Central Nervous System Insults Research Articles

Differential expression of genes in the RhoA/ROCK pathway in the hippocampus and cortex following intermittent hypoxia and high intensity interval training.

Neuroplasticity is regulated by a balance of neurotrophic factors and inhibitory molecules that are permissive and restrictive to central nervous system (CNS) adaptation, respectively. Intermittent hypoxia (IH) and high intensity interval training (HIIT) are known to upregulate neurotrophic factors which are associated with improvements in learning and memory and greater functional recovery following CNS insults. We investigated whether the RhoA/ROCK signaling pathway (known to restrict neuroplasticity) is also modulated by IH and HIIT in the hippocampus, cortex, and lumbar spinal cord of male Wistar rats. The gene expression of 25 RhoA/ROCK signaling pathway components was determined following IH or IH combined with HIIT (30 minutes/day, five days/week, for six weeks). IH included ten three-minute bouts which alternated between hypoxia (15% O2) and normoxia. IH+HIIT synchronized the hypoxia protocol with treadmill training at speeds of 50 cm.s-1 during hypoxia, and 15 cm.s-1 during normoxia. In the hippocampus, IH and IH+HIIT significantly downregulated aggrecan and Nogo-receptor 2 mRNA which are involved in the inhibition of neuroplasticity. However, IH and IH+HIIT significantly upregulated genes including Lingo-1, Ncan, NgR3, and Sema4d in the cortex. This is the first time IH and HIIT have been linked to the modulation of plasticity inhibiting pathways. These results provide a fundamental step towards elucidating the interplay between the neurotrophic and inhibitory mechanisms involved in experience-driven neural plasticity which will aid in optimizing physiological interventions for the treatment of cognitive decline or neurorehabilitation.

Peripartum Torpor: A Chilling Case Report and Review of the Literature

Purpose: To report a rare case of peripartum maternal hypothermia and bradycardia. Methods: Case report. Results: Torpor is a transient state of hibernation with hypothermia and bradycardia. Hypothermia is defined as an abnormally low core body temperature less than 36°C.1 Sinus bradycardia is defined as less than 60 beats/min. While occasionally hypothermia or bradycardia is seen in obstetric patients undergoing vaginal delivery, when combined together, it can be a rare, life-threatening state that requires prompt intervention to prevent adverse maternal and fetal outcomes. A 23 year-old G2P0102 at 33+3 weeks of gestation was admitted to the high risk obstetric service for preterm labor complicated by fetal growth restriction. She had a history of preeclampsia in a previous pregnancy, but otherwise denied any chronic medical problems. Upon arrival, her vital signs showed a temperature of 37°C, a pulse of 53 bpm, and blood pressure of 126/62 mmHg. Her white blood cell count was 12.4 x 109/L and hemoglobin was 11.3 g/dL. She received betamethasone for fetal lung maturity and penicillin for Group B streptococcus prophylaxis. As her cervix continued to dilate, she received an epidural for pain management. Once she was in active labor, she became bradycardic with a pulse in the 30s-40s bpm, as confirmed by EKG. She was completely asymptomatic at this time, and fetal heart tones were reassuring with a baseline between 110’s-130’s bpm. She delivered vaginally with 150 mL of estimated blood loss, and her bradycardia continued postpartum even after the epidural was discontinued. When she complained of feeling cold, multiple attempts with different oral and axillary thermometers could not obtain a reading. She was warmed with forced-air warming blankets, warmed blankets, and hot packs in her groin and axilla. During this time, discussion with the NICU staff revealed that her baby was also hypothermic at 33.3°C and hypoglycemic at 28 mg/dL at birth. Other than feeling cold, the patient continued to be asymptomatic despite hypotension and bradycardia. She appeared somnolent but was responsive to questions. Her uterus was firm with minimal vaginal bleeding and no purulent or foul-smelling vaginal discharge. Repeat laboratory testing revealed a white blood count of 19 x 109/L and lactate was 3.3 mmol/L. Her comprehensive metabolic panel was unremarkable. A chest x-ray was clear. A C-reactive protein was < 0.3 mg/dL and sedimentation rate was 14 mm/h. A rectal continuous thermometer was placed, which eventually recorded a temperature at 33.3°C and upon recheck was 31.7°C. A multidisciplinary team, including Anesthesia, Internal Medicine, and Neurology, evaluated the patient due to concern for a central nervous system insult. She received fluid resuscitation and broad-spectrum antibiotics for sepsis protocol. Due to the concern for potential septic shock, the decision was made to transport her to the Medical ICU for further management. As she was leaving Labor & Delivery, her temperature had increased to 36.9°C and her pulse to 61. Thyroid studies the next day revealed a normal Free T4 of 1.00 ng/dL and a high thyroid stimulating hormone level of 9.55 uIU/mL. However, despite an extensive workup, no clear etiology of her hypothermia and bradycardia was identified. Intervention with fluids and application of forced-air warming system resolved the hypothermia in less than 6 hours without relapse. Antibiotics were discontinued after one day due to low suspicion for systemic infection. She remained vitally stable and was discharged on postpartum day 2 without further complications. Conclusions: Maternal hypothermia is relatively common during cesarean delivery; however, very few cases report maternal hypothermia during vaginal delivery. An English language literature search for maternal hypothermia during vaginal delivery yielded less than 10 case reports – few of which identified a cause of the hypothermia – and none of which reported simultaneous maternal bradycardia. While our case is a very rare presentation and the etiology is still unknown, it highlights the importance of prompt recognition of vital sign derangements in peripartum patients as well as multidisciplinary attention.

