Long-lasting cognitive deficits after surgery in aged individuals, referred to as perioperative neurocognitive disorder (NCD), are a significant public health concern. Such postoperative cognitive deficits are dependent on the presence of microglia in the brain, which, when activated, trigger neuroinflammation. The objective of our study was to determine whether modulation of α5-GABAA receptors by the α5-positive allosteric modulator (α5-PAM), MP-III-022, would improve cognitive deficits after surgery. MP-III-022 (1 mg·kg-1·day-1 in the drinking water) was administered to mice 3 days prior to laparotomy and throughout the study. Chronologically aged mice (21-24 months old) and mice with ablation of dentate gyrus hilar somatostatin interneurons (4-5months old), a model for hippocampal ageing, were used. Cognitive functions were assessed using a battery of behavioural tests. Immunohistochemistry and Golgi staining were used to analyse microglial activation and dendritic spine density. In both types of mice, we found that laparotomy reduced the percentage of spontaneous alternations in the Y maze, novel object recognition, and contextual fear conditioning, while these deficits were attenuated with MP-III-022 treatment, indicating prevention or reversal of postoperative cognitive impairments. Laparotomy increased hippocampal microglial activation-associated measures and reduced dendritic spine density, and these changes were attenuated by MP-III-022 treatment. The α5-PAM, MP-III-022, essentially abolished laparotomy-induced cognitive deficits and structural alterations. Positive allosteric modulation of α5-GABAA receptors may represent a novel therapeutic strategy to prevent the development of perioperative neurocognitive deficits in aged individuals.

General anesthesia is often compared to sleep but may more closely resemble a medically induced coma. While all three states involve a loss of awareness, the extent of their neural similarity remains unclear. Electrophysiological markers, such as delta activity (< 4 Hz), are present in slow wave sleep, disorders of consciousness (DoC, including coma), and propofol anesthesia but are absent during rapid eye movement (REM) sleep. Frontal alpha oscillations are a key feature of propofol anesthesia and detectable via intraoperative EEG. However, it remains unclear whether alpha and delta activity fully define the brain state. Using whole-head EEG, we analyzed brain activity in individuals under propofol anesthesia, during sleep, or in DoC in the intensive care unit. Our spectral parameterization and similarity analyses revealed that propofol anesthesia exhibits spatiotemporal patterns resembling both coma and sleep. We introduced a spectral orthogonalization approach, identifying unique signatures of propofol anesthesia, including posterior slow waves, frontocentral delta, and reduced aperiodic activity. Critically, the reduction in aperiodic activity partially overlaps with REM sleep and may reflect decreased cortical excitability, contributing to reduced arousal, muscle atonia, and immobility common to both states. These results imply that propofol anesthesia creates a brain state where some features resemble sleep while others are more similar to coma. Embracing its full spatiotemporal complexity could improve titration of sedation, thus minimizing excessive suppression and the risk of postoperative cognitive deficits.

Melatonin prescribing characteristics and delirium outcomes: A health system database-based study.

Vacuoles, E1 enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome is a recently described multisystem disease. Opportunistic infections in VEXAS syndrome are increasingly being recognized and attributed to multiple factors, including immune dysregulation due to an aberrant ubiquitination pathway, secondary effects from chronic immunosuppressive treatments and underlying patient comorbidities. Given the limited consensus on antimicrobial prophylaxis, clinical practice is heterogeneous, with varying treatment outcomes. Herein, we report a rare case of cryptococcal meningitis in a patient with treatment-refractory VEXAS syndrome, on chronic moderate-dose corticosteroids (an average of 20mg prednisolone equivalent per day) and ruxolitinib. The patient initially presented with acute confusion and fevers, with elevated inflammatory markers and worsening cytopenia. The differential diagnoses included an acute flare of VEXAS syndrome and intercurrent infection. Further testing revealed the presence of Cryptococcus neoformans in the cerebrospinal fluid. Treatment with prolonged antifungal therapy was successful. The case raises important considerations, firstly regarding antimicrobial - particularly antifungal - prophylaxis given limited evidence in the literature, secondly a prompt diagnosis and treatment of cryptococcal infections, and finally regular interval screening for opportunistic infections in this vulnerable patient cohort. A multidisciplinary approach to care is required to improve morbidity and mortality from atypical infections in VEXAS syndrome.

Role of AQP4 mediated glymphatic system dysfunction in postoperative neuroinflammation and cognitive dysfunction.

Confusion beyond the usual suspects.

