Acute and long-term SARS-CoV-2 infection and neurodegeneration processes—circulus vitiosus

COVID-19 Infection and Risk for Neuropsychiatric Symptoms

It is estimated that about 90% of older adults with dementia experience neuropsychiatric symptoms.1 These symptoms include but are not limited to agitation, aggression, delusions, and hallucinations. Neuropsychiatric symptoms are often treated with antipsychotics. However, the use of antipsychotics in the dementia population is associated with an increased risk of death, mostly due to cerebrovascular events. All antipsychotic medications (both first generation and second generation) have a Black Box Warning for increased mortality in elderly patients with dementia-related psychosis.The Centers of Medicare and Medicaid Services (CMS) have taken steps to help reduce this risk with its initiative to decrease the rate of antipsychotic use for inappropriate indications by 15% in every nursing facility.2 In September 2013, the American Psychiatric Association (APA) targeted five ways to decrease the inappropriate use of antipsychotics as first-line treatment for those with neuropsychiatric and behavioral symptoms associated with dementia.3 APA specifically recommends non-pharmacologic interventions as first line therapy. The initiatives to decrease the use of antipsychotics by both CMS and APA highlight the importance of this health care issue in the elderly population.Mr. Smith is a 76 year old Caucasian male who was admitted to the psychiatric hospital from a local emergency room on Day 1 with a chief complaint of depression with suicidal ideation (SI) and aggression. He stated he was confused and wanted to kill himself by slitting his wrist. He presents with paranoia as he thinks someone is trying to kill him. Prior to hospitalization, he resided at a Nursing Home Center for one year and prior to the facility he lived with his wife in their private home. Shortly after entering the rehabilitation and nursing center, he began showing signs of aggression such as throwing a thermometer and grabbing another resident's arm. These behaviors were not characteristic of his usual demeanor while residing in the community with his wife.Mr. Smith denies tobacco, alcohol, and illicit drug use. His past medical history includes multi-infarct dementia (dates and number of events unknown), mood disorder not otherwise specified, pernicious anemia, multiple subdural hematomas (dates unknown), acid reflux with a history of appendectomy, hyperlipidemia, coronary artery disease with a history of CABG, and hypertension. He also presented to the hospital with an acute community-acquired urinary tract infection (UTI), which was diagnosed at the emergency room and an antibiotic regimen was started. As for Mr. Smith's aggression during his hospital stay, he was emotionally labile on admission, yelling out for “hot coffee” and his wife. He also became physically aggressive towards staff, kicking and hitting nurses on his second day of admission. This aggressive behavior deescalated by day 5. He also experienced episodes of drowsiness and was noted to be sleeping through meals, mostly lunch and dinner. While in the hospital Mr. Smith began having periodic episodes of back pain, with a pain score of eight out of ten on two occurrences. He also experienced a ten out of ten pain attributed to emotional stressors, specifically missing his wife.Patient reported Allergies: NSAIDs, cefuroxime, ciprofloxacin, haloperidol, hydromorphone, phenytoin, quetiapine and paroxetineMr. Smith's agitation and aggression can be described as a symptom secondary to multi-infarct dementia. His level of agitation and aggression is mild to moderate as he is not harming himself or harming others. Mr. Smith did pose a threat to staff and himself at the beginning of his hospital stay showing physical aggression Mr. Smith's acute change in behavior can be explained by several triggers. The duration of his mental status change is unknown, but his wife reported he has been declining since he was living with her in the community. This impairment led to his placement in the nursing home. The recent change in environment, UTI, and acute pain episodes can be contributing to his neuropsychiatric symptoms, including agitation and aggression, as well as altered mental status. Changing environments from a familiar home setting with his wife to a skilled nursing facility filled with strangers and different daily activities has most likely negatively impacted his quality of life, resulting in changes in behavior. During his time at the nursing facility, Mr. Smith developed a complicated community acquired UTI that was diagnosed at the ER. In elderly patients with UTIs, a change in mental status is commonly seen as a presenting symptom and usually resolves with the treatment of the infection. For Mr. Smith, the severity of his behaviors diminished with the resolution of his UTI by day 5.Another