[Clinical features of acyclovir encephalopathy without acute kidney injury].

INTRODUCTION: Few reports have described acyclovir (ACV) encephalopathy without acute kidney injury (AKI). OBJECTIVE: This study clarified the clinical features of ACV encephalopathy without AKI compared to that with AKI. METHODS: Creatinine (Cre) levels were measured on admission. After admission, Cre was measured in a timely manner for the first seven hospital days. The minimum Cre level in these measurements was then determined. ACV encephalopathy was defined when two criteria were met: 1) neurological symptoms appeared after valacyclovir (VACV) administration, and 2) neurological symptoms improved after VACV discontinuation. AKI was defined when the Cre level on admission was >1.5 times higher than the minimum Cre level. The subjects were divided into AKI and non-AKI groups based on these findings. RESULTS: Eighteen patients had ACV encephalopathy (5 males, mean age 81.3±5.5 years old). All patients were prescribed VACV 3,000 mg/day. The minimum Cre was 1.93±1.76 mg/dL. AKI occurred in 10 (56.6%) patients. VACV was discontinued in all patients, and emergency hemodialysis treatment was administered in 10 (55.6%) patients. All patients recovered. Compared to the AKI group, the non-AKI group had a lower history of taking a Ca-blocker (33.3% vs 80.0%, p=0.092), a lower rate of emergency dialysis (16.9% vs 70.0%, p=0.059) and a longer time to clinical improvement (3.67±1.86 vs 2.20±0.63 days, p=0.073). CONCLUSION: ACV encephalopathy without AKI is characterized by a low rate of emergency dialysis, which may be linked to a prolonged duration of symptoms.

Superoxide dismutase nanozymes: current status and future perspectives on brain disease treatment and diagnosis.

Superoxide dismutase (SOD) is an important metalloenzyme that catalyzes the dismutation of superoxide radicals (O2˙-) into hydrogen peroxide (H2O2) and oxygen (O2). However, the clinical application of SOD is severely limited due to its structural instability and high cost. Compared with natural enzymes, nanomaterials with enzyme-like activity, nanoenzymes, are more stable, economical and easy to modify and their activity can be adjusted. Certain nanozymes that exhibit SOD-like activity have been created and shown to help prevent illnesses brought about by oxidative stress. These SOD-like nanozymes offer an important solution to the problems associated with the clinical application of SOD. In this review, we briefly introduce neurodegenerative diseases, present the research progress of SOD-like nanoenzymes in the diagnosis and treatment of brain diseases, review their mechanism of action in the treatment and diagnosis of brain diseases, and discuss the shortcomings of the current research with a view to providing a reference for future research. We expect more highly active SOD-like nanoenzymes to be developed with a wide range of applications in the diagnosis and treatment of brain diseases.

The incidence and predictors of antibiotic-associated encephalopathy: a multicenter hospital-based study.

This study aimed to evaluate the incidence and likelihood of antibiotic-associated encephalopathy (AAE), comparing rates among the classes of antibiotics in monotherapy or in combination therapy. We also investigated the associations between the incidence of AAE and the glomerular filtration rate (GFR) and electroencephalogram features. Consecutive admissions that used any kind of antibiotics to treat infectious diseases were identified from six hospitals. We classified antibiotics according to three distinct pathophysiologic mechanisms and clinical subtypes. We searched for the incidence of AAE as the primary outcome. A total of 97,433 admission cases among 56,038 patients was identified. Cases that received type 1 antibiotics had significantly more frequent AAE compared to those that received type 2 antibiotics (adjusted odds ratio [OR], 2.62; 95% confidence interval [CI] 1.15-5.95; P = 0.021). Combined use of type 1 + 2 antibiotics was associated with a significantly higher incidence of AAE compared to the use of type 2 antibiotics alone (adjusted OR, 3.44; 95% CI 1.49-7.93; P = 0.004). Groups with GFR < 60 mL/min/1.73 m2 had significantly higher incidence rates of AAE compared to those with GFRs ≥ 90 mL/min/1.73 m2 among cases that received type 1 + 2 antibiotics. Detection of spike-and-wave or sharp-and-wave patterns on electroencephalogram was significantly more common in the combination therapy group. Combination use of antibiotics was associated with a higher incidence of AAE compared to monotherapy. The incidence of AAE significantly increased as renal function decreased, and epileptiform discharges were more likely to be detected in cases receiving combined antibiotics.