Early recognition and management of acute deterioration is essential to reduce the risk of patients experiencing catastrophic events, such as cardiac arrest, and to prevent potentially avoidable deaths. Common signs and symptoms of acute deterioration include increased respiratory rate, alteration in skin temperature, increased heart rate, hypotension, reduced urine output and acute onset confusion. Nurses undertake clinical monitoring and observation of patients in acute care settings and are therefore ideally placed to recognise and act on these signs and symptoms. This article explores the pathophysiology of common signs and symptoms of acute deterioration in relation to body systems, aligned with the airway, breathing, circulation, disability and exposure (ABCDE) approach and with reference to the National Early Warning Score (NEWS) 2 'track and trigger' tool. The author also considers the contribution of clinical intuition, clinical judgement and effective communication in the management of the deteriorating patient.

Acute confusion after a walk in the forest: Lyme neuroborreliosis encephalitis.

Delirium is common in patients admitted to hospital, and may sometimes be the first sign of a serious underlying condition. Identifying a specific cause can be complex, especially in patients without clear precipitating factors. A woman in her sixties was admitted to hospital with neurological symptoms and acute confusion. Delirium of unknown origin was suspected. Blood tests revealed elevated troponins and ECG showed subtle ST changes, but she reported no chest pain. CT revealed infarctions in the kidney and spleen, and brain MRI showed multiple embolic infarctions. Despite negative blood cultures and absence of other signs of infection, bacterial endocarditis was suspected, and empirical antibiotics were started. Transthoracic echocardiography was initially inconclusive, and transoesophageal echocardiography (TEE) was not feasible due to her cognitive state. PET-CT showed pathological FDG uptake in cervical lymph nodes, and biopsy revealed metastatic adenocarcinoma. As her delirium gradually improved, TEE revealed aortic valve vegetations. Cardiac MRI demonstrated embolic myocardial infarction. With a negative infectious workup and confirmed malignancy, the diagnosis of non-bacterial thrombotic endocarditis was established. Anticoagulation with low-molecular-weight heparin was initiated. This case highlights the importance of a broad diagnostic approach in delirium when initial evaluation does not reveal a clear cause.

Neuronal intranuclear inclusion disease (NIID) is an extremely rare, slowly progressive neurodegenerative disorder characterized by episodic neurological and psychiatric symptoms. Diagnosis is challenging due to non-specific presentations, often leading to misdiagnosis. Key diagnostic features include characteristic diffusion-weighted imaging (DWI) abnormalities, eosinophilic intranuclear inclusions on skin biopsy, and GGC repeat expansions in the NOTCH2NLC gene. A 56-year-old woman presented with acute onset confusion, disorientation, personality changes (inappropriate verbal outbursts), and aimless wandering. Symptoms were episodic and fluctuating. Past history included a right hemispheric ischemic stroke with residual hemiparesis, type 2 diabetes mellitus, and organophosphate poisoning. Initial admission diagnosis was "metabolic encephalopathy." Serial brain MRI+DWI over 3 years consistently showed symmetric hyperintensity on DWI along the corticomedullary junction in bilateral fronto-parieto-temporal white matter, semioval centers, and corpus callosum (ribbon sign). Cerebrospinal fluid analysis showed normal protein levels and lymphocytic pleocytosis (118.80 cells/μL). Episodic cognitive fluctuations persisted despite standard medical management. Given the characteristic DWI findings and clinical course, NIID was suspected. Genetic testing confirmed a pathogenic heterozygous NOTCH2NLC GGC repeat expansion (n=16/101 repeats). Skin biopsy and EMG were declined. Family history revealed a daughter with suspected cognitive issues. A diagnosis of NIID was confirmed. This report details the first genetically confirmed case of NIID in our region, presenting primarily with episodic psychiatric symptoms. It highlights the diagnostic challenge and the critical role of recognizing the characteristic DWI ribbon sign and performing genetic testing for NOTCH2NLC expansions, especially in cases with unexplained episodic neuropsychiatric decline. Increased awareness and accessibility of genetic testing will likely lead to more frequent diagnosis of NIID in China.