Prevention of epileptogenesis - are we there yet?

To review recent progress in preventing epileptogenesis in patients with epilepsy. The recent success of epilepsy prevention and disease modification in tuberous sclerosis using simple EEG biomarkers to guide treatment initiation, and the identification of biomarkers to enrich the targeted patient population has made clinical trials of epilepsy prevention after acquired central nervous system (CNS) insults such as traumatic brain injury, stroke or infection both feasible and timely. Two such trials are currently on-going to prevent poststroke epilepsy. No disease-modifying or preventive treatments exist for epilepsy, and their development remains a major unmet need.. We have entered though the era of change in the treatment of epilepsy from symptomatic only to disease prevention. In this review, we summarize developments and review opportunities, challenges, and potential solutions to develop preventive treatment for acquired epilepsies in humans. The 'Holy Grail' of epilepsy is within our reach.

Reactive Astrocytes and Emerging Roles in Central Nervous System (CNS) Disorders.

In addition to their many functions in the healthy central nervous system (CNS), astrocytes respond to CNS damage and disease through a process called "reactivity." Recent evidence reveals that astrocyte reactivity is a heterogeneous spectrum of potential changes that occur in a context-specific manner. These changes are determined by diverse signaling events and vary not only with the nature and severity of different CNS insults but also with location in the CNS, genetic predispositions, age, and potentially also with "molecular memory" of previous reactivity events. Astrocyte reactivity can be associated with both essential beneficial functions as well as with harmful effects. The available information is rapidly expanding and much has been learned about molecular diversity of astrocyte reactivity. Emerging functional associations point toward central roles for astrocyte reactivity in determining the outcome in CNS disorders.

Diverse signaling mechanisms and heterogeneity of astrocyte reactivity in Alzheimer's disease.

Alzheimer's disease (AD) affects various brain cell types, including astrocytes, which are the most abundant cell types in the central nervous system (CNS). Astrocytes not only provide homeostatic support to neurons but also actively regulate synaptic signaling and functions and become reactive in response to CNS insults through diverse signaling pathways including the JAK/STAT, NF-κB, and GPCR-elicited pathways. The advent of new technology for transcriptomic profiling at the single-cell level has led to increasing recognition of the highly versatile nature of reactive astrocytes and the context-dependent specificity of astrocyte reactivity. In AD, reactive astrocytes have long been observed in senile plaques and have recently been suggested to play a role in AD pathogenesis and progression. However, the precise contributions of reactive astrocytes to AD remain elusive, and targeting this complex cell population for AD treatment poses significant challenges. In this review, we summarize the current understanding of astrocyte reactivity and its role in AD, with a particular focus on the signaling pathways that promote astrocyte reactivity and the heterogeneity of reactive astrocytes. Furthermore, we explore potential implications for the development of therapeutics for AD. Our objective is to shed light on the complex involvement of astrocytes in AD and offer insights into potential therapeutic targets and strategies for treating and managing this devastating neurodegenerative disorder.