Exosome-Based Macromolecular neurotherapeutic drug delivery approaches in overcoming the Blood-Brain barrier for treating brain disorders.

Delivering drugs to the brain is a complex challenge in medical research, particularly for disorders like Alzheimer's and Parkinson's. The blood-brain barrier restricts the entry of many therapeutic molecules, hindering their effectiveness. Nanoparticles, a potential solution, face issues like toxicity and limited approvals. A new avenue explores the use of small extracellular vesicles (sEVs), i.e., exosomes, as natural carriers for drug delivery. sEVs, tiny structures below 150 nm, show promise due to their minimal immune response and ability to precisely deliver drugs. This review focuses on the potential of sEVs-based drug delivery systems for treating neurological disorders, brain cancers, and other brain-related issues. Notably, bioengineered sEVs-carrying therapeutic compounds exhibit promise in early studies. The unique features of sEVs, such as their small size and natural properties, position them as candidates to overcome challenges in drug delivery to the brain. Ongoing clinical trials and research into sEVs behavior within the body further highlight their potential for revolutionizing drug delivery and addressing complex brain conditions.

Propofol and Dexmedetomidine Ameliorate Endotoxemia-Associated Encephalopathy via Inhibiting Ferroptosis.

Background: Sepsis is recognized as a multiorgan and systemic damage caused by dysregulated host response to infection. Its acute systemic inflammatory response highly resembles that of lipopolysaccharide (LPS)-induced endotoxemia. Propofol and dexmedetomidine are two commonly used sedatives for mechanical ventilation in critically ill patients and have been reported to alleviate cognitive impairment in many diseases. In this study, we aimed to explore and compare the effects of propofol and dexmedetomidine on the encephalopathy induced by endotoxemia and to investigate whether ferroptosis is involved, finally providing experimental evidence for multi-drug combination in septic sedation. Methods: A total of 218 C57BL/6J male mice (20-25 g, 6-8 weeks) were used. Morris water maze (MWM) tests were performed to evaluate whether propofol and dexmedetomidine attenuated LPS-induced cognitive deficits. Brain injury was evaluated using Nissl and Fluoro-Jade C (FJC) staining. Neuroinflammation was assessed by dihydroethidium (DHE) and DCFH-DA staining and by measuring the levels of three cytokines. The number of Iba1+ and GFAP+ cells was used to detect the activation of microglia and astrocytes. To explore the involvement of ferroptosis, the levels of ptgs2 and chac1; the content of iron, malondialdehyde (MDA), and glutathione (GSH); and the expression of ferroptosis-related proteins were investigated. Conclusion: The single use of propofol and dexmedetomidine mitigated LPS-induced cognitive impairment, while the combination showed poor performance. In alleviating endotoxemic neural loss and degeneration, the united sedative group exhibited the most potent capability. Both propofol and dexmedetomidine inhibited neuroinflammation, while propofol's effect was slightly weaker. All sedative groups reduced the neural apoptosis, inhibited the activation of microglia and astrocytes, and relieved neurologic ferroptosis. The combined group was most prominent in combating genetic and biochemical alterations of ferroptosis. Fpn1 may be at the core of endotoxemia-related ferroptosis activation.

Molecular Dynamic Simulations to Determine Individualized Therapy: Tetrabenazine for the GNAO1 Encephalopathy E246K Variant.

INTRODUCTION: GNAO1 encephalopathy is characterized by severe hypotonia, psychomotor retardation, epilepsy, and movement disorders. Genetic variations in GNAO1 have been linked to neurological symptoms including movement disorders like dystonia. The correlation between the E246K mutation in the Gα subunit and aberrant signal transduction of G proteins has been established but no data are reported regarding the efficacy of medical treatment with tetrabenazine. METHODS: Molecular modeling studies were performed to elucidate the molecular mechanisms underlying this mutation. We developed drug efficacy models using molecular dynamic simulations that replicated the behavior of wild-type and mutated proteins in the presence or absence of ligands. RESULTS AND DISCUSSION: We demonstrated that the absence of the mutation leads to normal signal transduction upon receptor activation by the endogenous ligand, but not in the presence of tetrabenazine. In contrast, the presence of the mutation resulted in abnormal signal transduction in the presence of the endogenous ligand, which was corrected by the drug tetrabenazine. Tetrabenazine was identified as a promising therapeutic option for pediatric patients suffering from encephalopathy due to an E246K mutation in the GNAO1 gene validated through molecular dynamics. This is a potential first example of the use of this technique in a rare neurological pediatric disease.