contributing factor to his agitation is his sporadic episodes of back pain. He denied pain on admission but later needed as needed doses of acetaminophen for complaints of pain. The first dose was given for “all-over aching pain” and for the other two occasions (day 5 and day 8) of acetaminophen use, Mr. Smith experienced severe back pain with an eight out of ten pain score. Nursing also noted that Mr. Smith experienced a ten out of ten emotional pain due to heartache and missing his wife. Although it is unclear if the medication relieved his pain, he was observed to be more at ease after the doses of pain medication. Thus, his uncontrolled back pain and emotional discomfort could have played a role in his development of agitation and aggression.Mr. Smith's previous treatment with olanzapine an indication of dementia, thus not in compliance with the FDA Black Box Warning as well as both CMS's and APA's recommendations for appropriate antipsychotic use. Using olanzapine chronically for the treatment of dementia places Mr. Smith at an increased risk for preventable death and other approaches should be utilized prior to antipsychotic therapy. The data for the use of this medication class in patients with dementia are for symptomatic management not treatment of dementia. Therefore, the long term use of olanzapine for the treatment of his dementia is inappropriate, highlighting the importance of documenting specific indications for antipsychotics in the dementia population.Elderly patients are at an even greater risk for anticholinergic side effects. These effects include dry mucous membranes, constipation, dehydration, and possible delirium; he did not complain of any of these side effects. Currently, Mr. Smith is taking three different anticholinergic medications: olanzapine, trazodone, and famotidine. His anticholinergic burden score is a 3 according to the Anticholinergic Risk Scale, with olanzapine having the greatest burden. Those with a score of 3 or more are at the highest risk for anticholinergic adverse events.4 He does not complain of thirst or dry mouth. However, he may already be experiencing dehydration with a BUN/SCr of 22. These medications also place Mr. Smith at a greater risk for falls, self-harm and worsening agitation due to constipation discomfort, dizziness, confusion, impaired vision, and delirium. There are other viable alternatives to these anticholinergic agents that do not pose as great a risk, for example the use of calcium carbonate or a proton pump inhibitor for GERD and sleep hygiene techniques for insomnia instead of olanzapine.In addition to the anticholinergic medications increasing Mr. Smith's risk of falls, he is also taking clonazepam, as needed lorazepam, and zolpidem, which are all listed in The Beers Criteria for Inappropriate Medications for Older Adults.5 The clonazepam is a home medication, which he was taking for an unknown duration of time. Older adults are particularly sensitive to benzodiazepine and non-benzodiazepine hypnotics, especially longer-acting agents like clonazepam, because they have a decreased metabolism of the medications resulting in accumulation. Mr. Smith's increased exposure to chronic long-acting clonazepam puts him at a high risk for cognitive impairment, delirium, falls, fractures, and behavioral disinhibition. Mr. Smith's subdermal hematoma head wounds show evidence of a past history of falls, making him more likely to fall again. Therefore, a conservative approach should be taken with benzodiazepine therapy and a shorter acting agent may be more appropriate, if needed at all.The first line therapy for neuropsychiatric symptoms in patients with dementia is non-pharmacologic modalities as recommended by APA and CMS. In the unit where Mr. Smith resides, the available interventions include music therapy, recreational therapy, purposeful activities, and vibroacoustic therapy. These non-pharmacologic modalities should be utilized as interventions during agitated episodes and prior to triggers of agitation as well as part of his daily care. Environmental modifications, such as large clocks and a regular daily routine, should be utilized to prevent further escalation of neuropsychiatric symptoms due to an abrupt change in environment as he is now in a hospital setting. To address his emotional pain of missing his wife, a large picture of her should be placed in his room to help console and redirect him during these episodes.First, it is important to address Mr. Smith's primary agitation-trigger: his episodic back pain. Mr. Smith's allergy or intolerance of NSAIDs limits the options for pain management. As previous use of acetaminophen eased Mr. Smith's pain, prophylactic dosing of acetaminophen before possible painful activities such as physical therapy would be appropriate. This medication poses potential hepatic toxicity, thus the total daily amount should not exceed 3 grams. Mr. Smith does not have an underlying liver