Neurobiomarker and body temperature responses to recreational marathon running

ObjectivesTo assess how biomarkers indicating central nervous system insult (neurobiomarkers) vary in peripheral blood with exertional-heat stress from prolonged endurance exercise. DesignObservational study of changes in neuron specific enolase (NSE), S100 calcium-binding protein B (S100β), Glial Fibrillary Acid Protein (GFAP) and Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) at Brighton Marathon 2022. MethodsIn 38 marathoners with in-race core temperature (Tc) monitoring, exposure (High, Intermediate or Low) was classified by cumulative hyperthermia – calculated as area under curve of Time × Tc > 38 °C – and also by running duration (finishing time). Blood was sampled for neurobiomarkers, cortisol and fluid-regulatory stress surrogates, including copeptin and creatinine (at rested baseline; within 30 min of finishing; and at 24 h). ResultsFinishing in 236 ± 40 min, runners showed stable GFAP and UCH-L1 across the marathon and next-day. Significant (P < 0.05) increases from baseline were shown post-marathon and at 24 h for S100β (8.52 [3.65, 22.95] vs 39.0 [26.48, 52.33] vs 80.3 [49.1, 99.7] ng·L−1) and post-marathon only for NSE (3.73 [3.30, 4.32] vs 4.85 [4.45, 5.80] μg·L−1, P < 0.0001). Whilst differential response to hyperthermia was observed for cortisol, copeptin and creatinine, neurobiomarker responses did not vary. Post-marathon, only NSE differed by exercise duration (High vs Low, 5.81 ± 1.77 vs. 4.69 ± 0.73 μg·L−1, adjusted P = 0.0358). ConclusionsSuccessful marathon performance did not associate with evidence for substantial neuronal insult. To account for variation in neurobiomarkers with prolonged endurance exercise, factors additional to hyperthermia, such as exercise duration and intensity, should be further investigated.

Psychological Burden Among Patients With Inherited Bleeding Disorders in Madinah Province, Saudi Arabia.

Introduction Hereditary bleeding disorders, such as hemophilia and von Willebrand disease (VWD), result from specific deficiencies or malformations in the coagulation cascade proteins. These disorders can significantly impact both physical and psychological health. Complications such as depression, anxiety, and stress (DAS) can further exacerbate these impacts. Despite their significance, detailed prevalence data remain limited, especially for regions such as Madinah province in Saudi Arabia. This study aimed to determine the prevalence of DAS and their associated risk factors among patients with hereditary bleeding disorders in Madinah province, Saudi Arabia. Methods We conducted a cross-sectional study using telephonic interviews involving patients diagnosed with severe hemophilia A or B or VWD attending a hematology clinic in Madinah. Patients over 10 were included, and the study excluded those with central nervous system insults and platelet count concerns. The validated and reliable Depression Anxiety Stress Scale-21-item questionnaire and Statistical Product and Service Solutions (SPSS), version 26.0 (IBM SPSS Statistics for Windows, Armonk, NY), facilitated data collection and analysis, respectively. Results Of the 44 patients studied, 25% exhibited symptoms of depression, 45.5% showed signs of anxiety, and 29.5% had stress symptoms. Regarding symptom severity, 9.1% of patients experienced extremely severe depression, 15.9% had moderate anxiety, and 13.6% reported moderate stress. The prevalence of these psychological issues varied with patients' age and economic status. Notably, a significantly higher rate of depression was observed in patients over 15 years (42.9% vs. 8.7%; p=0.009). Additionally, while not statistically significant, patients with a high economic status reported increased rates of DAS. Conclusions Patients with inherited bleeding disorders, particularly those older than 15, manifest significant psychological distress. There is a pressing need for enhanced awareness, specialized screenings, and tailored counseling services to improve treatment adherence and overall quality of life. Given the findings, a comprehensive national study in Saudi Arabia is highly recommended, alongside the integration of specialized psychological services.

