Persistent Neurological Symptoms Research Articles

PREDITORES PARA A PERSISTÊNCIA DE SINTOMAS NEUROLÓGICOS DA COVID-19 UM ANO APÓS O DIAGNÓSTICO: Estudo de coorte

Knowledge about the frequency and predictive variables of persistent neurological manifestations associated with COVID-19 can contribute to directing the best treatment and recovery. The objective of this study was to identify the risk factors for the persistence of neurological symptoms (NSP) one year after the diagnosis of COVID-19. This is prospective research, carried out using a questionnaire sent to participants one month and one year after the diagnosis of COVID-19. To identify PSN risk factors after one year of diagnosis, the frequency of data relating to: sex; age; race/color; education; hospitalization; comorbidities and functional status present after 1 month and neurological symptoms (fatigue, headache, body pain, ageusia, anosmia, discouragement, irritability/mental confusion) present after one month and one year of diagnosis. Bivariate, multivariate and regression analyzes were performed. 379 patients with the following characteristics participated: age: median of 37 (29-49) years; color/race: white (69.1%); gender: female (64.9%); education: higher education (63.1%); hospitalized (9.2%); comorbidities: (33.24%), (13.7% - obesity). Regarding functional status: 55.1% altered; neurological symptoms after one month and after one year, respectively: frequency (57.5%), (38.5%), fatigue (30.3%), (19%) respectively. The predictor variables for PSN one year after diagnosis were comorbidities (P<0.003), changes in functional status and/or neurological symptoms one month after diagnosis: (P<0.001), respectively. One year after diagnosis, 38.5% presented persistent neurological symptoms, with a prevalence of fatigue (19.0%), and the risk factors were the presence of comorbidity, neurological symptoms and changes in functional status one month after diagnosis.

Brain and cognitive changes in patients with long COVID compared with infection-recovered control subjects.

Between 2.5 and 28% of people infected with SARS-CoV-2 suffer Long COVID or persistence of symptoms for months after acute illness. Many symptoms are neurological, but the brain changes underlying the neuropsychological impairments remain unclear. This study aimed to provide a detailed description of the cognitive profile, the pattern of brain alterations in Long COVID and the potential association between them. To address these objectives, 83 patients with persistent neurological symptoms after COVID-19 were recruited, and 22 now healthy controls chosen because they had suffered COVID-19 but did not experience persistent neurological symptoms. Patients and controls were matched for age, sex and educational level. All participants were assessed by clinical interview, comprehensive standardized neuropsychological tests and structural MRI. The mean global cognitive function of patients with Long COVID assessed by ACE III screening test (Overall Cognitive level - OCLz= -0.39± 0.12) was significantly below the infection recovered-controls (OCLz= +0.32± 0.16, p< 0.01). We observed that 48% of patients with Long COVID had episodic memory deficit, with 27% also impaired overall cognitive function, especially attention, working memory, processing speed and verbal fluency. The MRI examination included grey matter morphometry and whole brain structural connectivity analysis. Compared to infection recovered controls, patients had thinner cortex in a specific cluster centred on the left posterior superior temporal gyrus. In addition, lower fractional anisotropy (FA) and higher radial diffusivity (RD) were observed in widespread areas of the patients' cerebral white matter relative to these controls. Correlations between cognitive status and brain abnormalities revealed a relationship between altered connectivity of white matter regions and impairments of episodic memory, overall cognitive function, attention and verbal fluency. This study shows that patients with neurological Long COVID suffer brain changes, especially in several white matter areas, and these are associated with impairments of specific cognitive functions.

Psychosis Due to Osmotic (Pontine) Myelinolysis in Non-Hodgkin’s Lymphoma: Case Report

Introduction: central pontine myelinolysis (CPM) is rare neurological condition. The severe symptoms of neurologic and psychiatric disorders accompanying this condition are not sufficiently disclosed in the literature. Most often CPM develops on infusion therapy and forced correction of hyponatremia. The complexity of diagnosis and the lack of certain algorithms for the management of this category of patients cause a high frequency of disability, persistent neurological and psychiatric symptoms, and lethal outcomes.The aim was to present and analyze clinical picture of psychosis in CPM on the example of non-Hodgkin’s lymphoma case report. Patient and method: clinical analysis of disorders in 14-years old patient with diagnosis of non-Hodgkin’s lymphoma.Results: clinical polymorphism of psychotic features, catatonic disorders, neurological symptoms at the end stage and development of psychosis associated with CPM during cytotoxic treatment. A year and a half follow-up of the first generation antipsychotics administration is presented.Conclusion: CPM may occur on cytotoxic infusion therapy in patients with non-Hodgkin’s lymphoma and be accompanied by severe psychotic disorders. Thus, practitioners should be aware of the risks of this condition, its diagnostic and therapeutic options when working with these patients.