disorder and his liver enzymes are currently within normal limits.The available medications that have shown some efficacy in the treatment of agitation/aggression in dementia include selective-serotonin reuptake inhibitors, cholines-terase inhibitors, second generation antipsychotics, and mood stabilizers. Valproate and carbamazepine are the mood stabilizers that have been studied for the treatment of these target symptoms. The use of valproate is not recommended, due to lack of efficacy and significantly higher adverse drug reactions (ADRs). There is also currently not enough data to support the use of carbamazepine due to mixed study results, making mood stabilizers a last line treatment. The cholinesterase inhibitors, donepezil and galantamine, may provide some benefit as evidence shows small improvements in the target symptoms, but clinical significance is unknown. Mr. Smith does not have a compelling indication for cholinesterase inhibitors because he has vascular dementia not Alzheimer's dementia.Low-dose risperidone, olanzapine and aripiprazole are the only antipsychotics that have shown benefit in the treatment of neuropsychiatric symptoms. Risperidone (1mg/dose) improved the overall behavioral and psychiatric symptoms of dementia and olanzapine (5–10 mg/dose) improved aggression/agitation, hallucinations, and delusions.1 Aripiprazole (5–15 mg/dose) improved overall neuropsychiatric symptoms in those with Alzheimer's type dementia.6 During his olanzapine therapy at the nursing home there was no documentation of adverse effects. However, during his hospital stay he is experiencing episodes of drowsiness possibly due to olanzapine therapy causing him to sleep through meals, which is negatively impacting his nutritional status. As mentioned previously, the use of antipsychotics in patients with dementia poses an increased risk of cerebrovascular-related mortality. Mr. Smith has multiple risk factors that increase his likelihood of cerebrovascular accidents (CVA),including age greater than 75, gender, hyperlipidemia, hypertension, and a history of stroke(s).Therefore, the use of antipsychotics are not an appropriate choice for him as he is already at an increased risk of developing a CVA and antipsychotics can further increase this risk.Although they are well-tolerated, antidepressants in general do not appear to be very effective in treating neuropsychiatric symptoms. Citalopram is the only antidepressant that has shown to be beneficial in the treatment of neuropsychiatric symptoms.7 However, citalopram can potentially increase the risk of myocardial infarction (MI) and QTc prolongation.8 According to the Framingham risk assessment, Mr. Smith has a 20% or greater risk of having an MI in the next 10 years as he already has coronary artery disease and has had symptomatic carotid artery disease resulting in multiple strokes. However, the risk of citalopram appears to be lower than other antidepressants such as paroxetine.8 Furthermore, in a recent study comparing citalopram and risperidone, citalopram 20 mg daily had similar efficacy in reducing neuropsychiatric symptoms as risperidone and had a significantly lower side effect burden with no incidence of MI or QTc prolongation.9 The risk of MI with citalopram is dose dependent and would not likely occur at a lower dose of 20 mg. Mr. Smith's is also at a high risk of having a recurrent stroke. The incidence of antipsychotics increasing risk of a cerebrovascular events is much higher than citalopram's risk of MIs.1,9 Therefore, citalopram 20 mg daily is both safe and effective and would be a viable option for Mr. Smith, as he also has the compelling-indication of depression.Non-pharmacologic therapy will be initiated as first-line. Music therapy, the Somatron chair, and/or purposeful activities should be used at the onset of unknown agitation and in anticipation of agitation triggers. Daily routine for Mr. Smith including meals at the same time and orienting environmental modifications (e.g., large clock, wife's photo in room, name on door and other labeled areas) to help decrease agitation due to environmental changes should be continued. The standing order of olanzapine should be discontinued.After the initiation of these non-pharmacologic interventions, Mr. Smith's neuropsychiatric symptoms are expected to improve. However, if Mr. Smith continues to show signs of uncontrolled agitation/aggression, citalopram 20 mg daily should be initiated. The full benefit of citalopram is expected to occur after at least two weeks of therapy. Therefore, olanzapine 5 mg every 6 hours as needed will be available for incidences of severe agitation, which is defined as physically harming himself and/or others. Mr. Smith should be monitored for the resolution of agitation, aggressive behavior, depression and changes in mood. He should also be monitored for the adverse effects of confusion, gastrointestinal upset, sedation, and chest pain.