Astrocytes in functional recovery following central nervous system injuries.

Astrocytesareincreasinglyrecognisedas partaking incomplex homeostatic mechanisms critical for regulating neuronal plasticity following central nervous system (CNS) insults. Ischaemic stroke and traumatic brain injury are associated with high rates of disability and mortality. Depending on the context and type of injury, reactive astrocytes respond with diverse morphological, proliferative and functional changes collectively known as astrogliosis, which results in both pathogenic and protective effects. There is a large body of research on the negative consequences of astrogliosis following brain injuries. There is also growing interest in how astrogliosis might in some contexts be protective and help to limit the spread of the injury. However, little is known about how astrocytes contribute to the chronic functional recovery phase following traumatic and ischaemic braininsults. In this review, we explore the protective functions of astrocytes in various aspects of secondary brain injury such as oedema, inflammation and blood-brain barrier dysfunction. We also discuss the current knowledge on astrocyte contribution to tissue regeneration, including angiogenesis, neurogenesis, synaptogenesis,dendrogenesis and axogenesis. Finally, we discuss diverse astrocyte-related factors that, if selectively targeted, could form the basis of astrocyte-targeted therapeutic strategies to better address currently untreatable CNS disorders.

A 5-year Retrospective Review Of Attention Deficit Hyperactivity Disorder In Children In Zaria, North West Nigeria

Background:Attention deficit hyperactivity disorder (ADHD) is characterized by inattention and/or hyperactivity-impulsivity that impair an individuals functioning and development. Children with ADHD are at risk of poor academic performance, dropping out of school, low self-esteem, teenage pregnancies, engaging in criminal behaviour, sustaining physical injuries and poor social skills. Objective: We carried out a 5- year retrospective review of cases of ADHD in our Paediatrics Neurology Clinic to determine the epidemiology, symptomatology and risk factors for ADHD in our setting. Materials and Methods: Case folders of all children with an established diagnosis of ADHD who were being seen at the paediatric neurology clinic of Ahmadu Bello University Teaching Hospital, Zaria from 1st January 2015 to 31st December 2019 were retrieved and relevant information such as sociodemographic characteristics, symptoms, age at presentation and perinatal or childhood central nervous system insult were extracted. Statistical analysis was done using Epi Info statistical software version 7. Results: A total of thirty (30) children were on follow-up for ADHD in the Paediatrics Neurology clinic of Ahmadu Bello University Teaching Hospital, Zaria during the study period. Twenty-four of them were males (80%) while 6 were females (20%). Their ages at presentation ranged from 2 to 15 years for boys (mean±SD =5.2 ±2.99) and from 2 to 5 years for girls (mean±SD =3.0 ±1.26). More than half (63.3% n= 19/30) were less than 5 years of age as at the time of first presentation to the clinic. Majority, (93.3% ,n= 28/30) had a history of CNS insult prior to onset of ADHD symptoms. Conclusion: Attention deficit hyperactivity disorder (ADHD) is increasingly being seen in environment, most cases occur in boys less than 5 years of age. Avoiding injuries to a childs central nervous system early in life can significantly decrease the likelihood of ADHD in them.

Complement C4-deficient mice have a high mortality rate during PTZ-induced epileptic seizures, which correlates with cognitive problems and the deficiency in the expression of Egr1 and other immediate early genes.