Proteomic Changes in the Hippocampus after Repeated Explosive-Driven Blasts.

Repeated blast-traumatic brain injury (blast-TBI) has been hypothesized to cause persistent and unusual neurological and psychiatric symptoms in service members returning from war zones. Blast-wave primary effects have been supposed to induce damage and molecular alterations in the brain. However, the mechanisms through which the primary effect of an explosive-driven blast wave generate brain lesions and induce brain consequences are incompletely known. Prior findings from rat brains exposed to two consecutive explosive-driven blasts showed molecular changes (hyperphosphorylated-Tau, AQP4, S100β, PDGF, and DNA-polymerase-β) that varied in magnitude and direction across different brain regions. We aimed to compare, in an unbiased manner, the proteomic profile in the hippocampus of double blast vs sham rats using mass spectrometry (MS). Data showed differences in up- and down-regulation for protein abundances in the hippocampus of double blast vs sham rats. Tandem mass tag (TMT)-MS results showed 136 up-regulated and 94 down-regulated proteins between the two groups (10.25345/C52B8VP0X). These TMT-MS findings revealed changes never described before in blast studies, such as increases in MAGI3, a scaffolding protein at cell-cell junctions, which were confirmed by Western blotting analyses. Due to the absence of behavioral and obvious histopathological changes as described in our previous publications, these proteomic data further support the existence of an asymptomatic blast-induced molecular altered status (ABIMAS) associated with specific protein changes in the hippocampus of rats repeatedly expsosed to blast waves generated by explosive-driven detonations.

Association between COVID-19 and outstanding academic performance at a Spanish university

BackgroundSARS-CoV-2 is the causative agent of COVID-19 identified in December 2019, an acute infectious respiratory disease that can cause persistent neurological and musculoskeletal symptoms such as headache, fatigue, myalgias difficulty concentrating, among others including acute cerebrovascular disease with a prevalence of 1–35%. The aim of this study is to evaluate the impact of COVID-19 in undergraduate students on their academic performance as an indicator of their intellectual ability and performance in a university that maintained 100% face-to-face teaching during the 2020–2021 academic year.MethodsA total of 7,039 undergraduate students were analyzed in a prospective cohort study at the University of Navarra. A questionnaire including sociodemographic and behavioral questions was sent. PCRs were performed throughout the academic year for the diagnosis of SARS-CoV-2 infection and students’ academic results were provided by the academic center, adjusted descriptive and multivariate models were performed to assess the association.ResultsA total of 658 (9.3%) participants were diagnosed with COVID-19, almost 4.0% of them achieved outstanding academic results, while uninfected students did so in 7.3%. SARS-CoV-2 infection was associated with a significant decrease in having outstanding academic results (OR = 0.57; 95% CI: 0.38–0.86).ConclusionHaving COVID-19 disease, decreased academic performance in undergraduate students. Therefore, it is necessary to prevent infection even in the youngest sections of the population.

Clinical Characteristics and Outcomes of Unusual Venous Thrombosis Sites Among Veterans with Myeloproliferative Neoplasms

