Cholinesterase inhibitor use in amyloid PET-negative mild cognitive impairment and cognitive changes.

BACKGROUND: Cholinesterase inhibitors (ChEIs) are prescribed for Alzheimer's disease (AD) and sometimes for mild cognitive impairment (MCI) without knowing underlying pathologies and its effect on cognition. We investigated the frequency of ChEI prescriptions in amyloid-negative MCI and their association with cognitive changes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. METHODS: We included participants with amyloid positron emission tomography (PET)-negative MCI from the ADNI. We analyzed the associations of ChEI use with cognitive changes, brain volume, and cerebrospinal fluid (CSF) total tau (t-tau), hyperphosphorylated tau181 (p-tau181), and p-tau181/t-tau ratio. RESULTS: ChEIs were prescribed in 27.4% of amyloid PET-negative MCI and were associated with faster cognitive decline, reduced baseline hippocampal volume and entorhinal cortical thickness, and a longitudinal decrease in the frontal lobe cortical thickness. CONCLUSIONS: The association between ChEI use and accelerated cognitive decline may stem from underlying pathologies involving reduced hippocampal volume, entorhinal cortical thickness and faster frontal lobe atrophy. We suggest that ChEI use in amyloid PET-negative MCI patients might need further consideration, and studies investigating the causality between ChEI use and cognitive decline are warranted in the future.

Enzyme ChE, cholinergic therapy and molecular docking: Significant considerations and future perspectives.

Enzyme Che plays an essential role in cholinergic and non-cholinergic functions. It is present in the fertilized/unfertilized eggs and sperm of different species. Inclusion criteria for data collection from electronic databases NCBI and Google Scholar are enzyme AChE/BChE, cholinergic therapy, genomic organization and gene transcription, enzyme structure, biogenesis, transport, processing and localization, molecular signaling and biological function, polymorphism and influencing factors. Enzyme Che acts as a signaling receptor during hematopoiesis, protein adhesion, amyloid fiber formation, neurite outgrowth, bone development, and maturation, explaining the activity out of synaptic neurotransmission. Polymorphism in the Che genes correlates to various diseases and diverse drug responses. In particular, change accompanies cancer, neurodegenerative, and cardiovascular disease. Literature knowledge indicates the importance of Che inhibitors that influence biochemical and molecular pathways in disease treatment, genomic organization, gene transcription, structure, biogenesis, transport, processing, and localization of Che enzyme. Enzyme Che polymorphism changes indicate the possibility of efficient and new inhibitor drug target mechanisms in diverse research areas.

Recent Advances in Medicinal Chemistry of Memantine Against Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic progressive, age-related neurodegenerative brain disorder characterized by the irreversible decline of memory and other cognitive functions. It is one of the major health threat of the 21st century, which affects around 60% of the population over the age of 60 years. The problem of this disease is even more major because the existing pharmacotherapies only provide symptomatic relief without addressing the basic factors of the disease. It is characterized by the extracellular deposition of amyloid ß (Aß) to form senile plaques, and the intracellular hyperphosphorylation of tau to form neurofibrillary tangles (NFTs). Due to the complex pathophysiology of this disease, various hypotheses have been proposed, including the cholinergic, Aß, tau, oxidative stress, and the metal-ion hypothesis. Among these, the cholinergic and Aß hypotheses are the primary targets for addressing AD. Therefore, continuous advances have been made in developing potential cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists to delay disease progression and restore cholinergic neurotransmission. In this review article, we tried to comprehensively summarize the recent advancement in NMDA receptor antagonist (memantine) and their hybrid analogs as potential disease-modifying agents for the treatment of AD. Furthermore, we also depicted the design, rationale, and SAR analysis of the memantine-based hybrids used in the last decade for the treatment of AD.

Effect of sugammadex with neostigmine on postoperative bowel function and on recovery of neuromuscular functions: A randomized controlled trial.

