Neurological Manifestations Research Articles

Early-life immune activation is a vulnerability factor for adult epileptogenesis in neurofibromatosis type 1 in male mice

IntroductionPatients with Neurofibromatosis type 1 (NF1), the most common neurocutaneous disorder, can develop several neurological manifestations that include cognitive impairments and epilepsy over their lifetime. It is unclear why certain patients with NF1 develop these conditions while others do not. Early-life immune activation promotes later-life seizure susceptibility, neurocognitive impairments, and leads to spontaneous seizures in some animal models of neurodevelopmental disorders, but the central nervous system immune profile and the enduring consequences of early-life immune activation on the developmental trajectory of the brain in NF1 have not yet been explored. We tested the hypothesis that early-life immune activation promotes the development of spatial memory impairments and epileptogenesis in a mouse model of NF1.MethodsMale wild-type (WT) and Nf1+/− mice received systemic lipopolysaccharide (LPS) or saline at post-natal day 10 and were assessed in adulthood for learning and memory deficits in the Barnes maze and underwent EEG recordings to look for spontaneous epileptiform abnormalities and susceptibility to challenge with pentylenetetrazole (PTZ).ResultsWhereas early-life immune activation by a single injection of LPS acutely elicited a comparable brain cytokine signature in WT and Nf1+/− mice, it promoted spontaneous seizure activity in adulthood only in the Nf1+/− mice. Early-life immune activation affected susceptibility to PTZ-induced seizures similarly in both WT and Nf1+/−mice. There was no effect on spatial learning and memory regardless of mouse genotype.DiscussionOur findings suggest second-hit environmental events such as early-life immune activation may promote epileptogenesis in the Nf1+/− mouse and may be a risk-factor for NF1-associated epilepsy.

Exploring clinical variability in gelsolin amyloidosis: Brazilian family case study with confocal microscopy.

Genetic mutations or inflammatory, degenerative, or neoplastic conditions can trigger amyloidosis. Hereditary gelsolin amyloidosis is a genetic disorder primarily marked by amyloid fibrils composed of misfolded gelsolin fragments. We present three sisters with AGel amyloidosis, illustrating its clinical diversity. Patient 1, a 51-year-old, had bilateral ptosis, ocular discomfort, and dry eye syndrome due to cranial nerve involvement. Patient 2, a 53-year-old, experienced progressive bilateral visual impairment. Patient 3, a 50-year-old, exhibited right eye ectropion. Genetic analysis, with the identical mutation, heterozygous c.640G > A (p.Asp214Asn) mutation, confirmed AGel amyloidosis diagnoses, with common findings including lattice corneal amyloidosis, reduced corneal sensitivity, and recurrent corneal erosions. Neurological manifestations included ataxia and peripheral neuropathy, with skin abnormalities observed in patient 1. Ocular involvement severity and distribution varied among patients. Common ocular and neurological manifestations validated AGel amyloidosis diagnoses, reinforcing its hereditary basis. Neurological symptoms highlighted the disorder's impact on various organ systems, while skin abnormalities contributed to ocular discomfort. Variable ocular involvement emphasized the disorder's heterogeneity. These patients emphasize hereditary gelsolin amyloidosis's clinical diversity and suggest potential environmental influences on disease expression. Genetic confirmation and confocal microscopy findings reaffirm the genetic basis while raising questions about assessing systemic disease severity, necessitating further investigation in larger cohorts. Ophthalmologists' specialized care is crucial for managing ocular symptoms, given the absence of a universal cure.

Correlation between early computed tomography findings and neurological outcome in pediatric traumatic brain injury patients.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in children. Head computed tomography (CT) is frequently utilized for evaluating trauma-related characteristics, selecting treatment options, and monitoring complications in the early stages. This study assessed the relationship between cranial CT findings and early and late neurological outcomes in pediatric TBI patients admitted to the pediatric intensive care unit (PICU). The study included children aged 1month to 18years who were admitted to the PICU due to TBI between 2014 and 2020. Sociodemographic data, clinical characteristics, and cranial CT findings were analyzed. Patients were categorized based on their Glasgow Coma Scale (GCS) score. Of the 129 patients, 83 (64%) were male, and 46 (36%) were female, with a mean age of 6.8years. Falls (n = 51, 39.5%) and in-vehicle traffic accidents (n = 35, 27.1%) were the most common trauma types observed. Normal brain imaging findings were found in 62.7% of the patients, while 37.3% exhibited intracranial pathology. Hemorrhage was the most frequent CT finding. Severe TBI (n = 26, p = 0.032) and mortality (n = 9, p = 0.017) were more prevalent in traffic accidents. The overall mortality rate in the study population was 10.1%. In children with TBI, cranial CT imaging serves as an essential initial method for patients with neurological manifestations. Particularly, a GCS score of ≤ 8, multiple hemorrhages, diffuse cerebral edema, and intraventricular bleeding are associated with sequelae and mortality.