Myeloproliferative Neoplasms (MPNs) may be complicated by venous thrombosis at unusual sites, which may include portal veins, hepatic veins, and cerebral sinuses. We have previously reported on the association of Agent Orange and the development of MPNs among Veterans. The incidence and timing from Service-Connected Exposures (SCE) of Veterans to the development of MPNs and thrombosis at atypical sites have not been defined. We examine the natural history, clinical characteristics, and outcomes of the Veterans with MPNs, who developed Renal Vein Thrombosis (RVT), Splanchnic Vein Thrombosis (SVT), Budd Chiari Syndrome (BCS), and Cerebral Venous Sinus Thrombosis (CVST). Utilizing the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database from January 1, 2006 - January 26, 2023, Veterans with MPNs, RVT, SVT, BCS, and CVST were identified through ICD-9 and -10 codes, and, subsequently, a retrospective chart review was performed upon those Veterans with MPNs and unusual thrombosis sites. Military toxin exposures were verified through Veterans' duration and location of service. Time to MPN diagnosis refers to time from first year of cumulative SCE until year of MPN diagnosis. Among 12,352,664 Veterans, there were 435 RVT, 156 SVT and BCS, 140 CVST, and 93,269 MPNs identified. Among those with MPNs, there were 9 BCS, 4 RVT, 5 SVT, 2 RVT &amp; SVT, and 9 CVST. CVST was observed only in Vietnam Veterans; 13/20 (65%) of RVT, SVT or BCS cases had SCE from the Gulf War (Table 1). Five/20 of the MPN subjects with RVT, SVT, or BCS had documented pre-existing thrombophilic risk factors, which included malignancy, heparin-induced thrombocytopenia, and splenectomy, whereas 2/9 CVST with MPN had associated alcohol abuse and tooth infection. All non-MPN Veterans with RVT, SVT, or BCS had thrombophilic risk factors, including malignancy, infection, and surgery. One had BCS from Paroxysmal Nocturnal Hemoglobinuria. Median time to MPN diagnosis from SCE was 20 (3-62) years with 13 (65%) thrombotic events occurring at the same time of MPN diagnosis among Veterans with RVT, SVT, or BCS. Six (30%) had their thrombosis recognized prior to their MPN diagnosis, median 6 (1-10) years, while 1 had a thrombotic event 16 years after his MPN diagnosis (Figure 1). Veterans with MPN and CVST had a substantially longer median time from SCE to the time of MPN diagnosis, 42 (24-52) years. No CVST was observed concurrent to the time of MPN diagnosis. Among Veterans with MPN and CVST, 5 (56%) had thrombosis before MPN diagnosis and 4 (44%) had thrombosis after MPN diagnosis, median 5 (2-10) years and 7 (1-21) years, respectively. Among Veterans with MPN and RVT, SVT, or BCS, 17 (85%) had portal hypertension complications, 8 (40%) had undergone endovascular interventions, and all individuals were placed on indefinite systemic anticoagulation, with warfarin most commonly prescribed. Among Veterans with BCS, 3 underwent liver transplantation. Among Veterans with CVST, 2 (22%) had concurrent CNS hemorrhage, 5 (56%) had persistent neurologic symptoms, and 1 had transformation of his MPN to Chronic Myelomonocytic Leukemia. In summary, thrombotic episodes at unusual sites among Veterans with MPNs are rare events but convey substantial morbidity and mortality, particularly among those with RVT, SVT, and BCS. We describe a significantly shorter median time to MPN diagnosis in Veterans with RVT, SVT, and BCS compared to CVST with a difference of 22 years. All MPN subjects with RVT, SVT, or BCS had JAK2 V617F mutations, with majority of thromboses noted at the time of MPN diagnosis. Future studies should include potential role of SCE in acquisition of driver mutations and CHIPs and progression of mutagenesis.

Neurological risks of COVID-19 in women: the complex immunology underpinning sex differences.

The COVID-19 pandemic has uncovered many mysteries about SARS-CoV-2, including its potential to trigger abnormal autoimmune responses. Emerging evidence suggests women may face higher risks from COVID-induced autoimmunity manifesting as persistent neurological symptoms. Elucidating the mechanisms underlying this female susceptibility is now imperative. We synthesize key insights from existing studies on how COVID-19 infection can lead to immune tolerance loss, enabling autoreactive antibodies and lymphocyte production. These antibodies and lymphocytes infiltrate the central nervous system. Female sex hormones like estrogen and X-chromosome mediated effects likely contribute to dysregulated humoral immunity and cytokine profiles among women, increasing their predisposition. COVID-19 may also disrupt the delicate immunological balance of the female microbiome. These perturbations precipitate damage to neural damage through mechanisms like demyelination, neuroinflammation, and neurodegeneration - consistent with the observed neurological sequelae in women. An intentional focus on elucidating sex differences in COVID-19 pathogenesis is now needed to inform prognosis assessments and tailored interventions for female patients. From clinical monitoring to evaluating emerging immunomodulatory therapies, a nuanced women-centered approach considering the hormonal status and immunobiology will be vital to ensure equitable outcomes. Overall, deeper insights into the apparent female specificity of COVID-induced autoimmunity will accelerate the development of solutions mitigating associated neurological harm.

CNS Involvement of DLBCL Presenting with an Unusual Non-Enhancing Infiltrative Mass.