BACKGROUND: Early recovery of neuromuscular and bowel function after abdominal surgery are important clinical indicators of postoperative recovery. This study aimed to investigate the effects of sugammadex, and neostigmine added to sugammadex, on postoperative bowel function and recovery from neuromuscular blocking agents. METHODS: Ninety gynecological surgery patients, aged 18 to 65 years, with American Society of Anesthesiologists of 1 to 2 were randomly assigned to 3 groups: sugammadex 2 mg/kg (Group S), sugammadex 1 m/kg with neostigmine 20 µg/kg + atropine 10 µg/kg (Group S1N), and sugammadex 1.5 mg/kg with neostigmine 20 µg/kg + atropine 10 µg/kg (Group S2N), for reversal at the end of surgery during moderate block (train-of-four [TOF] count 1-2). Propofol, remifentanil, rocuronium, and sevoflurane were used for general anesthesia, and neuromuscular function was assessed using kinemyography. The primary outcomes assessed the effects of sugammadex alone and in combination with neostigmine on the time to first flatus. The secondary outcomes included time to first defecation and recovery time; defined as the administration of reversal agent to TOF ratio 90%. RESULTS: Data from 90 female patients who underwent abdominal gynecological surgery were analyzed. No significant differences were found between the groups in term of the time to first flatus, defecation, or postoperative nausea and vomiting after surgery. However, significant differences were observed in the time to reach a TOF ratio 90% (P < .001) and extubation time (P = .003). CONCLUSION: The addition of neostigmine to sugammadex did not affect bowel function recovery. However, combining 20 µg/kg neostigmine with 1.5 mg/kg sugammadex or 2 mg/kg sugammadex alone antagonized moderate-depth nondepolarizing neuromuscular blockade with similar efficacy.

Current pharmacophore based approaches for the development of new anti-Alzheimer's agents.

Amyloid beta peptide (Aß) and hyperphosphorylated neuronal tau proteins accumulate in neurofibrillary tangles in Alzheimer's disease (AD), a chronic neurodegenerative illness. Chronic inflammation in the brain, which promotes disease progression, is another feature of the Alzheimer's disease pathogenesis. Approximately 60-70 % of dementia cases are caused by AD. The development of effective therapies for the treatment of AD is urgently needed given the severity of the condition and its rapidly rising prevalence. Cholinesterase inhibitors, beta-amyloid (A-beta), tau inhibitors, and many other medications are currently used as preventive medicine for AD. These medications can temporarily suppress dementia symptoms but cannot halt or reverse the disease's progression. Many international pharmaceutical companies have tried numerous times to develop an amyloid clearing medication based on the amyloid hypothesis, but without success. Therefore, the amyloid theory may not be entirely plausible. This review mainly covers the recent and important reported pharmacophores as the starting point to discuss already known targets like tau, butyrylcholinesterase, amyloid beta, and acetylcholinesterase and covers the literature between years 2019-2024.

Co-Designing a Consult Patient Decision Aid for Continuation Versus Deprescribing Cholinesterase Inhibitors in People Living with Dementia.

BACKGROUND AND OBJECTIVE: As dementia progresses, people living with dementia may take high-risk, unnecessary, or ineffective medicines. Cholinesterase inhibitors (ChEIs) may have benefit in some people with dementia; however, up to one third are continued when no longer necessary or safe. Our aim was to co-design a consult patient decision aid (CPtDA) to support shared decision making between healthcare professionals and consumers about continuing or deprescribing ChEIs. METHODS: A systematic process was employed to design and test the CPtDA prototype. First, a steering group composed of healthcare professionals and a consumer representative was assembled. Guided by the International Patient Decision Aids Standards, the steering group defined the CPtDA's purpose, scope, and target audience and drafted the prototype for further testing. Interviews with consumers and healthcare professionals were conducted to gain feedback on the content, format, structure, comprehensibility and usability of the CPtDA prototype. RESULTS: After the steering group developed the CPtDA prototype, interviews were conducted with 11 consumers and six healthcare professionals. The content and format of the decision aid were improved iteratively over three rounds after consolidating the feedback at each round. The main changes included rewording the purpose of the decision aid and simplifying its layout and format. Participants reported that the decision aid is comprehensible and may be useful in practice. CONCLUSIONS: Limited available resources guide shared decision making about deprescribing. This study resulted in a co-designed and alpha-tested CPtDA for people living with dementia and carers to help them review the ongoing need for their ChEIs. Further research is needed to explore using the CPtDA in practice to support people living with dementia and their carers engage in the shared decision-making process about continuing or deprescribing their ChEIs. Our co-designed CPtDA could help people living with dementia and their carers review their goals of care alongside their healthcare professional. This may prompt conversations about appropriately using ChEIs and increase the uptake of deprescribing.