Neurological diagnoses in hospitalized COVID-19 patients associated with adverse outcomes: A multinational cohort study.

Few studies examining the patient outcomes of concurrent neurological manifestations during acute COVID-19 leveraged multinational cohorts of adults and children or distinguished between central and peripheral nervous system (CNS vs. PNS) involvement. Using a federated multinational network in which local clinicians and informatics experts curated the electronic health records data, we evaluated the risk of prolonged hospitalization and mortality in hospitalized COVID-19 patients from 21 healthcare systems across 7 countries. For adults, we used a federated learning approach whereby we ran Cox proportional hazard models locally at each healthcare system and performed a meta-analysis on the aggregated results to estimate the overall risk of adverse outcomes across our geographically diverse populations. For children, we reported descriptive statistics separately due to their low frequency of neurological involvement and poor outcomes. Among the 106,229 hospitalized COVID-19 patients (104,031 patients ≥18 years; 2,198 patients <18 years, January 2020-October 2021), 15,101 (14%) had at least one CNS diagnosis, while 2,788 (3%) had at least one PNS diagnosis. After controlling for demographics and pre-existing conditions, adults with CNS involvement had longer hospital stay (11 versus 6 days) and greater risk of (Hazard Ratio = 1.78) and faster time to death (12 versus 24 days) than patients with no neurological condition (NNC) during acute COVID-19 hospitalization. Adults with PNS involvement also had longer hospital stay but lower risk of mortality than the NNC group. Although children had a low frequency of neurological involvement during COVID-19 hospitalization, a substantially higher proportion of children with CNS involvement died compared to those with NNC (6% vs 1%). Overall, patients with concurrent CNS manifestation during acute COVID-19 hospitalization faced greater risks for adverse clinical outcomes than patients without any neurological diagnosis. Our global informatics framework using a federated approach (versus a centralized data collection approach) has utility for clinical discovery beyond COVID-19.

Fabry disease: a rare disorder calling for personalized medicine.

Fabry Disease (FD) is a genetic disease caused by a deficiency in the activity of lysosomal galactosidase A (α-GalA), an enzyme responsible for the catabolism of globotriaosylceramide (Gb3). Since lysosomes are present throughout the body and play a crucial role in catabolism and recycling of cytosolic compounds, FD can affect multiple organs and result in various symptoms, including renal, cardiovascular, neurological, cutaneous, and ophthalmic manifestations. Due to the nonspecific symptoms and the rarity of FD, it is often diagnosed late in life. However, introducing targeted therapies such as enzyme replacement therapy (ERT) and chaperone therapy has significantly improved FD's natural history and prognosis by restoring α-GalA enzyme activity. Despite the advancements, there are limitations to the currently available therapies, which has prompted research into new potential treatments for FD, including alternative forms of enzyme replacement therapy, substrate reduction therapy, mRNA therapy, and genetic therapy. In this review, we analyze the epidemiology, pathophysiology, and treatment of FD, with particular emphasis on promising therapeutic opportunities that could shift the treatment of this rare disease from a standardized to a personalized approach soon.

Molecular Role of HIV-1 Human Receptors (CCL5–CCR5 Axis) in neuroAIDS: A Systematic Review