Central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL) is relatively uncommon, occurring in approximately 5% of cases, with the majority of instances manifesting during relapse and often associated with poor prognoses. The aim of this case report is to present a unique occurrence of non-enhancing relapse of CNS lymphoma. Significantly, the patient had recently encountered a disease involvement in the axilla region, and subsequent to scheduled chemotherapy, she developed persistent neurological symptoms, leading to the discovery of a relapse of the CNS lymphoma. Our focus will be on delineating the clinical presentation, elucidating the findings observed in clinical imaging, and detailing the therapeutic approaches employed in this specific case. By highlighting these aspects, we aim to provide valuable insights into the diagnosis of the atypical presentation of CNS lymphoma.

The breadth of the neutralizing antibody response to original SARS-CoV-2 infection is linked to the presence of Long COVID symptoms.

The associations between longitudinal dynamics and the breadth of SARS-CoV-2 neutralizing antibody (nAb) response with various Long COVID phenotypes before vaccination are not known. The capacity of antibodies to cross-neutralize a variety of viral variants may be associated with ongoing pathology and persistent symptoms. We measured longitudinal neutralizing and cross-neutralizing antibody responses to pre- and post-SARS-CoV-2 Omicron variants in participants infected early in the COVID-19 pandemic, before widespread rollout of SARS-CoV-2 vaccines. Cross-sectional regression models adjusted for clinical covariates and longitudinal mixed-effects models were used to determine the impact of the breadth and rate of decay of neutralizing responses on the development of Long COVID symptoms, as well as Long COVID phenotypes. We identified several novel relationships between SARS-CoV-2 antibody neutralization and the presence of Long COVID symptoms. Specifically, we show that, although nAb responses to the original, infecting strain of SARS-CoV-2 were not associated with Long COVID in cross-sectional analyses, cross-neutralization ID50 levels to the Omicron BA.5 variant approximately 4 months following acute infection was independently and significantly associated with greater odds of Long COVID and with persistent gastrointestinal and neurological symptoms. Longitudinal modeling demonstrated significant associations in the overall levels and rates of decay of neutralization capacity with Long COVID phenotypes. A higher proportion of participants had antibodies capable of neutralizing Omicron BA.5 compared with BA.1 or XBB.1.5 variants. Our findings suggest that relationships between various immune responses and Long COVID are likely complex but may involve the breadth of antibody neutralization responses.

A regulatory pathway model of neuropsychological disruption in Havana syndrome.

In 2016 diplomatic personnel serving in Havana, Cuba, began reporting audible sensory phenomena paired with onset of complex and persistent neurological symptoms consistent with brain injury. The etiology of these Anomalous Health Incidents (AHI) and subsequent symptoms remains unknown. This report investigates putative exposure-symptom pathology by assembling a network model of published bio-behavioral pathways and assessing how dysregulation of such pathways might explain loss of function in these subjects using data available in the published literature. Given similarities in presentation with mild traumatic brain injury (mTBI), we used the latter as a clinically relevant means of evaluating if the neuropsychological profiles observed in Havana Syndrome Havana Syndrome might be explained at least in part by a dysregulation of neurotransmission, neuro-inflammation, or both. Automated text-mining of >9,000 publications produced a network consisting of 273 documented regulatory interactions linking 29 neuro-chemical markers with 9 neuropsychological constructs from the Brief Mood Survey, PTSD Checklist, and the Frontal Systems Behavior Scale. Analysis of information flow through this network produced a set of regulatory rules reconciling to within a 6% departure known mechanistic pathways with neuropsychological profiles in N = 6 subjects. Predicted expression of neuro-chemical markers that jointly satisfy documented pathways and observed symptom profiles display characteristically elevated IL-1B, IL-10, NGF, and norepinephrine levels in the context of depressed BDNF, GDNF, IGF1, and glutamate expression (FDR < 5%). Elevations in CRH and IL-6 were also predicted unanimously across all subjects. Furthermore, simulations of neurological regulatory dynamics reveal subjects do not appear to be "locked in" persistent illness but rather appear to be engaged in a slow recovery trajectory. This computational analysis of measured neuropsychological symptoms in Havana-based diplomats proposes that these AHI symptoms may be supported in part by disruption of known neuroimmune and neurotransmission regulatory mechanisms also associated with mTBI.

Optimizing preclinical pediatric low-grade glioma models for meaningful clinical translation.