Alzheimer Disease: Treatment of Cognitive and Functional Symptoms.

Alzheimer disease is a progressive, neurodegenerative disorder characterized by the accumulation of amyloid beta plaques and hyperphosphorylated tau proteins. Alzheimer disease affects cognitive function, leading to memory loss and impairment in activities of daily living. Approximately 6.9 million people in the United States 65 years and older live with Alzheimer disease, a number expected to double by 2060. Although there is no cure for Alzheimer disease, treatments are available to manage symptoms. Tools such as the Diagnostic and Statistical Manual of Mental Disorders, 5th ed., criteria aid in identifying major neurocognitive disorders. The evaluation involves a comprehensive medical history, cognitive examinations, and collateral information. Nonpharmacologic interventions focus on psychosocial approaches, with music, sensory stimulation, and validation therapies showing some evidence of reducing responsive behaviors. Pharmacologic management, such as acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and the N-methyl-d-aspartate receptor antagonist memantine, targets symptom relief and disease progression. Vitamin E does not improve cognition but may mitigate functional decline. Brexpiprazole has been approved in the United States for treating agitation associated with Alzheimer disease. Anti-amyloid monoclonal antibody treatments are approved for mild cognitive impairment and mild Alzheimer disease, but they are controversial and safety concerns exist. Ineffective therapies include ginkgo biloba, nonsteroidal anti-inflammatory drugs, omega-3 fatty acids, and statins.

Survival After the Diagnosis of Mild-to-Moderate Alzheimer's Disease Dementia: A 15-Year National Cohort Study in Taiwan.

OBJECTIVES: Pharmacological and non-pharmacological interventions are mostly designed for patients with early Alzheimer's disease (AD) dementia. Long-term case management and planning for the remainder of life with disability require an estimation of the survival duration. METHODS: This cohort study utilized data from the National Health Insurance Research Database, Taiwan, to identify incident cases of mild-to-moderate AD dementia diagnosed from 2000 to 2002, followed through December 31, 2017. A multivariate Cox proportional hazards regression model was constructed to compare the independent effects of age, sex, and comorbidities on all-cause mortality risk. Cumulative survival rates and survival times were estimated. RESULTS: A total of 5258 incident cases were identified, all treated with cholinesterase inhibitors after diagnosis confirmation by an expert committee. During the 15-year follow-up period, 4331 deaths occurred. The 1-, 3-, 5-, 10-, and 15-year cumulative survival rates were 95, 92, 67, 37, and 18, respectively. The median (95% CI) survival time after diagnosis was 7.69 (7.46-7.90) years overall, 6.37 (6.06-6.65) years in men, and 8.81 (8.49-9.12) years in women. After stratification by age and number of comorbidities, the median survival time ranged from 13.72 (ages 40-64) to 5.29 (ages ≥ 80) years among those without comorbidities. For those with ≥ 3 comorbidities, the median survival times decreased to 6.43 for individuals diagnosed at ages 40-64 and to 2.98 years for those diagnosed at age 80 or older. CONCLUSIONS: This nationwide, large, long-term cohort study provided survival rates and durations from diagnosis to death, varying by sex, age group, and presence/number of comorbidities. This information can serve as a foundation for further cost-effectiveness studies on new treatments, and may aid clinicians, patients, and families in shared decision-making and advance personalized care planning for early dementia cases.

Drug Response of Iranian Alzheimer's Patients to Rivastigmine Concerning Their Genotype for VDR rs11568820 and MTHFR C677T Variants: A Pharmacogenetic and Association Study.