Effect of Gastrointestinal Symptoms in Patients With COVID-19

The COVID-19 Pandemic and Post-Infection Irritable Bowel Syndrome: What Lies Ahead for Gastroenterologists

Concerns about the effects of propranolol on the central nervous system (CNS) in the infantile hemangioma (IH) population have been raised. We conducted a meta-analysis of the CNS and sleep-related effects of oral propranolol in IH patients. PubMed, Embase, Cochrance, Web of Science, and Clinicaltrials.gov were searched for relevant studies. We included clinical trials that compared oral propranolol with other treatments among IH patients under 6 years old and monitored and reported any adverse events. Study characteristics, types and number of adverse events were abstracted. Cochrane Collaboration Risk of Bias Tool was used to assess risk of bias. Our main outcomes were CNS and sleep-related effects. Random-effects models were used to estimate the pooled risk ratio. We did not observe statistically significant associations between oral propranolol and CNS or sleep-related effects. Oral propranolol appeared to have a safer profile of CNS effects than corticosteroids (RR = 0.27, 95% CI 0.02–3.00), but had an increased risk versus non-corticosteroids (for CNS effect, RR = 1.40, 95% CI 0.86–2.27; for sleep-related effects, RR = 1.63, 95% CI 0.88–3.03). Despite no statistically significant associations, there were suggestive findings of increased CNS effects and sleep-related risk of propranolol versus non-corticosteroids. In practice, CNS and sleep-related events should be monitored more closely among IH patients treated with oral propranolol.

A multisystem diagnostic mystery: unilateral weakness, a rash, and lymphadenopathy.

2021 Workshop: Neurodegenerative Diseases in the Gut-Brain Axis—Parkinson's Disease

Objective Chronic diarrhea affects approximately 5% of the population. Opioids inhibit gastrointestinal motility, and opium tincture has shown anti-propulsive effects in healthy, but no controlled studies of its clinical efficacy exist. We aimed to investigate the anti-propulsive and central nervous system (CNS) effects of opium tincture in patients with chronic diarrhea. Materials and methods The study was a randomized, double-blinded, placebo-controlled, cross-over trial in subjects with chronic diarrhea refractory to standard treatment. Participants received opium tincture or placebo during two intervention periods, each lasting seven days. Bowel movements were recorded daily, and gastrointestinal transit time was investigated with the wireless motility capsule system. Gastrointestinal symptoms, health-related quality of life, and CNS effects (pupil size, reaction time, memory, and general cognition) were also investigated, along with signs of addiction. Results Eleven subjects (mean age: 45 ± 17 years, 46% males) with a median of 4.7 daily bowel movements were included. The number of daily bowel movements was reduced during opium tincture treatment to 2.3 (p = 0.045), but not placebo (3.0, p = 0.09). Opium tincture prolonged the colonic transit time compared to placebo (17 h vs. 12 h, p < 0.001). In both treatment arms, there were no changes in self-reported gastrointestinal symptoms, health-related quality of life, or CNS effects, and no indication of addiction was present. Conclusion Opium tincture induced anti-propulsive effects in patients with chronic diarrhea refractory to standard treatment. This indicates that opium tincture is a relevant treatment strategy for selected patients with chronic diarrhea. Moreover, no evidence of opioid-induced sedation or addiction was found. Trial Registration Number: NCT05690321 (registered 2023-01-10)

The mainstay of pharmacological treatment of overactive bladder (OAB) is anticholinergic therapy using muscarinic receptor antagonists (tertiary or quaternary amines). Muscarinic receptors in the brain play an important role in cognitive function, and there is growing awareness that antimuscarinic OAB drugs may have adverse central nervous system (CNS) effects, ranging from headache to cognitive impairment and episodes of psychosis. This review discusses the physicochemical and pharmacokinetic properties of OAB antimuscarinics that affect their propensity to cause adverse CNS effects, as observed in phase III clinical trials and in specific investigations on cognitive function and sleep architecture. PubMed/MEDLINE was searched for "OAB" plus "muscarinic antagonists" or "anticholinergic drug." Additional relevant literature was identified by examining the reference lists of papers identified through the search. Preclinical and clinical trials in adults were assessed, focusing on the OAB antimuscarinics approved in the United States. The blood-brain barrier (BBB) plays a key role in protecting the CNS, but it is penetrable. The lipophilic tertiary amines, particularly oxybutynin, are more likely to cross the BBB than the hydrophilic quaternary amine trospium chloride, for which there are very few reports of adverse CNS effects. In fact, in 2008 the US product labels for oral oxybutynin were modified to include the potential for anticholinergic CNS events and a warning to monitor patients for adverse CNS effects. Even modest cognitive impairment in the elderly may negatively affect independence; therefore, selection of an antimuscarinic OAB drug with reduced potential for CNS effects is advisable.