Therapeutic potential of saffron in brain disorders: From bench to bedside.

Saffron is a spice derived from the flower of Crocus sativus L., which has been used for centuries as a coloring and flavoring agent, as well as a source of medicinal compounds. Saffron contains various bioactive constituents, such as crocin, crocetin, safranal, picrocrocin, and kaempferol, that have shown potential benefits for human health. Among them, crocin is the most abundant and characteristic constituent of saffron, responsible for its bright red color and antioxidant properties. One of the most promising applications of saffron and its constituents is in the prevention and treatment of neurological disorders, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, and other brain disorders. Saffron and its constituents have been reported to exert neuroprotective effects through various mechanisms, such as modulating neurotransmitters, enhancing neurogenesis, reducing neuroinflammation, regulating oxidative stress, activating the Nrf2 signaling pathway, and modulating epigenetic factors. Several clinical and preclinical studies have demonstrated the efficacy and safety of saffron and its constituents in improving cognitive function, mood, and other neurological outcomes. In this review, we summarize the current evidence on the therapeutic potential of saffron and its constituents in neurological disorders, from bench to bedside. We also discuss the challenges and future directions for the development of saffron-based therapies for brain health.

Early IGF-1 receptor inhibition in mice mimics preterm human brain disorders and reveals a therapeutic target.

Besides recent advances in neonatal care, preterm newborns still develop sex-biased behavioral alterations. Preterms fail to receive placental insulin-like growth factor-1 (IGF-1), a major fetal growth hormone in utero, and low IGF-1 serum levels correlate with preterm poor neurodevelopmental outcomes. Here, we mimicked IGF-1 deficiency of preterm newborns in mice by perinatal administration of an IGF-1 receptor antagonist. This resulted in sex-biased brain microstructural, functional, and behavioral alterations, resembling those of ex-preterm children, which we characterized performing parallel mouse/human behavioral tests. Pharmacological enhancement of GABAergic tonic inhibition by the U.S. Food and Drug Administration-approved drug ganaxolone rescued functional/behavioral alterations in mice. Establishing an unprecedented mouse model of prematurity, our work dissects the mechanisms at the core of abnormal behaviors and identifies a readily translatable therapeutic strategy for preterm brain disorders.

Real-world comparison of terlipressin vs. octreotide as an adjuvant treatment in the management of variceal bleeding.

Variceal bleeding is a major complication and the leading cause of death in patients with cirrhosis and portal hypertension. This study aims to compare the efficacy and safety of terlipressin vs octreotide as an adjuvant to endoscopic management of patients with esophageal variceal bleeding in a real-time scenario. We reviewed the medical records of patients with esophageal variceal bleeding from January 2005 to December 2020 at our tertiary care Aga Khan University Hospital. Mortality was assessed after 6 weeks. A total of 842 patients with variceal bleed were evaluated. 624 patients (74.1%) and 218 patients (25.9%) received Terlipressin and Octreotide respectively. On multiple regression analysis, cardiac events during hospital stay (OR: 11.22), presence of Porto-systemic encephalopathy (OR: 3.79), and elevated bilirubin levels at the time of presentation were found to be independent risk factors for increased six weeks mortality. Moreover, cardiac events during hospital stay (OR: 3.26), Porto-systemic encephalopathy at presentation (OR: 3.06), and octreotide administration (OR: 1.80) were identified as independent risk factors for increased length of hospital stay. Terlipressin and Octreotide have similar outcomes in terms of control of bleeding, hospital stay, mortality, and side effects when used as adjuvant therapy for the management of variceal bleeding.

Hyperammonemic encephalopathy induced by valproic acid.