Alzheimer's disease is a neurodegenerative disorder with polygenic etiology. Genetic risk variants for Alzheimer's disease differ among populations. Thus, discovering them in each population is clinically important. A total of 118 patients and 97 controls for VDR rs11568820 and 88 patients and 100 healthy controls for MTHFR C677T polymorphism were genotyped to evaluate the association of these polymorphisms with late-onset Alzheimer's disease in the Iranian population, along with their impacts on the response to Rivastigmine treatment. The VDR C allele was significantly associated with Alzheimer's disease and provided protection against it (P = 0.003, RR = 1.14, 95% CI 1.04-1.24), while the T allele increased susceptibility (P = 0.003, RR = 1.93, 95% CI 1.23-3.02). These results were also considerable upon excluding the effect of APOE ε4 allele. The Prevalence-corrected Positive Predictive Value was 1.71% for the VDR CC genotype and 4% for the VDR CT genotype, indicating lower and almost twofold higher chances of developing Alzheimer's disease, respectively. No significant correlation was observed between MTHFR C677T and Alzheimer's disease. Based on our pharmacogenetic study, MTHFR T allele carriers lacking APOE ε4 allele showed a better response to Rivastigmine treatment after a 2-year follow-up. Moreover, patients with VDR CC genotype displayed milder Alzheimer's disease, particularly when coincided with the APOE ε4 allele. The VDR rs11568820 polymorphism affects both Alzheimer's disease risk and the response to Rivastigmine in Iranian patients. Also, MTHFR C677T polymorphism may play a role in the response to Rivastigmine, through a pathway that needs to be elucidated in future studies.

Moderation of Amyloid-ß Deposition on the Effect of Cholinesterase Inhibitors on Cognition in Mild Cognitive Impairment.

Background: Clinical trial findings on cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) are inconclusive, offering limited support for their MCI treatment. Given that nearly half of amnestic MCI cases lack cerebral amyloid-ß (Aß) deposition, a hallmark of Alzheimer's disease; this Aß heterogeneity may explain inconsistent results. Objective: This study aimed to assess whether Aß deposition moderates ChEI effects on amnestic MCI cognition. Methods: We examined 118 individuals with amnestic MCI (ages 55-90) in a longitudinal cohort study. Baseline and 2-year follow-up assessments included clinical evaluations, neuropsychological testing, and multimodal neuroimaging. Generalized linear models were primarily analyzed to test amyloid positivity's moderation of ChEI effects on cognitive change over 2 years. Cognitive outcomes included Mini-Mental Status Examination score, the total score of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery, and Clinical Dementia Rating-sum of boxes. Results: The analysis found no significant ChEI use x amyloid positivity interaction for all cognitive outcomes. ChEI use, irrespective of Aß status, was associated with more cognitive decline over the 2-year period. Conclusions: Aß pathology does not appear to moderate ChEI effects on cognitive decline in MCI.

Speech-related parameters are sensitive measures of acetylcholinesterase inhibitor therapy in mild Alzheimer's disease.

Our aim was to find out whether speech-related temporal parameters (SRTPs) are sensitive indicators of the clinical outcome in acetylcholinesterase (AChE) inhibitor therapy with donepezil, compared to the standard cognitive Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) used in clinical trials. In this 24-week-long, naturalistic, self-control, open-labeled, prospective pilot study with 10 mg donepezil on 20 mild AD patients, cognitive functions were evaluated using 15 different SRTPs analyzed by automatic speech recognition in the Speech-Gap Test® compared to ADAS-Cog test results. Among the SRTPs, the filled pause duration ratio significantly improved after 12 weeks of donepezil treatment. During the 24-week follow-up, additional SRTPs such as the filled pause count ratio and the filled pause frequency showed significant benefits. ADAS-Cog total scores showed a slight but not significant improvement compared to baseline after 12 and 24 weeks of donepezil treatment. Among the ADAS-Cog subtests, only orientation improved significantly after 24 weeks of donepezil treatment. Our results indicate that subtle changes in SRTPs measured by the Speech-Gap Test® could be considered as sensitive indicators of the efficacy of the pharmacotherapy in mild AD. According to our data, other cognitive domains did not show improvement in response to donepezil therapy rating by ADAS-Cog. Based on all of this, it is likely that examining and evaluating speech parameters may play an important role in determining the effects of pharmacological treatment of mild AD. The novelty of our study is that it applies the measurement of linguistic parameters as primary outcomes during a drug trial of mild AD in scientific research for the first time.