Complement system plays an important role in the immune defense against pathogens; however, recent studies demonstrated an important role of complement subunits C1q, C4, and C3 in normal functions of the central nervous system (CNS) such as non-functional synapse elimination (synapse pruning), and during various neurologic pathologies. Humans have two forms of C4 protein encoded by C4A and C4B genes that share 99.5% homology, while mice have only one C4B gene that is functionally active in the complement cascade. Overexpression of the human C4A gene was shown to contribute to the development of schizophrenia by mediating extensive synapse pruning through the activation C1q-C4-C3 pathway, while C4B deficiency or low levels of C4B expression were shown to relate to the development of schizophrenia and autism spectrum disorders possibly via other mechanisms not related to synapse elimination. To investigate the potential role of C4B in neuronal functions not related to synapse pruning, we compared wildtype (WT) mice with C3- and C4B- deficient animals for their susceptibility to pentylenetetrazole (PTZ)- induced epileptic seizures. We found that C4B (but not C3)-deficient mice were highly susceptible to convulsant and subconvulsant doses of PTZ when compared to WT controls. Further gene expression analysis revealed that in contrast to WT or C3-deficient animals, C4B-deficient mice failed to upregulate expressions of multiple immediate early genes (IEGs) Egrs1-4, c-Fos, c-Jus, FosB, Npas4, and Nur77 during epileptic seizures. Moreover, C4B-deficient mice had low levels of baseline expression of Egr1 on mRNA and protein levels, which was correlated with the cognitive problems of these animals. C4-deficient animals also failed to upregulate several genes downstream of IEGs such as BDNF and pro-inflammatory cytokines IL-1β, IL-6, and TNF. Taken together, our study demonstrates a new role of C4B in the regulation of expression of IEGs and their downstream targets during CNS insults such as epileptic seizures.

Biomarkers as prognostic determinants of epilepsy after post-acute central nervous system insults: a systematic review and meta-analysis (P3-5.017)

<h3>Objective:</h3> To conduct a systematic review of biofluid biomarkers to test their association with the risk of post-CNS insult epilepsy. <h3>Background:</h3> It remains unknown if there are shared common biological pathways of an epileptogenic mechanism associated with a range of cerebral insults i.e., stroke, traumatic brain injury, and infections; and if certain biological markers could predict the risk of post-CNS insult epilepsy. <h3>Design/Methods:</h3> We searched articles until January 25, 2022, in PubMed, Embase, PsycINFO, Google Scholar, and Web of Science. The primary outcome was the difference in mean biomarker levels in patients with post-CNS insult epilepsy compared to patients without post-CNS insult epilepsy. We used the modified quality score based on the Reporting Recommendations for Tumor Marker Prognostic Studies for risk of bias assessment. For each biomarker, the level difference was calculated using the pooled standardized mean difference (SMD) and 95% confidence intervals (CI). (PROSPERO CRD42021297110) <h3>Results:</h3> We included 22 studies of 1499 cases with post-CNS insult epilepsy and 7929 controls with no post-CNS insult epilepsy. They investigated 47 biomarkers in blood or cerebrospinal fluid (CSF). Of 22 studies, 21 had moderate-to-high risk of bias. A meta-analysis was possible for only 19 biomarkers. Only blood glucose levels in four studies were significantly higher in patients with post-stroke epilepsy (PSE) than in patients without PSE (SMD 0.44; CI 0.19 to 0.69). From individual studies, 15 biomarkers in blood and seven in CSF were significantly associated with post-CNS insult epilepsy. <h3>Conclusions:</h3> While several biomarkers were found to be associated with epilepsy due to CNS insults, we do not recommend using the reported biomarkers for use in clinical settings or clinical trials. A significant limitation of these studies is that they included fewer patients with CNS insults who developed post-cerebral insult epilepsy. Collaborative efforts to promote biomarker discovery are therefore warranted. <b>Disclosure:</b> Mr. Misra has nothing to disclose. Ms. Khan has nothing to disclose. The institution of Dr. Lam has received research support from NIH. Dr. Mazumder has nothing to disclose. Ms. Eldem has nothing to disclose. Dr. Gururangan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Ceribell Inc. Dr. Gururangan has stock in Ceribell Inc. The institution of Dr. Gururangan has received research support from NIH-NINDS. The institution of Dr. Gururangan has received research support from Leon Levy Foundation. Dr. Hickman has nothing to disclose. Dr. Goswami has nothing to disclose. Mrs. Funaro has nothing to disclose. The institution of Joan Montaner has received research support from spanish govt. Joan Montaner has received intellectual property interests from a discovery or technology relating to health care. Dr. Quinn has nothing to disclose. Dr. Liebeskind has received research support from Cerenovus. Dr. Liebeskind has received research support from Genentech . Dr. Liebeskind has received research support from Medtronic. Dr. Liebeskind has received research support from Stryker. Dr. Mishra has nothing to disclose.

Temporal single-cell atlas of non-neuronal retinal cells reveals dynamic, coordinated multicellular responses to central nervous system injury.

