaslighting/not getting anywhere," the Redditor noted, adding, "This thread has motivated me. I called Mayo Clinic and a few places today.”

https://people.com/25-year-old-with-neurological-disease-doesnt-sleep-reddit-post-8691686

Khan Z, Sankari A, Bollu PC. Fatal Familial Insomnia. 2024 Feb 25. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 29489284.

Excerpt

Fatal familial insomnia (FFI) is a very rare and fatal inherited neurodegenerative prion disease. The mode of inheritance of this disease is autosomal dominant and involves a mutation of the prion protein (PRNP) gene, leading to atrophy in the thalamic nucleus. Aggressively progressive insomnia, with subsequent autonomic (eg, tachycardia, hyperhidrosis, hypertension), cognitive (eg, short-term memory and attentional deficits), motor system (eg, balance problems), and endocrine dysfunction are hallmarks of the disease. The disease is currently incurable and has a mean course of 18 months, ultimately leading to death.

The earliest description of the disease dates back to 1765, with a report of an Italian man with symptoms suggestive of FFI. The disease was formally identified and clinically described in 1986 by Lugaresi E et al, followed by subsequent studies further describing its pathophysiology, etiology, and clinical course. A detailed history and neurological examination are of paramount importance as fatal familial insomnia is primarily a clinical diagnosis. Treatment is centered mainly on symptomatic relief and palliative care, as there is no cure for FFI.

Chronic primary adrenalitis

Published Aug. 6, 2024, 8:10 p.m. ET

An 8-year-old Missouri girl who died suddenly after falling ill on a flight to Chicago in June was suffering from at least five different illnesses at the time of her death, a new medical examiner’s report found.

Sydney Weston died June 13 from complications of chronic primary adrenalitis coupled with several infections, including enterovirus and strep, according to Peoria County Coroner Jamie Harwood.

She was also suffering from inflammation of the small intestines known as duodenitis and the thyroid gland inflammation commonly known as thyroiditis, according to 25 News Now.

The long list of conditions suggested Weston may have suffered from an autoimmune disorder which left her body attacking its own healthy cells and harming organ operation, Harwood found.

Sydney died on June 13 after she became unresponsive while flying with her parents from Joplin, Mo., to a vacation in the Windy City.

The plane was diverted to Peoria, Ill., for an emergency landing, but Sydney died after being rushed to a nearby hospital.

Results from a previously released preliminary autopsy were inconclusive but found that her body showed no signs of abuse, neglect or foul play.

Sydney was just a week away from celebrating her ninth birthday when she died.

“She will forever be remembered for the happiness she brought to every single person she encountered. Our hearts are heavy. She was our baby girl and we celebrate her beautiful life,” her obituary read.

https://nypost.com/2024/08/06/us-news/sydney-westons-cause-of-death-revealed-after-8-year-old-died-on-flight/

June 15 (UPI) -- Illinois authorities are investigating why an 8-year-old Missouri girl died after suffering a medical emergency on board a SkyWest Airlines flight to Chicago.

Sydney Weston of Carl Junction, Mo., was traveling with her family from Joplin, Mo., to Chicago when she "suddenly became ill and then unresponsive in flight," the Peoria County Coroner's Office said in a statement. SkyWest Airlines confirmed that the child was aboard flight 5121, operating as United Express, to Chicago O'Hare International Airport on Thursday.

The coroner's officer said the girl's family immediately alerted airline staff of her condition, and they began rendering aid.

The flight was re-routed to Peoria, Ill. When the plane landed, paramedics were on site to tend to the passenger.

"We appreciate the efforts of our crewmembers who responded quickly to assist and the medical personnel who met the aircraft," a SkyWest spokesperson said in a statement.

Weston was transported to OSF Healthcare Saint Francis Medical Center in Peoria, where she was pronounced dead at 8:05 a.m.

A preliminary autopsy on Friday to determine the cause of Weston's death was inconclusive, but authorities said they found no signs of abuse or neglect.

The coroner's office said additional tests will be conducted, and results might be available in four to six weeks.

"Once we have those tests completed, it is our hope that we will be able to provide a definitive and exact cause of death for this little girl and give her family some answers," the coroner's office said.

https://www.upi.com/Top_News/US/2024/06/15/girl-dies-medical-emergency-skywest-airlines/5551718473940/

Reflex epilepsy

What can be done to control unprovoked seizures in a 55-year-old woman with drug-resistant epilepsy who was admitted to the hospital?