Context: Acute confusional state (ACS) which is a frequent medical emergency among hospitalized patients is often associated with different factors, resulting from different etiologies. Electrolytic imbalance especially disturbance in sodium serum level, is considered one of the manageable factors in the management of ACS. Methodology: This cross-sectional observational study was conducted in the Department of Medicine, Shaheed Suhrawardy Medical College Hospital, Dhaka with a duration of six months. A total of 100 patients with clinically diagnosed ACS were enrolled. Each patient underwent clinical evaluation and various laboratory investigations including serum electrolytes measurement, with their consent. Data were analyzed using SPSS; p&lt;0.05 was considered as statistically significant Results: In this study, male patients were predominant (61%) and mean age of the patients was 6.38 years. Cerebrovascular disease was found to be the leading cause of ACS (38%), followed by pneumonia (14%) and meningitis (13%). Serum sodium disturbances were observed in 18% of cases—hyponatremia in 15% and hypernatremia in 3%—while 82% had normal sodium serum levels. Differences between sodium categories were not statistically significant (p &gt; 0.05). Most patients (76%) recovered without sequelae; mortality was 6%. Conclusion: ACS is a common medical condition in tertiary level hospital of Bangladesh, where Hyponatremia is a common complication. Patients who develop ACS have high disability, complication rate and longer length of stay than any other patients. Knowing the nature and timing of the disease, together with the identification of high-risk patients are essential to reduce complications and improve outcome. J Shaheed Suhrawardy Med Coll 2024; 16(2): 63-68

Neuropsychiatric (NP) manifestations are common, heterogeneous and severe in systemic lupus erythematosus (SLE) patients, with attribution to SLE remaining diagnostically challenging. Traditional classification focuses on clinical syndromes, overlooking neuropsychiatric systemic lupus erythematosus (NPSLE) immunological heterogeneity. To address the heterogeneity of NPSLE, this study aimed to delineate distinct disease subgroups by clustering patients based on their antibody profiles. These subgroups were then evaluated for diferences in clinical presentation and prognosis, to better characterize disease subsets and support individualized approaches to diagnosis and management. This retrospective single-center study included hospitalized SLE patients with NP manifestations, collecting demographic, clinical and laboratory data. Patients were classified as NPSLE or non-NPSLE by clinical judgment after excluding alternative causes. Hierarchical cluster analysis explored autoantibody-clinical feature associations. Among the 167 patients analyzed, 152 had NP manifestations attributed to SLE. Central nervous system (CNS) involvement was predominant (89.1%), with seizures, cerebrovascular disease, acute confusional state (ACS), and demyelinating syndrome being most prevalent manifestations. Hierarchical clustering of 152 NPSLE patients identified two subgroups: Cluster 1 (23.7%) demonstrated cerebrovascular injury as the predominant manifestation, with higher positivity rates of antiphospholipid antibodies (APLs) (P < 0.01) and a higher incidence of cerebrovascular disease (P < 0.01). Cluster 2 (76.3%) showed immune-mediated inflammatory profile, with higher positivity of anti-SSA (P < 0.01), antidsDNA (P < 0.05), and anti-RiboP antibodies (P < 0.05). Neurological involvement predominantly manifesting as ACS (P < 0.05), accompanied by a higher frequency of fever and joint involvement. In this study, NPSLE exhibited distinct serological profiles and segregated into two immunologically defined clusters, reflecting its clinical and biological heterogeneity, and suggesting that immunological profiling may enhance precise classification and personalized management of affected patients.

Comparison of standard and extended 3-hour EEG in older adults with acute confusion

Hemorrhagic central nervous system (CNS) metastases are well recognized in melanoma yet seldom represent the initial manifestation, and fulminant, steroid-refractory hepatitis from immune checkpoint inhibitors (ICIs) remains exceedingly rare. Here, we present a 54-year-old man with no prior medical history who was brought to the emergency department with acute confusion and aphasia and was found to have a large right frontal hemorrhagic mass with midline shift. Urgent craniotomy and hematoma evacuation revealed high-grade melanoma, BRAF V600-negative. Imaging identified stage IV disease with pulmonary and hepatic metastases. He was started on ipilimumab and nivolumab combination therapy outpatient; however, treatment was held after 2 cycles due to marked transaminitis, and prednisone was initiated for presumed ICI-related hepatitis. Despite corticosteroids, liver function progressively worsened over the following weeks, which required a second hospitalization and culminated in fulminant liver failure and encephalopathy. High-dose methylprednisolone offered minimal improvement. Although second-line immunosuppressants were considered, rapid deterioration prompted initiation of tocilizumab. His hospitalization was complicated by multiorgan failure and radiographic progression of CNS metastases, and he ultimately transitioned to comfort care and died on hospital day 7. This case demonstrates hemorrhagic CNS disease at diagnosis alongside early, fulminant, steroid-refractory ICI hepatitis and highlights the need for heightened hepatic surveillance and early escalation of immunosuppression during dual checkpoint blockade.