Chronic HIV-1 infection can cause neurological illness, also known as HIV-associated neurocognitive disorders (HAND). The elevated level of pro-inflammatory cytokines and chemokines, such as C-C Chemokine Ligand 5 (CCL5/RANTES), is one of the ways of causing HIV-1-mediated neuroinflammation. C-C Chemokine Receptor 5 (CCR5) is the main coreceptor for viral entry into host cells and for mediating induction of CCL5/RANTES. CCR5 and CCL5 are part of a correlated axis of immune pathways used for effective protection against the HIV-1 virus. The purpose of this paper was to review the literary knowledge about the immunopathological relationship between this immune complex and neuroAIDS. A systematic review of the literature was conducted based on the selection and search of articles, available in English, Spanish, or Portuguese in the time frame of 1990–2022, of primary and secondary types in the PUBMED, Science Direct, SciELO, and LILACS databases through descriptors (MeSH) together with “AND”: “CCR5”; “CCL5”; “neurological manifestations”; or “HIV”. The methodological quality of the articles was assessed using the JBI Checklists and the PRISMA 2020 writing guidelines were followed. A total of 36 articles were included in the final composition of the review. The main cells of the CNS affected by neuroAIDS are: neurons; microglia; astrocytes; and oligodendrocytes. Molecular devices and their associations with cellular injuries have been described from the entry of the virus into the host’s CNS cell to the generation of mental disorders. Furthermore, divergent results were found about the levels of CCL5/RANTES secretion and the generation of immunopathogenesis, while all condensed research for CCR5 indicated that elevation of this receptor causes more neurodegenerative manifestations. Therefore, new therapeutic and interventional strategies can be conditioned on the immunological direction proposed in this review for the disease.

Mapping ACE2 and TMPRSS2 co-expression in human brain tissue: implications for SARS-CoV-2 neurological manifestations.

The Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily targets respiratory cells, but emerging evidence shows neurological involvement, with the virus directly affecting neurons and glia. SARS-CoV-2 entry into a target cell requires co-expression of ACE2 (Angiotensin-converting enzyme-2) and TMPRSS2 (Trans membrane serine protease-2). Relevant literature on human neurological tissue is sparse and mostly focused on the olfactory areas. This prompted our study to map brain-wide expression of these entry proteins and assess age-related changes. The normal brain tissue samples were collected from cerebral cortex, hippocampus, basal ganglia, thalamus, hypothalamus, brain stem and cerebellum; and were divided into two groups - up to 40 years (n = 10) and above 40 years (n = 10). ACE2 and TMPRSS2 gene expression analysis was done using qRT-PCR and protein co-expression was seen by immunofluorescence. The ACE2 and TMPRSS2 gene expression was observed to be highest in hypothalamus and thalamus regions, respectively. Immunoreactivity for both ACE-2 and TMPRSS2 was observed in all examined brain regions, confirming the presence of these viral entry receptors. Co-localisation was maximum in hypothalamus. Our study did not find any trend related to different age groups. The expression of both these viral entry receptors suggests that normal human brain is susceptibility to SARS-CoV-2, perhaps which could be related to the cognitive and neurological impairment that occur in patients.

Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG.

ALG3-CDG is a rare congenital disorder of glycosylation (CDG) with a clinical phenotype that includes neurological manifestations, transaminitis, and frequent infections. The ALG3 enzyme catalyzes the first step of endoplasmic reticulum (ER) luminal glycan extension by adding mannose from Dol-P-Man to Dol-PP-Man5GlcNAc2 (Man5) forming Dol-PP-Man6. Such glycan extension is the first and fastest cellular response to ER stress, which is deficient in ALG3-CDG. In this study, we provide evidence that the unfolded protein response (UPR) and ER-associated degradation activities are increased in ALG3-CDG patient-derived cultured skin fibroblasts and there is constitutive activation of UPR mediated by the IRE1-α pathway. In addition, we show that N-linked Man3-4 glycans are increased in cellular glycoproteins and secreted plasma glycoproteins with hepatic or non-hepatic origin. We found that like other CDGs such as ALG1- or PMM2-CDG, in transferrin, the assembling intermediate Man5 in ALG3-CDG, are likely further processed into a distinct glycan, NeuAc1Gal1GlcNAc1Man3GlcNAc2, probably by Golgi mannosidases and glycosyltransferases. We predict it to be a mono-antennary glycan with the same molecular weight as the truncated glycan described in MGAT2-CDG. In summary, this study elucidates multiple previously unrecognized biochemical consequences of the glycan extension deficiency in ALG3-CDG which will have important implications in the pathogenesis of CDG.

Characterization Profiles of ANCA-associated Vasculitis with Neurological Manifestations (P7-14.007)

Characterization Profiles of ANCA-associated Vasculitis with Neurological Manifestations (P7-14.007)

Metastatic Acute Myeloid Leukemia Presenting as Foot Drop: A Rare Neurological Manifestation (P11-11.018)

Metastatic Acute Myeloid Leukemia Presenting as Foot Drop: A Rare Neurological Manifestation (P11-11.018)

Late-onset Parry-Romberg Syndrome with Atypical Neurological Manifestations: A Case Report (P11-11.015)

Late-onset Parry-Romberg Syndrome with Atypical Neurological Manifestations: A Case Report (P11-11.015)

The Neurological Manifestations of COVID-19: Meta-analysis of the Most Extensive Review of Published Case Reports (P11-13.008)

The Neurological Manifestations of COVID-19: Meta-analysis of the Most Extensive Review of Published Case Reports (P11-13.008)

Metformin Inhibits Zika Virus Infection in Trophoblast Cell Line.