Exploring the Non-Invasive Approaches to Carpal Tunnel Syndrome in Routine Clinical Practice: A Focus on the Role of Acetylcholinesterase Inhibitors.

The prevalence of N. medianus compression neuropathies remains high in clinical practice. The objective was to evaluate modalities of conservative treatments for carpal tunnel syndrome (CTS) focusing on the role of acetylcholinesterase inhibitors. This observational study involved 51 adult outpatients diagnosed with CTS. Patients were observed during routine clinical protocols and we compared two groups of 25 and 26 individuals, with the first group receiving basic therapy for CTS and 20 mg of ipidacrine (Neiromidin®) two or three times a day per os, while the second group received only basic therapy. The condition of all patients was assessed twice, with at least a one-month interval. The parameters evaluated included the Boston Carpal Tunnel Questionnaire (BCTQ); the Disabilities of the Arm, Shoulder, and Hand scale (DASH); and pain intensity on the Numeric Rating Scale (NRS). The mean reduction in DASH score was 12.3 (SD 7.7) in Group 1 and 7.1 (SD 6.3) in Group 2 (p < 0.01). Also, other scores showed statistically significant differences between the two groups: -2.3 vs. -1.0 for NRS, -0.89 vs. -0.44 for SSS, and -0.68 vs. -0.31 for FSS, respectively (p < 0.01). Moreover, these findings correlated positively with the global improvement (CGI-I) between the groups. The addition of ipidacrine to basic therapy led to improved recovery in patients with CTSs of varying severity.

Evaluation of the Ameliorative Potential of 3,5-bis(2-hydroxyethyl)-1,3,5-thiadiazinane-2-thione against Scopolamine-Induced Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, marked by cognitive impairment. Currently, the available treatment provides only symptomatic relief and there is a great need to design and formulate new drugs to stabilize AD. In the search for a new anti-Alzheimer's drug, 3,5-bis(2-hydroxyethyl)-1,3,5-thiadiazinane-2-thione (THTT), a tetrahydro-2H-1,3,5-thiadiazine-2-thione derivative, was investigated against a scopolamine-induced Alzheimer's model. The selected test compound was administered intraperitoneally in three doses (15 mg/kg, 30 mg/kg, and 45 mg/kg). The test compound exhibited an IC50 value of 69.41 µg/mL, indicating its ability to inhibit the acetylcholinesterase enzyme. An antioxidant DPPH assay revealed that the IC50 value of the test compound was 97.75 µg/mL, which shows that the test compound possesses antioxidant activity. The results of behavior tests including the Y-maze and elevated plus maze (EPM) show that the test compound improved short-term memory and spatial memory, respectively. Furthermore, in the Morris water maze (MWM) and light/dark model, the test compound shows improvements in learning and memory. Moreover, the results of histological studies show that the test compound can protect the brain against the harmful effects of scopolamine. Overall, the findings of our investigation suggest that our chosen test compound has disease-modifying and neuroprotective activities against the scopolamine-induced Alzheimer's model. The test compound may be beneficial, subject to further elaborate investigation for anti-amyloid disease-modifying properties in AD.

The combination of donepezil and cognitive training for improving treatment outcomes for alcohol use disorder: Design of a randomized controlled trial.

BACKGROUND: The development of alcohol use disorder (AUD) is a major concern in public health, and cognitive impairments caused by alcohol are involved in this process. Emerging neurobiological evidence suggests that donepezil, an anticholinesterase agent, may improve AUD treatment outcomes by enhancing neurocognitive functioning. Previous research has also suggested that cognitive remediation therapy (CRT) could potentially improve cognitive function and AUD treatment outcomes. We present the rationale and design of a trial to evaluate the combination of donepezil and cognitive remediation therapy (donepezil + CRT) as an intervention for AUD. METHODS: We propose a 13-week, randomized, double-blind, placebo-controlled, between-subjects trial comparing 4 groups (donepezil + CRT vs. donepezil alone vs. CRT alone vs. placebos) as an intervention for AUD. The main goal of the study is to evaluate if donepezil + CRT is superior to placebo in reducing heavy drinking days and improving neurocognitive functioning. A total of 160 patients (4 groups, 40 per each group) with AUD between the ages of 18-80 years will be recruited at Yale University and the VA Connecticut Healthcare System. Primary outcome measures include 1) heavy drinking by Timeline Follow Back (TLFB) over 13 weeks and 2) global neurocognitive functioning by a global index of neurocognitive function score at 7 and 13 weeks. DISCUSSION: This protocol paper describes the rationale and proposed methods for the randomized controlled trial for improving AUD treatment outcomes. This project has significant clinical potential to help patients suffering from AUD by improving their cognition and reducing alcohol consumption. TRIAL REGISTRATION: NCT05042102.