Non-neuronal cells are key to the complex cellular interplay that follows central nervous system insult. To understand this interplay, we generated a single-cell atlas of immune, glial and retinal pigment epithelial cells from adult mouse retina before and at multiple time points after axonal transection. We identified rare subsets in naive retina, including interferon (IFN)-response glia and border-associated macrophages, and delineated injury-induced changes in cell composition, expression programs and interactions. Computational analysis charted a three-phase multicellular inflammatory cascade after injury. In the early phase, retinal macroglia and microglia were reactivated, providing chemotactic signals concurrent with infiltration of CCR2+ monocytes from the circulation. These cells differentiated into macrophages in the intermediate phase, while an IFN-response program, likely driven by microglia-derived type I IFN, was activated across resident glia. The late phase indicated inflammatory resolution. Our findings provide a framework to decipher cellular circuitry, spatial relationships and molecular interactions following tissue injury.

Can the administration of platelet lysates to the brain help treat neurological disorders?

Neurodegenerative disorders of the central nervous system (CNS) and brain traumatic insults are characterized by complex overlapping pathophysiological alterations encompassing neuroinflammation, alterations of synaptic functions, oxidative stress, and progressive neurodegeneration that eventually lead to irreversible motor and cognitive dysfunctions. A single pharmacological approach is unlikely to provide a complementary set of molecular therapeutic actions suitable to resolve these complex pathologies. Recent preclinical data are providing evidence-based scientific rationales to support biotherapies based on administering neurotrophic factors and extracellular vesicles present in the lysates of human platelets collected from healthy donors to the brain. Here, we present the most recent findings on the composition of the platelet proteome that can activate complementary signaling pathways in vivo to trigger neuroprotection, synapse protection, anti-inflammation, antioxidation, and neurorestoration. We also report experimental data where the administration of human platelet lysates (HPL) was safe and resulted in beneficial neuroprotective effects in established rodent models of neurodegenerative diseases such as Parkinson’s disease, Alzheimer's disease, traumatic brain injury, and stroke. Platelet-based biotherapies, prepared from collected platelet concentrates (PC), are emerging as a novel pragmatic and accessible translational therapeutic strategy for treating neurological diseases. Based on this assumption, we further elaborated on various clinical, manufacturing, and regulatory issues that need to be addressed to ensure the ethical supply, quality, and safety of HPL preparations for treating neurodegenerative and traumatic pathologies of the CNS. HPL made from PC may become a unique approach for scientifically based treatments of neurological disorders readily accessible in low-, middle-, and high-income countries.Graphical abstract

Relationship between epileptic seizures and spiritual distress

Epilepsy is a chronic disease of the brain characterized by an enduring (i.e., persisting) predisposition to generate seizures, unprovoked by any immediate central nervous system insult, and by the neurobiologic, cognitive, psychological, and social consequences of seizure recurrences. Spiritual distress is defined as "a disruption in the life principle that pervades a person's entire being and that integrates and transcends one's biological and psychological nature.” It is well know that stress, anxiety, depression, mood disorders, sleep deprivation and fatigue are seizure-triggering factors. Some patients with epilepsy also experienced that their epilepsy had a spiritual causes. Based on our observations and the literature data, we think that spiritual distress/causes are a seizure trigger in patients with epilepsy and responsible from seizure in some people.