Zika virus (ZIKV) infections have been associated with severe clinical outcomes, which may include neurological manifestations, especially in newborns with intrauterine infection. However, licensed vaccines and specific antiviral agents are not yet available. Therefore, a safe and low-cost therapy is required, especially for pregnant women. In this regard, metformin, an FDA-approved drug used to treat gestational diabetes, has previously exhibited an anti-ZIKA effect in vitro in HUVEC cells by activating AMPK. In this study, we evaluated metformin treatment during ZIKV infection in vitro in a JEG3-permissive trophoblast cell line. Our results demonstrate that metformin affects viral replication and protein synthesis and reverses cytoskeletal changes promoted by ZIKV infection. In addition, it reduces lipid droplet formation, which is associated with lipogenic activation of infection. Taken together, our results indicate that metformin has potential as an antiviral agent against ZIKV infection in vitro in trophoblast cells.

Spinal schistosomiasis mimickingspinal tumour: a case report

Introduction and importance: Schistosomiasis, a parasitic disease, is caused by blood flukes from the schistosoma genus. Neuroschistosomiasis is the most severe form of schistosomiasis, which occurs when the host’s brain and spinal cord react to the deposition of eggs, leading to neurological symptoms. Neuroschistosomiasis causes various signs and symptoms, such as myelopathy, radiculopathy, and elevated intracranial pressure. Case presentation: A 12-year-old child from Ethiopia who presented with progressive weakness in his lower extremities that has been ongoing for 2 months. Alongside the weakness, the patient also experienced tingling sensations and numbness in his lower extremities. Additionally, he had bladder and bowel incontinence. Spinal MRI showed signs suggestive of myxopapillary ependymoma, but the histopathology result showed schistosomiasis. Postoperatively, the patient had a slight improvement in terms of lower extremity weakness (flickering of the digits). However, there was no improvement in his continence ability. Clinical discussion: The most common neurological manifestation of Schistosoma mansoni infection is myelopathy, which includes subacute myeloradiculopathy and acute transverse myelitis. The cauda equina and conus medullaris are the areas most frequently affected. Conclusion: When spinal schistosomiasis presents itself as a mimicking spinal tumour, it poses a complex clinical challenge that necessitates a comprehensive interdisciplinary approach to ensure accurate diagnosis and effective treatment. It is imperative for healthcare practitioners to enhance their knowledge and awareness of this uncommon parasitic infection, particularly in regions where it is prevalent.

SCA 15 presenting with parkinsonism–dystonia, tremor, and psychosis in an Indian woman

Abstract Spinocerebellar ataxias (SCAs) represent a diverse group of hereditary and progressive neurological disorders characterized by their onset in adulthood and commonly exhibit autosomal dominant inheritance. These disorders typically involve multiple brain regions, including the cerebellum, spinal cord, basal ganglia, brainstem, and cortical areas, leading to varied and heterogeneous clinical presentations. In particular, SCA 15 is recognized as an adult-onset, slowly progressive cerebellar syndrome, often accompanied by various other neurological manifestations. In this report, we present a novel clinical phenotype of parkinsonism–dystonia syndrome co-occurring with cerebellar features in a genetically confirmed case of SCA 15.

Neurocysticercosis in a Nigerian woman -missed diagnosis of a neglected disease and surgical management

Neurocysticercosis is a rarely diagnosed but significant clinical problem from infestation with taenia solium. It occurs as a result of ingestion of infested pork and the mode of transmission is usually feco-oral. It is commonly associated with non-specific neurologic manifestations expected of intracranial space-occupying lesions with its most common neurological presentation being seizures. However, its diagnosis without seizure is rarely reported. We report a recent experience in this regard and outcome of this disease which was inadvertently managed surgically. A good history and high index of suspicion especially in developing and low socioeconomic region is helpful for diagnosis in the presence of appropriate radiological findings. Prognosis is good when treatment is tailored to well selected cases. Treatment options include medical with or without surgical removal of encapsulated cyst. A high index of suspicion will be helpful in making appropriate diagnosis and proper management of this disease.