Preoperative management and postoperative complications in 9 dogs undergoing surgical treatment of thymic-associated myasthenia gravis.

Objective: Thymoma-associated paraneoplastic syndromes in dogs and cats include myasthenia gravis, hypercalcemia, exfoliative dermatitis, erythema multiforme, T-cell lymphocytosis, myocarditis, anemia, and polymyositis. Paraneoplastic myasthenia gravis (MG) is the most commonly reported paraneoplastic syndrome in dogs with thymic epithelial tumors. The objective of this study was to examine cases of canine thymic-associated MG treated surgically, with the specific objective of providing an updated clinical picture of the preoperative management, postoperative complications, and outcomes of these cases. Animals: Nine dogs with paraneoplastic MG underwent surgical removal of a thymic epithelial tumor. Procedure: Medical records of dogs with MG that received surgical treatment of a thymic epithelial tumor between January 1, 2012 and October 1, 2022 were obtained from 4 veterinary teaching hospitals. Descriptions of perioperative MG management, complications, and outcomes were reported. Results: Six of the 9 dogs received medical therapy for MG, with either a cholinesterase inhibitor (4 dogs) or a cholinesterase inhibitor and immunosuppressive agent (2 dogs), before surgery. The median duration of medical therapy for MG before surgery was 7.5 d (range: 2 to 60 d). Three of 9 dogs experienced immediate postoperative complications and were euthanized. Six of 9 dogs (66.6%) survived to discharge and 3 of 6 dogs that survived to discharge were alive at the time of writing. At the time of writing, 3 of 6 dogs had complete resolution of clinical signs attributable to MG and 2 of 6 had partial resolution. The median time from surgery to resolution of clinical signs of MG in these dogs was 63 d (range: 2 to 515 d). Conclusion: Dogs with thymic epithelial tumors and paraneoplastic MG are at a high risk for perioperative complications. Clinical relevance: The findings of this study corroborate previous literature stating that paraneoplastic MG is a poor prognostic indicator for dogs with thymic epithelial tumors, while also highlighting the variation in approaches to clinical management of thymic-associated MG in veterinary medicine and the lack of established protocols guiding perioperative management.

