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.

[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.

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.

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.

[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.

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.

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.

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.

[Extracorporeal support treatment in severe malaria]. / Tratamiento con sostén extracorpóreo en malaria grave.

Malaria is a wide-spread disease in tropical areas. The severe form is characterized by organic involvement and/or hyperparasitaemia. Criteria for early monitoring in intensive care rooms are defined; without a timely and early treatment, severe malaria has a 100% mortality. Although the literature in these cases is not extensive, extracorporeal therapy used sequentially for hepatic and renal detoxification is a useful and safe tool that can be used in intensive care. We describe the case of a 36-year-old man with a diagnosis of severe malaria according to WHO criteria. He began treatment with intravenous artesunate and due to a torpid evolution, a sudden increase in bilirubinemia with encephalopathy, parameters of acute kidney injury and acute pulmonary edema, undergoes extracorporeal sequential treatment, coupled with plasma filtration adsorption, high-exchange plasmapheresis, and continuous hemodiafiltration with favorable evolution. This case shows that extracorporeal support in trained hands and in a timely manner is effective when organ failure evolves rapidly to achieve stability and provide necessary time for definitive treatment, in this case rapid action antimalarials until parasitemia becomes negative.

La malaria es una enfermedad con amplia distribución en áreas tropicales. En su forma grave se caracteriza por afección orgánica y/o hiperparasitemia. Se definen los criterios para el monitoreo temprano en las salas de terapia intensiva, debido a que sin tratamiento oportuno y precoz la malaria grave tiene una mortalidad de 100%. Si bien no es amplia la literatura en este aspecto la terapia extracorpórea en forma secuencial para detoxificación hepática y renal es una herramienta útil y segura que puede ser utilizada en terapia intensiva. Se describe un caso de un varón de 36 años con diagnóstico de malaria grave según criterio de la Organización Mundial de la Salud (OMS) que comenzó con tratamiento con artesunato endovenoso y por evolución tórpida, ascenso brusco de bilirrubinemia con encefalopatía, parámetros de lesión renal aguda y edema agudo de pulmón, realiza tratamiento extracorpóreo secuencial, plasma filtración acoplada a adsorción, plasmaféresis de alto intercambio y hemodiafiltración continua con evolución favorable. En conclusión, el caso presentado nos demuestra que el rol del sostén extracorpóreo en manos entrenadas y en forma oportuna es crucial cuando el fallo de órganos evoluciona rápidamente para lograr dar estabilidad y otorgar el tiempo necesario para la acción del tratamiento definitivo en este caso, los antimaláricos de acción rápida hasta negativización de la parasitemia.

Pseudoatrofia cerebral y cerebelosa asociada a ácido valproico. Descripción de tres casos pediátricos / Cerebral and cerebellar pseudoatrophy associated with valproic acid. Report of three pediatric cases

Introducción La pseudoatrofia cerebral y cerebelosa es un efecto adverso infrecuente del ácido valproico (VPA) que debemos conocer por sus implicaciones diagnósticas y terapéuticas. Caso clínico Presentamos tres casos de niños de entre 5 y 9 años, con epilepsia y resonancia magnética craneal previa normal, que llevaban el fármaco con dosis correctas. La pseudoatrofia se manifiesta de forma subaguda con síntomas e imagen de atrofia cerebral y/o cerebelosa, reversible tras la retirada del fármaco. Discusión y conclusiones. Se trata de un tipo de encefalopatía relacionada con VPA diferente a la encefalopatía tóxica dependiente de la dosis, la encefalopatía hiperamoniémica o la relacionada con fallo hepático. En niños, cursa con deterioro cognitivo, motor, anímico y conductual, y puede acompañarse de descompensación epiléptica. La retirada del fármaco conlleva una recuperación completa clinicorradiológica, y la disminución de dosis, una mejoría. (AU)