To present a case of suspected colistin-induced neurotoxicity, likely resulting from drug accumulation during treatment of multidrug-resistant Pseudomonas aeruginosa (PA) bacteremia. An 18-year-old female with no prior medical history was admitted to the coronary care unit with fulminant myocarditis, requiring mechanical circulatory support and ultimately left-ventricular assist device implantation. Three weeks later, she developed PA bacteremia. Despite multiple targeted antibiotic regimens, PA persisted in subsequent blood cultures. Colistimethate sodium (CMS) was initiated at 2 × 4.5 MIU, the recommended dose according to serum creatinine-based renal function (eGFR ~ 133mL/min/1.73m2). On day 4, the patient developed an acute confusional state with hallucinations. While serum creatinine remained stable, cystatin C and 24-hour urine clearance indicated impaired renal function (eGFR ~ 32 mL/min/1.73m2). As therapeutic drug monitoring (TDM) was unavailable, the CMS dose was reduced to 2 × 2.5 MIU based on cystatin C-estimated renal function, leading to resolution of neurological symptoms within 3 days. CMS was continued for 10days, leading to improved inflammatory markers and clinical stabilization. Colistin-induced neurotoxicity should be considered in patients with new-onset neuropsychiatric symptoms, particularly in the setting of renal dysfunction or high cumulative exposure. Reliance on serum creatinine alone may misrepresent renal function; incorporation of cystatin C or urine clearance can improve dosing accuracy and reduce toxicity risk. When therapeutic alternatives are limited, dose reduction rather than discontinuation may be an appropriate strategy. Broader implementation of TDM is essential to optimize dosing and minimize adverse outcomes in clinical practice.

Perioperative neurocognitive disorders (PNDs) represent a significant challenge in the perioperative setting, while the pathophysiology of PNDs remains unclear. Utilizing a murine model of abdominal surgery, we found that abnormal glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) and hippocampus contributes to postoperative cognitive impairments. Increases in the frequency of miniature excitatory postsynaptic currents in both the mPFC and CA1 neurons indicate enhanced presynaptic glutamate release while having little effect on inhibitory neurotransmission. Surgery also enhances glutamate release from presynaptic terminals in the Schaffer collateral pathway. In addition, abdominal surgery increased the activation of microglia and astrocytes, elevated central inflammatory markers, and reduced excitatory amino-acid transporter-2 expression. Dexmedetomidine significantly mitigates the postoperative cognitive deficits by reducing inflammation and preserving neuronal structural complexity and dendritic spine stability, likely through inhibiting glutamate release and enhancing its reuptake. These findings advance our understanding of the etiology of PNDs and provide hints for potential intervention.

Neuropsychiatric (NP) involvement represents one of the major challenges in Systemic Lupus Erythematosus (SLE), often requiring individualized therapeutic strategies. While anifrolumab inhibits the type I interferon receptor 1 (IFNAR1) and is approved for the treatment of moderate-to-severe SLE, randomized controlled trials have not evaluated its efficacy in NPSLE. We examined the pathophysiological rationale for inhibiting IFN-α using anifrolumab in NPSLE. To supplement this, we report an original case of NPSLE successfully treated with anifrolumab, along with similar cases identified through a systematic literature review (SLR) of Medline/PubMed and Embase, performed in accordance with PRISMA and CABARET guidelines. Overexpression of IFN-α is linked to neurological symptoms in patients with inflammatory NPSLE, such as psychosis and seizures. Blocking the IFNAR1 with anifrolumab provides a direct rationale for treating this subset of NPSLE. The SLR identified seven case reports of female patients with inflammatory NPSLE where anifrolumab was used as a rescue therapy following conventional treatment failure. NPSLE manifestations were heterogeneous, including psychosis, headache, and acute confusional state, which limits the generalizability of our findings. A 52-year-old female with SLE and seizures from our Lupus Clinic who received anifrolumab after failing multiple treatments was also reported. After an average of 11.7 months, all patients showed improvement, 87% (7 out 8) achieving complete NP symptom resolution and 62% reaching SLE remission. No emerging safety issues were reported. Preliminary observations suggest a potential benefit of anifrolumab in NPSLE, but evidence remains insufficient to establish clinical efficacy and warrants further controlled studies.