Prise en charge préopératoire et complications postopératoires chez 9 chiens subissant un traitement chirurgical de la myasthénie grave associée au thymus. Objectif: Les syndromes paranéoplasiques associés au thymome chez le chien et le chat comprennent la myasthénie grave, l'hypercalcémie, la dermatite exfoliative, l'érythème polymorphe, la lymphocytose à cellules T, la myocardite, l'anémie et la polymyosite. La myasthénie paranéoplasique (MG) est le syndrome paranéoplasique le plus fréquemment rapporté chez les chiens atteints de tumeurs épithéliales thymiques. L'objectif de cette étude était d'examiner les cas de MG canine associée au thymus traités chirurgicalement, dans le but spécifique de fournir un tableau clinique actualisé de la prise en charge préopératoire, des complications postopératoires et des résultats de ces cas. Animaux: Neuf chiens atteints de MG paranéoplasique ont subi l'ablation chirurgicale d'une tumeur épithéliale thymique. Procédure: Les dossiers médicaux des chiens atteints de MG ayant reçu un traitement chirurgical d'une tumeur épithéliale thymique entre le 1er janvier 2012 et le 1er octobre 2022 ont été obtenues auprès de 4 hôpitaux universitaires vétérinaires. Des descriptions de la prise en charge péri-opératoire de la MG, des complications et des résultats ont été rapportées. Résultats: Six des 9 chiens ont reçu un traitement médical pour la MG, avec soit un inhibiteur de la cholinestérase (4 chiens), soit un inhibiteur de la cholinestérase et un agent immunosuppresseur (2 chiens), avant la chirurgie. La durée médiane du traitement médical de la MG avant la chirurgie était de 7,5 jours (plage : 2 à 60 jours). Trois des neuf chiens ont présenté des complications postopératoires immédiates et ont été euthanasiés. Six des 9 chiens (66,6 %) ont survécu jusqu'à leur sortie et 3 des 6 chiens qui ont survécu jusqu'à leur sortie étaient en vie au moment de la rédaction. Au moment de la rédaction de cet article, 3 chiens sur 6 présentaient une résolution complète des signes cliniques attribuables à la MG et 2 chiens sur 6 présentaient une résolution partielle. Le délai médian entre l'intervention chirurgicale et la résolution des signes cliniques de MG chez ces chiens était de 63 jours (plage : 2 à 515 jours). Conclusion: Les chiens atteints de tumeurs épithéliales thymiques et de MG paranéoplasique présentent un risque élevé de complications périopératoires. Pertinence clinique: Les résultats de cette étude corroborent la littérature antérieure indiquant que la MG paranéoplasique est un indicateur de mauvais pronostic pour les chiens atteints de tumeurs épithéliales thymiques, tout en soulignant également la variation des approches de prise en charge clinique de la MG associée au thymus en médecine vétérinaire et le manque de protocoles établis de gestion guidant les interventions périopératoires.(Traduit par Dr Serge Messier).

Analysis of events from sudden isolated dysarthria to diagnosis of myasthenic crisis: myasthenia gravis mimicking acute lacunar stroke-a case report.

BACKGROUND: Myasthenic crisis (MC) is a life-threatening complication of myasthenia gravis (MG), necessitating ventilation. Achieving a safe and timely diagnosis of myasthenic crisis with atypical, isolated presentation is a considerable challenge particularly in elderly patients, where myasthenia gravis can present with isolated dysarthria in rare instances, giving a clinical impression of lacunar stroke. CASE PRESENTATION: We present a compelling case of a 73-year-old Caucasian female presenting with abrupt onset of isolated dysarthria. Despite initial treatment for a presumed lacunar stroke, subsequent evaluations led to her diagnosis of a myasthenic crisis. Within 72 h of admission, the patient developed dysphagia and shortness of breath, requiring supplemental oxygen. The case highlights the sequential progression of events from the atypical presentation of isolated dysarthria and its course to the management of a myasthenic crisis. CONCLUSION: Our reported case focuses on the discussion of myasthenia that mimicked a lacunar stroke and was finally diagnosed at a critical time of medical crisis. This case highlights the imperative notion that isolated dysarthria in elderly individuals warrants vigilant monitoring for possible myasthenia gravis, given the low incidence of lacunar stroke presenting with only dysarthria.

Physostigmine reversal of delirium from second generation antipsychotic exposure: a retrospective cohort study from a regional poison center.