COVID-19 Beyond the Lungs: Neuropsychiatric Symptoms and EEG Correlations

Abstract: COVID-19, previously considered a mere respiratory illness affecting predominantly the adult age, is today acknowledged as the cause of a wide spectrum of multisystemic signs and symptoms, ranging from mild to severe degrees, including neurological manifestations. Even if less frequently than adults, pediatric patients may also develop severe COVID-19 and present with peculiar clinical pictures, including multi-system inflammatory syndrome (MIS-C) and neuropsychiatric manifestations. Mounting evidence is available on the potential pathogenic mechanisms underpinning the nervous system involvement and on the Post-COVID19 sequelae. However, little is known about EEG changes that may come along with them, particularly in the pediatric age. Herein, we briefly overview the neuropsychiatric COVID-19-related features in pediatric patients and the reported potential EEG correlates. Further research may help unravel new insights and provide new biomarkers regarding diagnosis, prognosis, and treatment options for post-- COVID-19 neuro-cognitive disorders.

Cardiac Rhythm Aberrations in Subacute Sclerosing Panencephalitis: Insights From Heart Rate Variability Analysis.

Subacute sclerosing panencephalitis (SSPE) is a fatal neurological disorder resulting from persistent measles virus infection within the brain. Although neurological manifestations have been well-documented, the impact of SSPE on cardiac autonomic function, assessed through heart rate variability (HRV), remains understudied. In this prospective single-center study conducted from January 2022 to March 2023 in Southern India, 30 consecutive SSPE patients and age- and sex-matched controls underwent electrocardiogram recordings for HRV analysis. Various HRV parameters were assessed, including time-domain metrics (SD of normal-to-normal intervals, root mean square of successive differences between normal heartbeats, percentage of successive normal interbeat intervals greater than 50 msec), SD1 and SD2 for Poincaré plot analysis, and frequency-domain metrics (low frequency %, high frequency %, low frequency:high frequency ratio). In the study, SSPE patients exhibited markedly reduced HRV. Specifically, SD of normal-to-normal intervals (P = 0.003), percentage of successive normal interbeat intervals greater than 50 msec (P = 0.03), and SD2 (P = 0.0016) were significantly lower compared with controls. Frequency-domain analysis did not reveal significant distinctions. Correlation analysis demonstrated a negative relationship between percentage of successive normal interbeat intervals greater than 50 msec and SSPE severity (r = -0.37, P = 0.042). Heart rate variability did not significantly differ between SSPE stages or with clinical variables. The interbeat interval range showed a narrower distribution in SSPE subjects. Our study highlights the clinical relevance of HRV analysis in SSPE and autonomic dysfunction throughout the disease course underscoring its importance in SSPE. This investigation provides valuable insights into cardiac autonomic dysfunction probably because of affliction of the central autonomic networks caused by the disease process and may be a contributing factor to mortality in SSPE.

Multifaceted superoxide dismutase 1 expression in amyotrophic lateral sclerosis patients: a rare occurrence?

Abstract Amyotrophic lateral sclerosis (ALS) is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex, brainstem, and spinal cord. While the typical clinical phenotype of ALS involves both upper and lower motor neurons, human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions, expanding the phenotype of ALS. Although superoxide dismutase 1 (SODI) mutations represent a minority of ALS cases, the SODI gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies. Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SODI (SODI-ALS), no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation. In this narrative review, we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS. The multifaceted expression of SODI could deepen our understanding of the pathogenic mechanisms, pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.

COVID 19- Biochemical and Other Mechanisms associated with Neuropathy and Stroke.

The Coronavirus (SARS-C0V-2) caused COVID 19 disease, commencing from China in December 2019 and soon in 2020 its neurological manifestations were noted. The viral spike (S) protein binding with host cell receptor angiotensin-converting enzyme 2 (ACE2) with assistance of membrane fusion protease (TMPRSS) caused viral entry in host cells. We searched 47 articles using PubMed from January 2021 to January 2023. The initial pooling of virus in nasal mucosa was followed by spread to respiratory and other tissues. This review highlights the neuropathy and stroke mechanisms. The role of receptors, enzymes, proteins and genes in neuropathological mechanisms are highlighted. Vascular endothelial effects, choroid plexus and Blood Brain Barrier disruptions were noted. The epigenetic neuropathological mechanisms need to be explored further to help in designing new therapeutic modalities. The post vaccination neurological manifestations as well as the post COVID effects both need further attention to promptly diagnose and start timely treatment.