Valproate (VPA) is broad-spectrum antiepileptic drug. Several adverse reactions including hepatotoxicity, fetal risk and pancreatitis are well known and labelled as boxed warnings in the USA. One adverse reaction that is less well known but clinically significant for its severe morbidity is hyperammonemic encephalopathy. We present a case of woman with hyperammonemic encephalopathy following the initiation of VPA therapy; she had a favourable outcome with discontinuation of the drug and prompt treatment with lactulose and L-carnitine.

L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study.

GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes.

Hispolon inhibits neuronal ferroptosis by promoting the expression of Nrf-2.

Research has shown that neuronal ferroptosis is associated with various central nervous system diseases, including Parkinson's disease, acute brain injury, and spinal cord injury. Inhibiting neuronal ferroptosis can greatly alleviate the progression of these diseases. However, there is currently a lack of effective drugs to inhibit neuronal ferroptosis. In this study, we pretreated neuronal cells with Hispolon and subsequently induced a neuronal ferroptosis model using Erastin. We further assessed the changes in the protein expression levels of SLC7A11, GPX4, ACSL4, Nrf-2, and HO-1 using Western blot and immunofluorescence techniques. Additionally, we measured the intracellular levels of Fe2+, GSH, and MDA using relevant assay kits. The research findings revealed that after Hispolon treatment, the expression of the pro-ferroptosis protein ACSL4 decreased, while the expression of the ferroptosis-regulating proteins GPX4 and SLC7A11 increased. Moreover, the use of an Nrf-2-specific inhibitor was able to reverse the effects of Hispolon as mentioned above. In this study, we discovered that Hispolon can promote the expression of Nrf-2 and inhibit the occurrence of neuronal ferroptosis induced by Erastin.

[A case of Hashimoto's encephalopathy with acute onset of psychiatric symptoms and diffuse deep white matter lesions on brain MRI].

A 51-year-old man developed acute disturbances in consciousness and psychiatric symptoms one month prior to admission. He was referred and admitted to the Department of Psychiatry of our hospital and transferred to the neurology department because diffuse white matter lesions were found on his brain during MRI. 123I-IMP-SPECT showed extensive cerebral hypoperfusion mainly in the frontal lobes. Anti-Tg, anti-TPO, and anti-NAE antibodies were positive. These findings led to a diagnosis of Hashimoto's encephalopathy. The patient responded to steroid pulse therapy, high-dose steroid therapy, and intravenous immunoglobulin therapy, showing improvement in symptoms and imaging findings. Hashimoto's encephalopathy often presents with MRI findings similar to those of limbic encephalitis, when the patient presents with acute consciousness disturbance and psychiatric symptoms. However, this case showed diffuse white matter lesions, which may be clinically important for the differential diagnosis.

Nanotechnology for enhanced nose-to-brain drug delivery in treating neurological diseases.

Despite the increasing global incidence of brain disorders, achieving sufficient delivery towards the central nervous system (CNS) remains a formidable challenge in terms of translating into improved clinical outcomes. The brain is highly safeguarded by physiological barriers, primarily the blood-brain barrier (BBB), which routinely excludes most therapeutics from entering the brain following systemic administration. Among various strategies investigated to circumvent this challenge, intranasal administration, a noninvasive method that bypasses the BBB to allow direct access of drugs to the CNS, has been showing promising results. Nanotechnology-based drug delivery systems, in particular, have demonstrated remarkable capacities in overcoming the challenges posed by nose-to-brain drug delivery and facilitating targeted drug accumulation within the brain while minimizing side effects of systemic distribution. This review comprehensively summarizes the barriers of nose-to-brain drug delivery, aiming to enhance our understanding of potential physiological obstacles and improve the efficacy of nasal delivery in future trials. We then highlight cutting-edge nanotechnology-based studies that enhance nose-to-brain drug delivery in three key aspects, demonstrating substantial potential for improved treatment of brain diseases. Furthermore, the attention towards clinical studies will ease the regulatory approval process for nasal administration of nanomedicines targeting brain disease.

Ceftriaxone-induced encephalopathy in a patient with a normal renal function.