Pediatric low-grade gliomas (pLGGs) are the most common brain tumor in young children. While they are typically associated with good overall survival, children with these central nervous system tumors often experience chronic tumor- and therapy-related morbidities. Moreover, individuals with unresectable tumors frequently have multiple recurrences and persistent neurological symptoms. Deep molecular analyses of pLGGs reveal that they are caused by genetic alterations that converge on a single mitogenic pathway (MEK/ERK), but their growth is heavily influenced by nonneoplastic cells (neurons, T cells, microglia) in their local microenvironment. The interplay between neoplastic cell MEK/ERK pathway activation and stromal cell support necessitates the use of predictive preclinical models to identify the most promising drug candidates for clinical evaluation. As part of a series of white papers focused on pLGGs, we discuss the current status of preclinical pLGG modeling, with the goal of improving clinical translation for children with these common brain tumors.

Longitudinal analysis and treatment of neuropsychiatric symptoms in post-acute sequelae of COVID-19.

Persistent neuropsychiatric symptoms following acute COVID-19 infection are frequently reported. These include anxiety, depression, difficulty concentrating, fatigue, and insomnia. The longitudinal evolution of this neuropsychiatric burden is poorly understood and clinical guidelines concerning treatment are lacking. We sought to describe the longitudinal evolution of neuropsychiatric symptoms in the post-acute sequelae of COVID-19 (PASC) syndrome and examine symptom treatment at a single center. Consecutive participants experiencing persistent neurologic symptoms after acute COVID-19 infection were recruited from October 2020 to July 2022. Data collected included COVID-19 infection history, neurological exam and review of systems, Montreal Cognitive Assessment (MoCA), and self-reported surveys concerning neuropsychiatric symptoms and treatment. Data were collected at baseline and at 1-year follow-up. A total of 106 participants (mean age 48.6, females 67%) were included in the study. At 1-year follow-up, 72.5% of participants reported at least one neuropsychiatric symptom. Over half (52.5%) of participants reported persistent fatigue. At baseline, 38.8% of all participants had met the established MoCA cut-off score of < 26 for mild cognitive impairment; this decreased to 20.0% at 1year. COVID-19 infection severity was associated with neuro-PASC symptoms (including fatigue and anxiety) at 1year. Overall, 29% of participants started at least one new medication for COVID-19-associated neuropsychiatric symptoms. Of the participants who started new medications, fatigue was the most common indication (44.8%) followed by insomnia (27.6%). Neuropsychiatric symptoms related to neuro-PASC improve over time but can persist for over a year post-recovery. Most treatment modalities targeted neuro-PASC fatigue.

Neuropsychological measures of post-COVID-19 cognitive status.

COVID-19 may result in persistent symptoms in the post-acute phase, including cognitive and neurological ones. The aim of this study is to investigate the cognitive and neurological features of patients with a confirmed diagnosis of COVID-19 evaluated in the post-acute phase through a direct neuropsychological evaluation. Individuals recovering from COVID-19 were assessed in an out-patient practice with a complete neurological evaluation and neuropsychological tests (Mini-Mental State Examination; Rey Auditory Verbal Test, Multiple Feature Target Cancellation Test, Trial Making Test, Digit Span Forward and Backward, and Frontal Assessment Battery). Pre- and post-COVID-19 global and mental health status was assessed along with the history of the acute phase of infection. Post-COVID-19 cognitive status was modeled by combining persistent self-reported COVID-related cognitive symptoms and pathologic neuropsychological tests. A total of 406 individuals (average age 54.5 ± 15.1 years, 45.1% women) were assessed on average at 97.8 ± 48.0 days since symptom onset. Persistent self-reported neurological symptoms were found in the areas of sleep (32%), attention (31%), and memory (22%). The MMSE mean score was 28.6. In total, 84 subjects (20.7%) achieved pathologic neuropsychological test results. A high prevalence of failed tests was found in digit span backward (18.7%), trail making (26.6%), and frontal assessment battery (10.9%). Cognitive status was associated with a number of factors including cardiovascular disease history, persistent fatigue, female sex, age, anxiety, and mental health stress. COVID-19 is capable of eliciting persistent measurable neurocognitive alterations particularly relevant in the areas of attention and working memory. These neurocognitive disorders have been associated with some potentially treatable factors and others that may stratify risk at an early stage.

Lower systemic nitric oxide bioactivity, cerebral hypoperfusion and accelerated cognitive decline in formerly concussed retired rugby union players.