The patient's medical history indicated that she had been diagnosed with drug-resistant epilepsy more than 40 years before, at the age of 12, reported Seyed Mirsattari, MD, PhD, of Western University in London, Ontario, and co-authors in JAMA Neurologyopens in a new tab or window.

At age 37, she had undergone an anterior corpus callosotomy after subdural electroencephalography (EEG) electrodes revealed nonlocalizable bifrontal epilepsy marked by switching lateralization and rapid bilateral progression. The surgical procedure had no effect on her seizure semiology, nor was it associated with any appreciable clinical improvements.

The patient told clinicians that typically before a seizure came on, her stomach would feel enlarged and she would have a wave of warmth. This would be followed by simple monosyllabic vocalizations before she would lose awareness.

Clinicians learned that her seizures lasted about 2 minutes, and were usually "accompanied by manual automatisms of either hand and concomitant dystonic posturing of the contralateral arm." On some occasions, a seizure would be followed by an urgent need to urinate.

She explained that her seizures usually occurred at night. In discussing her history with physicians, the patient recalled that since she was a child, she had noticed that being in direct contact with a cold surface -- like when walking barefoot on cold tiles -- was sure to trigger a seizure.

The patient described similar effects with sudden exposure to cooler temperatures, for instance after quickly taking her sweater off in an air-conditioned space or walking into a pool of cool water without giving her body time to adjust to the change in temperature.

To assess her response, clinicians placed an ice pack on her back. This sensation immediately triggered her typical seizure.

The patient underwent a single-photon emission CT scan. The result, overlaying a T1-weighted MRI, "demonstrated ictal hyperperfusion of the right inferomedial and inferolateral frontal lobes, which represent the epileptogenic regions involved in the patient's cold reflex seizures," the authors explained.

During the ictal time frame, the team performed an EEG of her scalp. This revealed "muscle artifacts that obscured the onset of seizures, followed by rhythmic activity in the right temporal region with transfer to the left temporal region," they wrote.

Clinicians performed a subsequent stereoelectroencephalography (SEEG) with depth-electrode recordings. They interpreted the findings as suggesting that the patient's typical seizures originated from the right lateral orbitofrontal region. "The semiology of her cold-induced reflex seizure was consistent with her typical seizures captured on scalp EEG and SEEG, respectively," they noted.

Discussion

Reflex epilepsy is characterized by consistent seizures triggered by a specific stimulus. This may be generated internally, by stimuli such as cognitive demands or emotions, or external factors, such as lights, sounds, or temperature. Visual stimuli account for 75% to 80% of all triggers in reflex epilepsy, along with thinking, music, and eating, according to a 2021 paperopens in a new tab or window on reflex epilepsy.

Temperature-generated reflex epilepsyopens in a new tab or window typically occurs when hot water triggers temporal lobe seizures, the authors explained; cold-induced reflex epilepsy is very rare.

"This patient presented with focal-onset seizures with impaired awareness in response to the sensation of an ice pack," the team wrote. Results of the SEEG sampling suggested the seizures originated in the right orbitofrontal lobe, "and were associated with transfer of rhythmic activity between the right and left posterior supplementary motor cortices."

Another case report of cold-induced reflex epilepsy described a patient "whose epileptogenic zone likely originated from the prefrontal lobes with similar ictal findings of slow rhythm transfers between the temporal lobes on scalp EEG," they added.

While little is known about the brain activities involved in cold-induced reflex epilepsy, functional imaging studiesopens in a new tab or window indicate exposure to cold results in "increased activation of the orbitofrontal cortex, anterior cingulate, and posterior insula," which Mirsattari and team noted is similar to other primitive experiences related to pain, hunger, and thirst.

Reflex epilepsy often involves underlying hyperexcitability of the cortical region triggered by exposure to the offending stimulus, the authors said. "We postulate that cold-induced reflex epilepsy arises from hyperexcitability of the orbitofrontal cortex, although we cannot definitely exclude rapid seizure propagation from the insula."

Primary treatments for cold-induced reflex epilepsy include avoidance of cold stimuli and use of antiseizure medication. When the epilepsy is resistant to medical treatment, surgical resection of the culprit region can be considered, although this patient declined that option.

https://www.medpagetoday.com/casestudies/neurology/109848