Ceftriaxone-induced encephalopathy is an exceptionally rare adverse effect of this commonly used cephalosporin and is generally observed in patients undergoing haemodialysis or suffering from severe renal failure. We present a case of a fit woman in her mid-80s with a normal renal function who developed severe fluctuating neurological symptoms (aphasia, loss of contact, chorea-like tongue movements) while being treated with ceftriaxone for a urinary tract infection with bacteraemia. The symptoms began on day 4 of treatment and an adverse drug reaction was suspected on day 7, after exhaustive investigations failed to reveal another cause. A complete recovery was observed 3 days after discontinuing ceftriaxone. Our case highlights the need to consider the diagnosis of ceftriaxone encephalopathy, even if the traditional risk factors are lacking. In this article, we also provide a brief overview of the pathophysiology as well as a literature review concerning the subject.

A Case of Severe Lead Encephalopathy with Cardiac Arrest Managed During a Chelation Shortage.

INTRODUCTION: For many years, the standard of care in the USA has been to treat acute lead encephalopathy with a combination parenteral dimercaprol (BAL) and CaNa2EDTA. We present a case of a pediatric patient with severe lead encephalopathy, complicated by cardiac arrest, who was treated with an alternative regimen when CaNa2EDTA was unavailable. CASE REPORT: A 24-month-old male was brought by ambulance to an emergency department (ED) with new onset seizures and sustained a cardiac arrest. An initial blood lead concentration returned at 263 mcg/dl. The hospital was unable to obtain CaNa2EDTA due to the nationwide shortage. For this reason, the patient was chelated with BAL IM for 12 days and dimercaptosuccinic acid (DMSA) for 28 days. He received a second 5-day course of BAL due to rebounding blood lead concentrations. Eight days after cardiac arrest, he was extubated; however, despite ongoing therapy, subsequent follow-up 2 months later demonstrated persistent cognitive deficits. DISCUSSION: The combination of DMSA and BAL was effective in rapidly decreasing whole blood lead concentrations. Drug shortages continue to have implications for the management of poisoned patients. This case highlights how shortages of chelating agents complicate patient care.

Hashimoto Encephalopathy Presenting with Acute Psychosis and Inappropriate Secretion of Antidiuretic Hormone: A Rare Case Responding to Steroid Therapy.

BACKGROUND Hashimoto's encephalopathy (HE) is an autoimmune encephalopathy that can involve various symptoms including psychosis. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) may be a complication in some neurological diseases. However, the simultaneous occurrence of subacute psychosis and SIADH as the manifestation of HE, observed in the present case, has rarely been reported. CASE REPORT A 72-year-old man was hospitalized with a 4-month history of abnormal behaviors, including talkativeness, stopping consumption of coffee and cigarettes, hoarding garbage, and sleep disorders. On physical examination, increased and incoherent speech with flight of idea and delusion were observed. The Mini-Mental State Examination score was 28/30. Laboratory findings included hyponatremia due to SIADH and a positive result for anti-thyroid and anti-NH2 terminal of alpha-enolase antibodies. Cerebrospinal fluid examination revealed only elevation of IL-6. Brain magnetic resonance imaging was unremarkable; however, (I-123)-iodoamphetamine single-photon emission computed tomography showed extensive hyperperfusion involving the brainstem and bilateral frontal and medial temporal lobes. Electroencephalography showed generalized slow waves, but there were no epileptiform discharges. After 2 courses of high-dose intravenous methylprednisolone followed by oral prednisolone, his symptoms improved. Based on the findings of clinical features and steroid responsiveness, he was diagnosed with HE. Oral prednisolone and antipsychotic drugs were decreased without a relapse and he was discharged to his home. CONCLUSIONS Although psychosis complicating SIADH is rare, HE should be considered in the differential diagnosis because of its treatment efficacy.

Unusual case of sodium valproate-induced hyperammonaemia encephalopathy.

There is limited information about sodium valproate-induced hyperammonaemia encephalopathy (VPAIHE). The aim of this case report is to provide medical practitioners with a greater awareness of the possible development of hyperammonaemia due to sodium valproate use and its associated complications.This paper describes a middle-aged man with a history of bipolar affective disorder who was admitted with a manic relapse secondary to medication non-compliance. His admission was complicated by an intensive care unit admission to manage medical compromise in the context of sodium VPAIHE.