What is the central question of this study? What are the molecular, cerebrovascular and cognitive biomarkers of retired rugby union players with concussion history? What is the main finding and its importance? Retired rugby players compared with matched controls exhibited lower systemic nitric oxide bioavailability accompanied by lower middle cerebral artery velocity and mild cognitive impairment. Retired rugby players are more susceptible to accelerated cognitive decline. Following retirement from sport, the chronic consequences of prior-recurrent contact are evident and retired rugby union players may be especially prone to accelerated cognitive decline. The present study sought to integrate molecular, cerebrovascular and cognitive biomarkers in retired rugby players with concussion history. Twenty retired rugby players aged 64±5years with three (interquartile range (IQR), 3) concussions incurred over 22 (IQR, 6) years were compared to 21 sex-, age-, cardiorespiratory fitness- and education-matched controls with no prior concussion history. Concussion symptoms and severity were assessed using the Sport Concussion Assessment Tool. Plasma/serum nitric oxide (NO) metabolites (reductive ozone-based chemiluminescence), neuron specific enolase, glial fibrillary acidic protein and neurofilament light-chain (ELISA and single molecule array) were assessed. Middle cerebral artery blood velocity (MCAv, doppler ultrasound) and reactivity to hyper/hypocapnia ( / ) were assessed. Cognition was determined using the Grooved Pegboard Test and Montreal Cognitive Assessment. Players exhibited persistent neurological symptoms of concussion (U=109(41) , P=0.007), with increased severity compared to controls (U=77(41) , P<0.001). Lower total NO bioactivity (U=135(41) , P=0.049) and lower basal MCAv were apparent in players (F2,39 =9.344, P=0.004). This was accompanied by mild cognitive impairment (P=0.020, 95% CI, -3.95 to -0.34), including impaired fine-motor coordination (U=141(41) , P=0.021). Retired rugby union players with history of multiple concussions may be characterised by impaired molecular, cerebral haemodynamic and cognitive function compared to non-concussed, non-contact controls.

Detrimental effects of COVID-19 in the brain and therapeutic options for long COVID: The role of Epstein-Barr virus and the gut-brain axis.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in a serious public health burden worldwide. In addition to respiratory, heart, and gastrointestinal symptoms, patients infected with SARS-CoV-2 experience a number of persistent neurological and psychiatric symptoms, known as long COVID or "brain fog". Studies of autopsy samples from patients who died from COVID-19 detected SARS-CoV-2 in the brain. Furthermore, increasing evidence shows that Epstein-Barr virus (EBV) reactivation after SARS-CoV-2 infection might play a role in long COVID symptoms. Moreover, alterations in the microbiome after SARS-CoV-2 infection might contribute to acute and long COVID symptoms. In this article, the author reviews the detrimental effects of COVID-19 on the brain, and the biological mechanisms (e.g., EBV reactivation, and changes in the gut, nasal, oral, or lung microbiomes) underlying long COVID. In addition, the author discusses potential therapeutic approaches based on the gut-brain axis, including plant-based diet, probiotics and prebiotics, fecal microbiota transplantation, and vagus nerve stimulation, and sigma-1 receptor agonist fluvoxamine.

Patient-reported outcomes of neurologic and neuropsychiatric symptoms in mild COVID-19: a prospective cohort study.