Acute symptomatic seizures in adults: a study on etiological profile

Background: Acute symptomatic seizures are clinical seizures occurring in close temporal relationship with an acute central nervous system (CNS) insult, which may be metabolic, toxic, structural, infectious or inflammatory. Currently there is dearth of information on the epidemiology of acute symptomatic seizures among adult medical admissions in Bangladesh. This study was designed to determine the frequency of presentation and etiology of acute symptomatic seizures among adults.&#x0D; Methods: This was a cross-sectional study of adult patients admitted with new onset seizure under Neurology Department of BIRDEM General Hospital during the period of January 2019 to December 2020. Clinical assessment and relevant investigations were done and data were collected regarding their etiological diagnosis. Data were analyzed using statistical package for the social sciences (SPSS) version 23.&#x0D; Results: Total admission during the study period was 2920 and among them, 100 patients (male 62, female 38) were having their first symptomatic seizures giving a prevalence of 3.4%. They were between 18 to 82 years of age. The main etiology of acute symptomatic seizure was metabolic encephalopathy (42.0%) .It was followed by acute cerebrovascular disease (31.0%) and acute CNS infection (16%) . Acute cerebrovascular disease and metabolic encephalopathy were predominant causes of symptomatic seizure among the elderly and CNS infections among the middle aged adults. The majority (70.0%) of patients had generalized onset seizures. Focal seizures and focal to bilateral tonic clonic seazure were present in 22% and 8% of the patients respectively.&#x0D; Conclusion: This study showed that metabolic encephalopathy, acute cerebrovascular disease and CNS infections were the prominent causes of acute symptomatic seizures. Treatment strategies should aim for promt identification and management of these conditions as seizures may not recur when the underlying cause has been removed or the acute phase has elapsed.&#x0D; BIRDEM Med J 2022; 12(2): 99-105

High-Throughput Analysis of Astrocyte Cultures Shows Prevention of Reactive Astrogliosis by the Multi-Nutrient Combination Fortasyn Connect.

Astrocytes are specialized glial cells that tile the central nervous system (CNS) and perform numerous essential functions. Astrocytes react to various forms of CNS insults by altering their morphology and molecular profile, through a process known as reactive astrogliosis. Accordingly, astrocyte reactivity is apparent in many neurodegenerative diseases, among which one is Alzheimer’s disease (AD). Recent clinical trials on early-stage AD have demonstrated that Fortasyn Connect (FC), a multi-nutrient combination providing specific precursors and cofactors for phospholipid synthesis, helps to maintain neuronal functional connectivity and cognitive performance of patients. Several studies have shown that FC may act through its effects on neuronal survival and synaptogenesis, leading to reduced astrocyte reactivity, but whether FC can directly counteract astrocyte reactivity remains to be elucidated. Hence, we developed an in vitro model of reactive astrogliosis using the pro-inflammatory cytokines TNF-α and IFN-γ together with an automated high-throughput assay (AstroScan) to quantify molecular and morphological changes that accompany reactive astrogliosis. Next, we showed that FC is potent in preventing cytokine-induced reactive astrogliosis, a finding that might be of high relevance to understand the beneficial effects of FC-based interventions in the context of neurodegenerative diseases.

Insights into nervous system repair from the fruit fly.

Millions of people experience injury to the central nervous system (CNS) each year, many of whom are left permanently disabled, providing a challenging hurdle for the field of regenerative medicine. Repair of damage in the CNS occurs through a concerted effort of phagocytosis of debris, cell proliferation and differentiation to produce new neurons and glia, distal axon/dendrite degeneration, proximal axon/dendrite regeneration and axon re-enwrapment. In humans, regeneration is observed within the peripheral nervous system, while in the CNS injured axons exhibit limited ability to regenerate. This has also been described for the fruit fly Drosophila. Powerful genetic tools available in Drosophila have allowed the response to CNS insults to be probed and novel regulators with mammalian orthologs identified. The conservation of many regenerative pathways, despite considerable evolutionary separation, stresses that these signals are principal regulators and may serve as potential therapeutic targets. Here, we highlight the role of Drosophila CNS injury models in providing key insight into regenerative processes by exploring the underlying pathways that control glial and neuronal activation in response to insult, and their contribution to damage repair in the CNS.

The human anti-ganglioside GM1 autoantibody response following traumatic and surgical central nervous system insults