INTRODUCTION: Physostigmine is an effective antidote for antimuscarinic delirium. There is little evidence for its use to reverse delirium following second generation antipsychotic exposure. The purpose of this study is to describe the safety and effectiveness of physostigmine in reversing delirium from second generation antipsychotic exposure. METHODS: This is a retrospective cohort study of all patients reported to a single regional poison center treated with physostigmine following a second generation antipsychotic exposure from January 1, 2000 to April 15, 2021. The poison center electronic medical record was queried to identify cases and for data abstraction. The primary outcome was the positive response rate to physostigmine, as determined by two trained abstractors. Secondary outcomes included physostigmine dosing, and adverse events. RESULTS: Of 147 charts reviewed, 138 individual patients were included, and the response to physostigmine was reported in 128 patients. The most common second-generation antipsychotic exposure was quetiapine (97; 70.3 percent). A positive response to physostigmine was noted in 106/128 (82.8 percent) patients [95 percent confidence interval 68.9-83.6 percent]. Median number of physostigmine doses was 1 (interquartile range 1-3; range 1-9). The median total physostigmine dose received was 2 mg (interquartile range 2-6 mg; range 0.15-30 mg). The positive physostigmine response rate for patients with an antimuscarinic co-ingestion was not significantly different compared to patients with a different co-ingestion or no co-ingestion (25/34 versus 81/94; P = 0.09). Adverse events were reported in four (2.9 percent) patients, including one death. DISCUSSION: A positive response to physostigmine to treat antimuscarinic delirium from second generation antipsychotic exposure was reported in 82.8 percent of patients, which is similar to previous physostigmine studies. Adverse events were infrequent, and included diaphoresis (one 0.7 percent), seizure (one; 0.7 percent), and bradycardia (one; 0.7 percent). One (0.7%) patient suffered a cardiac arrest 60 minutes after receiving physostigmine to treat antimuscarinic delirium following having received increasing clozapine doses over the previous month. CONCLUSIONS: In this study, physostigmine appears to be a safe and effective treatment for antimuscarinic delirium from second generation antipsychotic exposure. Further studies are needed to validate the safety and effectiveness of physostigmine for this indication.

Impact of type 2 diabetes and its duration on incidence rates of dementia death and medication prescription in the Australian population during 2003-2016.

AIMS: To quantify rates of dementia treatment and death among Australians with type 2 diabetes relative to those without diabetes using linked national registries of Australia. METHODS: The study included 891,418 people with type 2 diabetes registered on the National Diabetes Services Scheme and a randomly sampled, population-based comparison group (n = 1,131,369). Outcomes included dementia death (all-cause dementia, Alzheimer's disease (AD) or vascular dementia), and first prescription of cholinesterase inhibitors or memantine. RESULTS: Excess dementia risk was observed in the diabetes group for the composite outcome of all-cause dementia death or dementia medication prescription but varied with age at diabetes diagnosis and its duration. At age 70, the rate of dementia death/medication prescription was ∼1.3 (95% CI 1.2, 1.3) and 1.1 (95% CI 1.1, 1.2) times higher in people with ten and five years of diabetes duration, respectively. Individual outcomes showed that diabetes was associated with a higher incidence of vascular dementia death, whereas an increased risk of AD death was only observed beyond âˆ¼10 years of diabetes duration. Further, the incidence of dementia medication prescription was lower among people with diabetes. CONCLUSIONS: A higher incidence of AD death in the setting of 10+ years of diabetes duration coupled with a lower incidence of AD treatment suggests an under-recognition of this dementia phenotype among people with type 2 diabetes.

Rivastigmine for treatment-refractory posttraumatic stress disorder: a systematic review.

We conducted a systematic review evaluating the efficacy of rivastigmine augmentation for treatment-refractory posttraumatic stress disorder (PTSD). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The databases Ovid MEDLINE, PubMed, CINAHL, and EMBASE were searched using key words: 'rivastigmine' OR 'Exelon' OR 'rivastigmine augmentation' OR 'Exelon augmentation' AND 'posttraumatic stress disorder*' OR 'post-traumatic stress disorder*' OR 'PTSD' OR 'combat disorder*' OR 'post-traumatic symptoms'. The asterisk specified plural forms of the relevant word. Four papers were identified, comprising one double-blind randomised controlled trial, one non-controlled open trial, one case series (presenting three case studies), and one paper with two case studies. The randomised controlled trial found no statistically significant difference in efficacy, using the PTSD CheckList-Military Version as the relevant outcomes measure, between the active add-on rivastigmine interventions and placebo or treatment as usual. The open trial, although reporting relatively positive outcomes, had a weak study design and lacked reporting of key information, including participant sex and age and pre-rivastigmine PTSD measures. The assessment of efficacy was based on participants' reporting of subjective benefits, and clinician-rating using a Clinical Global Impression, rather than established PTSD assessments scales. Although the five case studies reported improvement in PTSD symptoms, there were confounding factors and limitations in clinical and demographic data, warranting caution regarding attributed benefits. There is a lack of methodologically robust evidence supporting the efficacy of add-on rivastigmine for the treatment of refractory PTSD. Additional research may help in further evaluating its possible clinical efficacy.