INTRODUCTION Cerebral and cerebellar pseudoatrophy is a rare adverse effect of valproic acid (VPA) that we need to be aware of, due to its diagnostic and therapeutic implications. CASE REPORT We report three cases of children between 5 and 9 years old, with epilepsy and previous normal brain magnetic resonance imaging, who were taking the drug at correct doses. Pseudoatrophy manifests subacutely with symptoms and images of cerebral and/or cerebellar atrophy, reversible after drug withdrawal. Discussion and conclusions. This is a type of VPA-related encephalopathy, different from dose-dependent toxic encephalopathy, hyperammonaemic encephalopathy or encephalopathy related to liver failure. In children, it causes cognitive, motor, mood and behavioral deterioration, and may be accompanied by epileptic decompensation. Withdrawing the drug leads to complete clinical-radiological recovery, and reducing the dose leads to improvement. (AU)

Anti-NMDAR encephalitis secondary to acute necrotizing encephalopathy caused by herpes simplex virus infection in infants: Case series.

BACKGROUND: To describe the clinical characteristics of anti-NMDAR encephalitis secondary to acute necrotizing encephalopathy caused by herpes simplex virus encephalitis in infants, and aid in its early recognition, diagnosis and treatment. CASE PRESENTATION: A total of 4 infants were included; all presented with fever, seizures, and progressive disturbances of consciousness and were diagnosed with herpes simplex virus (HSV-1) encephalitis. Cerebrospinal fluid (CSF) protein levels progressively increased, and the head MRI showed necrotizing encephalopathy. There was no significant improvement or recurrence after treatment with acyclovir, dexamethasone, or immunoglobulins. CSF reexamination at 3 weeks to 3 months showed positive anti-NMDAR IgG antibodies and gradual improvement after high-dose methylprednisolone therapy. CONCLUSION: Infants with ANE associated with HSV can develop secondary anti-NMDAR encephalitis, recognition of which is critical to ensure the appropriate institution of immunotherapy after active CNS infection has been ruled out.

The battle of lipid-based nanocarriers against blood-brain barrier: a critical review.

Central nervous system integrity is the state of brain functioning across sensory, cognitive, emotional-social behaviors, and motor domains, allowing a person to realise his full potential. Thus, brain disorders seriously affect patients' quality of life. Efficient drug delivery to treat brain disorders remains a crucial challenge due to numerous brain barriers, particularly the blood-brain barrier (BBB), which greatly impacts the ultimate drug therapeutic efficacy. Lately, nanocarrier technology has made huge progress in overcoming these barriers by improving drug solubility, ameliorating its retention, reducing its toxicity, and targeting the encapsulated agents to different brain tissues. The current review primarily offers an overview of the different components of BBB and the progress, strategies, and contemporary applications of the nanocarriers, specifically lipid-based nanocarriers (LBNs), in treating various brain disorders.

Steroid-responsive encephalopathy associated with autoimmune thyroiditis presenting as cortisone sensible psychosis with reversible leukoencephalopathy.

INTRODUCTION: Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) is a frequently discussed neuropsychiatric syndrome with elevated thyroid antibodies in the context of various clinical neuropsychiatric phenotypes. MRI abnormalities are usually nonspecific and treatment can be complex. CASE STUDY: We present a case of a woman in her sixties with SREAT whose psychosis kept worsening under cortisone tapering. After three years with cortisone side effects, therapy was changed to plasmapheresis and rituximab treatment with an excellent initial response, subacute unexplained deterioration with extensive leukoencephalopathy on MRI shortly after, and full recovery with regression of leukoencephalopathy afterwards. DISCUSSION: SREAT varies in clinical and diagnostic presentation. Its precise pathophysiology is unknown, as are the best treatment protocols. The case illustrates that some patients with SREAT syndrome might end up in constellations, in which it proves difficult to wean off steroid treatment and illustrates treatment alternatives such as plasmapheresis and/or rituximab. In addition, it highlights leukoencephalopathy as possible MRI finding in the context of SREAT. Further research is necessary to fully comprehend the (potentially different) pathomechanisms and courses of SREAT.