Predictors of the central nervous system (CNS) directed autoantibody response after acute CNS injury are poorly understood. We analyzed titers of IgG and IgM autoantibodies to ganglioside GM1 in serial serum specimens collected from human patients following acute spinal cord injury (SCI), traumatic brain injury (TBI) and brain tumor resection. We also assessed putative predictors of the autoantibody titers. We enrolled 19 patients with acute SCI, 14 patients with acute severe TBI, and 19 patients undergoing brain tumor resection. We also enrolled 25 control subjects. Some SCI, TBI and tumor patients exhibited elevated IgG titers as compared with control values; some SCI and TBI patients exhibited an acute peak in IgG titers, most commonly 14 days after insult. Some clinical and radiographic measures of injury severity correlated with IgG titer elevation in SCI and TBI patients but not tumor patients. Our study demonstrates that diverse CNS insults are followed by increased IgG autoimmune antibody titers to the CNS antigen ganglioside GM1, however the response inherent to each insult type is unique. IgG autoimmune antibody titers to GM1 merit further study as a biomarker of traumatic injury severity that can be measured in delayed fashion after CNS insult. These human data help to inform which patients with CNS insults are at risk for CNS-directed autoimmunity as well as the time course of the response.

Anti-Inflammatory CDGSH Iron-Sulfur Domain 2: A Biomarker of Central Nervous System Insult in Cellular, Animal Models and Patients.

Spinal cord injury (SCI) promotes brain inflammation; conversely, brain injury promotes spinal neuron loss. There is a need to identify molecular biomarkers and therapeutic targets for central nervous system (CNS) injury. CDGSH iron-sulfur structural domain 2 (CISD2), an NF-κB antagonist, is downregulated after injury in vivo and in vitro. We aimed to examine the diagnostic value of CISD2 in patients with CNS insult. Plasma and cerebrospinal fluid (CSF) CISD2 levels were decreased in 13 patients with CNS insult and were negatively correlated with plasma IL6 levels (associated with disease severity; r = −0.7062; p < 0.01). SCI-induced inflammatory mediators delivered through CSF promoted mouse brain inflammation at 1 h post-SCI. Anti-CISD2 antibody treatment exacerbated SCI-induced inflammation in mouse spine and brain. Lipopolysaccharide-stimulated siCISD2-transfected EOC microglial cells exhibited proinflammatory phenotypes (enhanced M1 polarization, decreased M2 polarization, and increased intranuclear NF-κB p65 translocation). Plasma and CSF CISD2 levels were increased in three patients with CNS insult post-therapeutic hypothermia. CISD2 levels were negatively correlated with plasma and CSF levels of inflammatory mediators. CISD2 inhibition and potentiation experiments in cells, animals, and humans revealed CISD2 as a biomarker for CNS insult and upregulation of CISD2 anti-inflammatory properties as a potential therapeutic strategy for CNS insult.

Central Diabetes Insipidus in Children and Adolescents: Twenty-Six Year Experience from a Single Centre.

Introduction Paediatric cohorts of central diabetes insipidus (CDI) have shown varying prevalence for different causes of CDI. The objective of this study was to determine the causes of CDI and long-term outcome in children and adolescents from a Tertiary Paediatric Endocrinology unit. Methods The clinic database was searched to identify patients with CDI managed between 1993 and 2019. Relevant clinical information was collected from patient records. Results A total of 138 CDI patients, median age 6 years (range <1–18) at presentation, were identified. Principal CDI aetiologies were craniopharyngioma (n = 44), acute central nervous system (CNS) insult (n = 33), germinoma (n = 15), postneurosurgery (indication other than craniopharyngioma and germinoma, n = 20), midline CNS malformation (n = 14), Langerhans cell histiocytosis (n = 5), and familial (n = 2). Idiopathic CDI in this cohort was infrequent (n = 5). Patients with CNS malformations/infections presented with CDI at a younger age compared to patients with CNS tumours (p < 0.0001). Five patients, initially presenting as idiopathic CDI, were subsequently diagnosed with germinoma after a median interval of 3.3 years. All patients with CDI related to craniopharyngioma and nearly all (87%) patients with CDI related to germinoma had concomitant GH, ACTH, and TSH deficiency. The majority of patients who manifested CDI due to acute CNS insult either deceased (30%) or had transient CDI (33.3%). Conclusion Surgery for craniopharyngioma was the most common underlying aetiology of CDI with ubiquitous occurrence of panhypopituitarism in these patients. Manifestation of CDI in patients with acute CNS insult carries poor prognosis. We affirm that neuroimaging assessment in idiopathic CDI should be continued beyond 3 years from diagnosis as a significant number of patients exhibited progression of infundibular thickening 3 years post-CDI diagnosis.