Perioperative neurocognitive disorder (PND) is one of the most prevalent neurological complications in elderly surgical patients. Dysregulated lipid metabolism is a hallmark of aging and is strongly associated with cognitive dysfunction. This study aimed to investigate whether ω-6 polyunsaturated fatty acid (PUFA) metabolism contribute to PND and examined whether fatty acid desaturase 1 (FADS1) represents a key regulatory link between fatty acid metabolism and PND in aged mice. An anesthesia/surgery-induced cognitive dysfunction model was established via laparotomy in 18-month-old C57BL/6J mice under 1.4% isoflurane anesthesia. Non-targeted metabolomics was performed in both mouse hippocampal tissue and human serum from post-operative cognitive dysfunction (POCD) patients to identify altered metabolic pathways. FADS1 expression was evaluated by western blotting and qPCR, and bilaterally hippocampal injection of recombinant AAV-shFads1 was used for gene knockdown. Behavioral outcomes were assessed using open field, Barnes maze, Y-maze, and fear conditioning tests. Western blotting, ELISA, and immunofluorescence were applied to evaluate downstream metabolic pathways, inflammatory cytokines, glial activation, and synaptic plasticity. Neuronal activity was assessed by sparse labeling, in vivo calcium fiber photometry, and in vivo electrophysiology. In addition, dietary docosahexaenoic acid (DHA) supplementation was administered to evaluate its effect on lipid metabolism, neuroinflammation, and postoperative cognitive function. Anesthesia/surgery significantly upregulated hippocampal FADS1 expression (1.91-fold [0.37] vs. 1.00-fold [0.43]; p < 0.01), leading to dysregulation of ω-6 PUFA metabolism. Elevated FADS1 promoted arachidonic acid (AA) accumulation (p < 0.01) and its downstream conversion to prostaglandin D2 (PGD2; p < 0.001), activating the prostaglandin D Receptor 1 (DP1) signaling cascade. This cascade induced a cytokine storm, microglial and astrocytic activation, reduced pyramidal neuron activity, synaptic dysfunction, and cognitive impairment. Knockdown of FADS1 reversed these metabolic disturbances, suppressed inflammatory responses, and improved learning and memory, whereas pharmacological DP1 activation abolished these protective effects. Consistently, serum metabolomics in POCD patients revealed persistent dysregulation of AA metabolism, supporting clinical relevance of this pathway. Furthermore, preoperative DHA supplementation attenuated FADS1 upregulation reduced PGD2/DP1 signaling, and partially rescued postoperative cognitive deficits in aged mice. These findings highlight anesthesia/surgery could disrupt ω-6 PUFA metabolism, notably activating the PGD2/DP1 pathway, which promotes postoperative neuroinflammation, synaptic vulnerability, and cognitive decline. FADS1 emerges as a pivotal regulator of this pathway, and therapeutic modulation of the FADS1–PGD2–DP1 axis may offer a promising strategy for mitigating PND in the aging brain.

Abstract Introduction Out-of-hours (OOH) services provide emergency primary care outside normal GP hours, serving patients with higher health needs. Delirium affects 25% of hospitalised older adults, causes distress to patients and carers, and leads to poor outcomes. However, little is known about delirium presentations and prevalence in OOH services. We aimed to investigate delirium occurrence and management using case records from an OOH service in South-West England. Methods The OPEN database contains 33,345 consultations of patients ≥65 attending the OOH service between April 2019–March 2020. We screened consultations for delirium symptoms during April and July 2019, and January 2020. Records were reviewed by two GPs independently using DSM-V criteria to identify probable or possible delirium. We validated our search strategy by reviewing a random sample of 100 consultations initially classified as ‘search-negative’ and assessed inter-rater reliability. Patient characteristics were compared using Chi-squared tests. Results Of 4288 consultations with patients ≥65 in the study periods, 394 (9.2%) involved possible or probable delirium. A further 76 (1.8%) had end-of-life delirium and were excluded from further analysis. Patients with delirium were similar in age to those without, but more likely to live in residential care (29% vs. 14%, p &amp;lt; 0.001) and have dementia (46% vs. 11%, p &amp;lt; 0.001). 67% of delirious patients required home visits, compared to 22% without delirium (p &amp;lt; 0.001). Delirium was not available as a coded diagnosis; only 6% of cases were coded as ‘Acute Confusion,’ whilst 20.9% were coded ‘Urinary Tract Infection.’ Patients with delirium were admitted to hospital twice as often as those without (21% vs 10%, p &amp;lt; 0.001). Conclusions Delirium is a common OOH presentation, representing ~10% of consultations with patients ≥65. These patients often have cognitive impairment, require home visits, and are more likely to be hospitalised. Improved recognition and coding could support better management and service planning.

Advancing dementia identification using machine learning and real-world sequential health data.