Various neurologic manifestations have been reported in patients with COVID-19, mostly in retrospective studies of patients admitted to hospital, but there are few data on patients with mild COVID-19. We examined the frequency and persistence of neurologic/neuropsychiatric symptoms in patients with mild COVID-19 in a 1-year prospective cohort study, as well as assessment of use of health care services and patient-reported outcomes. Participants in the Alberta HOPE COVID-19 trial (hydroxychloroquine v. placebo for 5 d), managed as outpatients, were prospectively assessed 3 months and 1 year after their positive test result. They completed detailed neurologic/neuropsychiatric symptom questionnaires, the telephone version of the Montreal Cognitive Assessment (T-MoCA), the Kessler Psychological Distress Scale (K10) and the EuroQol EQ-5D-3L (measure of quality of life). Close informants completed the Mild Behavioural Impairment Checklist (MBI-C) and the Informant Questionnaire on Cognitive Decline in the Elderly. We also tracked use of health care services and neurologic investigations. The cohort consisted of 198 participants (87 female [43.9%] median age 45 yr, interquartile range 37-54 yr). Of the 179 participants with symptom assessments, 139 (77.6%) reported at least 1 neurologic symptom, the most common being anosmia/dysgeusia (99 [55.3%]), myalgia (76 [42.5%]) and headache (75 [41.9%]). Forty patients (22.3%) reported persistent symptoms at 1 year, including confusion (20 [50.0%]), headache (21 [52.5%]), insomnia (16 [40.0%]) and depression (14 [35.0%]); 27/179 (15.1%) reported no improvement. Body mass index (BMI), a history of asthma and lack of full-time employment were associated with the presence and persistence of neurologic/neuropsychiatric symptoms; female sex was independently associated with both (presence: odds ratio [OR] adjusted for age, race, BMI, history of asthma and neuropsychiatric history 5.04, 95% confidence interval [CI] 1.58 to 16.10). Compared to participants without persistent symptoms, those with persistent symptoms had more hospital admissions and family physician visits, and worse MBI-C scores and less frequent independence for instrumental activities at 1 year (83.8% v. 97.8%, p = 0.005). Patients with any or persistent neurologic symptoms had worse psychologic distress (K10 score ≥ 20: adjusted OR 12.1, 95% CI 1.4 to 97.2) and quality of life (median EQ-5D-3L visual analogue scale rating 75 v. 90, p < 0.001); 42/84 (50.0%) had a T-MoCA score less than 18 at 3 months, as did 36 (42.9%) at 1 year. Participants who reported memory loss were more likely than those who did not report such symptoms to have informant-reported cognitive-behavioural decline (1-yr MBI-C score ≥ 6.5: adjusted OR 15.0, 95% CI 2.42 to 92.60). Neurologic/neuropsychiatric symptoms were commonly reported in survivors of mild COVID-19, and they persisted in 1 in 5 patients 1 year later. Symptoms were associated with worse participant- and informant-reported outcomes. Trial registration: ClinicalTrials.gov, no. NCT04329611.

Mild traumatic brain injury history is associated with lower brain network resilience in soldiers.

Special Operations Forces combat soldiers sustain frequent blast and blunt neurotrauma, most often classified as mild traumatic brain injuries. Exposure to repetitive mild traumatic brain injuries is associated with persistent behavioural, cognitive, emotional and neurological symptoms later in life. Identifying neurophysiological changes associated with mild traumatic brain injury exposure, in the absence of present-day symptoms, is necessary for detecting future neurological risk. Advancements in graph theory and functional MRI have offered novel ways to analyse complex whole-brain network connectivity. Our purpose was to determine how mild traumatic brain injury history, lifetime incidence and recency affected whole-brain graph theoretical outcome measures. Healthy male Special Operations Forces combat soldiers (age = 33.2 ± 4.3 years) underwent multimodal neuroimaging at a biomedical research imaging centre using 3T Siemens Prisma or Biograph MRI scanners in this cross-sectional study. Anatomical and functional scans were preprocessed. The blood-oxygen-level-dependent signal was extracted from each functional MRI time series using the Big Brain 300 atlas. Correlations between atlas regions were calculated and Fisher z-transformed to generate subject-level correlation matrices. The Brain Connectivity Toolbox was used to obtain functional network measures for global efficiency (the average inverse shortest path length), local efficiency (the average global efficiency of each node and its neighbours), and assortativity coefficient (the correlation coefficient between the degrees of all nodes on two opposite ends of a link). General linear models were fit to compare mild traumatic brain injury lifetime incidence and recency. Nonparametric ANOVAs were used for tests on non-normally distributed data. Soldiers with a history of mild traumatic brain injury had significantly lower assortativity than those who did not self-report mild traumatic brain injury (t148 = 2.44, P = 0.016). The assortativity coefficient was significantly predicted by continuous mild traumatic brain injury lifetime incidence [F1,144 = 6.51, P = 0.012]. No differences were observed between recency groups, and no global or local efficiency differences were observed between mild traumatic brain injury history and lifetime incidence groups. Brain networks with greater assortativity have more resilient, interconnected hubs, while those with lower assortativity indicate widely distributed, vulnerable hubs. Greater lifetime mild traumatic brain injury incidence predicted lower assortativity in our study sample. Less resilient brain networks may represent a lack of physiological recovery in mild traumatic brain injury patients, who otherwise demonstrate clinical recovery, more vulnerability to future brain injury and increased risk for accelerated age-related neurodegenerative changes. Future longitudinal studies should investigate whether decreased brain network resilience may be a predictor for long-term neurological dysfunction.

Persistent neurological symptoms and elevated intracranial pressures in a previously healthy host with cryptococcal meningitis

Cryptococcal meningoencephalitis can occur in both previously healthy and immunocompromised hosts. Here, we describe a 55 year-old HIV-negative male with no known prior medical problems, who presented with three months of worsening headaches, confusion, and memory changes without fever. Magnetic resonance imaging of the brain demonstrated bilateral enlargement/enhancement of the choroid plexi, with hydrocephalus, temporal and occipital horn entrapments, as well as marked periventricular transependymal cerebrospinal fluid (CSF) seepage. CSF analysis yielded a lymphocytic pleocytosis and cryptococcal antigen titer of 1:160 but sterile fungal cultures. Despite standard antifungal therapy and CSF drainage, the patient had worsening confusion and persistently elevated intracranial pressures. External ventricular drainage led to improved mental status but only with valve settings at negative values. Ventriculoperitoneal shunt placement could thus not be considered due to a requirement for drainage into the positive pressure venous system. Due to this persistent CSF inflammation and cerebral circulation obstruction, the patient required transfer to the National Institute of Health. He was treated for cryptococcal post-infectious inflammatory response syndrome with pulse-taper corticosteroid therapy, with resultant reductions in CSF pressures along with decreased protein and obstructive material, allowing successful shunt placement. After tapering of corticosteroids, the patient recovered without sequelae. This case highlights (1) the necessity to consider cryptococcal meningitis as a rare cause of neurological deterioration in the absence of fever even in apparently immunocompetent individuals and (2) the potential for obstructive phenomena from inflammatory sequelae and the prompt response to corticosteroid therapy.

Ferroptosis and multi-organ complications in COVID-19: mechanisms and potential therapies.

COVID-19 is an infectious disease caused by SARS-CoV-2, with respiratory symptoms as primary manifestations. It can progress to severe illness, leading to respiratory failure and multiple organ dysfunction. Recovered patients may experience persistent neurological, respiratory, or cardiovascular symptoms. Mitigating the multi-organ complications of COVID-19 has been highlighted as a crucial part of fighting the epidemic. Ferroptosis is a type of cell death linked to altered iron metabolism, glutathione depletion, glutathione peroxidase 4 (GPX4) inactivation, and increased oxidative stress. Cell death can prevent virus replication, but uncontrolled cell death can also harm the body. COVID-19 patients with multi-organ complications often exhibit factors related to ferroptosis, suggesting a possible connection. Ferroptosis inhibitors can resist SARS-CoV-2 infection from damaging vital organs and potentially reduce COVID-19 complications. In this paper, we outline the molecular mechanisms of ferroptosis and, based on this, discuss multi-organ complications in COVID-19, then explore the potential of ferroptosis inhibitors as a supplementary intervention for COVID-19. This paper will provide a reference for the possible treatment of SARS-CoV-2 infected disease to reduce the severity of COVID-19 and its subsequent impact.

Analysis of neurological disorders in people who had COVID-19 in Brazil

Introduction: After coronavirus infectious disease (COVID-19) infection, many patients have residual and persistent neurological symptoms. The severity and extent of these symptoms is still unknown Methods: Over 1 year, a virtual questionnaire was applied, using Google Forms, to people who had confirmed COVID-19 infection in Brazil, analyzing the neurological symptoms that persisted after infection, their duration and the relationship between them and the severity of the acute infection. Findings: Out of 1194 people who answered the questionnaire, 947 (79.5%) were eligible for symptoms analysis. Among these patients, 6.8% needed hospitalization (39.2% of them required oxygen therapy and 26.6% needed orotracheal intubation). The incidence of symptoms were headache (65,8%), smell disfunction (59,6%), taste disfunction (51,8%), muscle weakness (51,8%), memory impairment (42,8%), dizziness (37,7%), mental confusion (22,4%), difficulty walking (20%), and visual changes (9,1%). In most cases, symptoms improved within a month, despite a significant percentage of patients persisting with symptoms for several months. However, memory impairment was significantly more persistent, with 39.7% of the patients having it for more than a year. And this was frequent even in those who did not need hospitalization in the acute phase of the disease, with 24.2% of all nonhospitalized patients having this complain for more than 6 months. Interpretation: Many COVID-19 patients have persistent neurological symptoms after the acute infection has ended. In some cases the symptoms can last a long time. Despite being a self-reported study, it is very likely that there is a significant functional impact in this population and it is clear that we need to research effective therapeutic strategies for these conditions.