Background and Aim: The global pandemic of COVID-19 has posed an enormous threat to the economy and people's lives across various countries. Patients with COVID-19 most commonly present with respiratory symptoms. However, gastrointestinal (GI) symptoms can also occur. We aimed to study the relationship between GI symptoms and disease prognosis in patients with COVID-19.Methods: In a single-center and retrospective cohort study, the outcomes in COVID-19 patients with or without GI symptoms were compared. The propensity score is a conditional probability of having a particular exposure (COVID-19 patients with GI symptoms vs. without GI symptoms) given a set of baseline measured covariates. Survival was estimated using the Kaplan-Meier method, and any differences in survival were evaluated with a stratified log-rank-test. To explore the GI symptoms associated with ARDS, non-invasive ventilator treatment, tracheal intubation, tracheotomy, and CRRT, univariable and multivariable COX regression models were used.Results: Among 1,113 eligible patients, 359 patients with GI symptoms and 718 without GI symptoms had similar propensity scores and were included in the analyses. Patients with GI symptoms, as compared with those without GI symptoms, were associated with a similar risk of death, but with higher risks of ARDS, non-invasive mechanical ventilation in COVID-19 patients, respectively.Conclusions: The presence of GI symptoms was associated with a high risk of ARDS, non-invasive mechanical ventilation and tracheal intubation in patients with COVID-19 but not mortality.

This article reports the results of neurobehavioral tests on C(5)-C(10) normal paraffinic constituents (n-paraffins). Shortly after exposure, effects were evaluated in several domains including clinical effects, motor activity, functional observations, and visual discrimination performance. The representative C(5) n-paraffin, n-pentane, did not produce any evidence of acute central nervous system (CNS) effects at levels up to 20 000 mg/m(3). Similarly, there was no compelling evidence that n-octane (C(8)) produced CNS effects at 14 000 mg/m(3), the highest concentration tested. n-decane (C(10)) produced minor, reversible acute CNS effects at 5000 mg/m(3), with 1500 mg/m(3) as the no-effect level. Consistent with literature data, there seemed to be a relationship between increasing molecular weight up to C(10) and acute CNS effects. However, the CNS effects were reversible. Repeated exposures did not provide evidence of metabolic induction.

IntroductionThe SARS-CoV-2 virus, responsible for COVID-19, has been shown to affect the central nervous system (CNS), leading to a wide range of acute and long-term neuropsychiatric symptoms. These symptoms can profoundly impair cognitive and emotional functioning, highlighting the need for a deeper understanding of their underlying mechanisms and clinical manifestations. Addressing these sequelae is critical for developing effective management strategies and improving patient outcomes. Long COVID has been associated with conditions such as brain fog, depression, anxiety, and fatigue, which can further exacerbate pre-existing mental health conditions and impair quality of life.ObjectivesThis review aims to examine the neuropsychiatric manifestations associated with COVID-19, focusing on both acute and long-term (long COVID) effects, and to explore potential pathophysiological mechanisms, including neuroinflammation and immune dysregulation.MethodsA systematic review of literature was conducted by searching databases such as PubMed and Scopus, using terms like ‘COVID-19’, ‘neuropsychiatric symptoms’, ‘long COVID’, ‘inflammation’, and ‘CNS involvement’. Only peer-reviewed articles published between 2020 and 2023 were included, with an emphasis on studies reporting acute neuropsychiatric symptoms and post-acute sequelae of COVID-19.KeywordsCOVID-19, neuropsychiatric symptoms, long COVID, neuroinflammation, interleukin-6, CNS involvementResultsAcute neuropsychiatric manifestations of COVID-19 include encephalopathy, delirium, seizures, and mood disturbances. Approximately 22.5% of COVID-19 patients present with neuropsychiatric symptoms during the acute phase, including anxiety, depression, and cognitive impairment. In long COVID, persistent symptoms such as fatigue, depression, anxiety, sleep disorders, and cognitive dysfunction have been reported, with neuroinflammation and elevated interleukin-6 (IL-6) levels proposed as key mechanisms. Neuropsychiatric symptoms are observed in both hospitalized and non-hospitalized individuals, with risk factors including severe infection, female sex, and pre-existing mental health conditions.ConclusionsCOVID-19 is associated with a broad spectrum of neuropsychiatric symptoms that persist beyond the acute phase. The underlying pathophysiology likely involves immune dysregulation, cytokine-mediated neuroinflammation, and direct viral invasion of the CNS. Early recognition and targeted interventions are essential to mitigate long-term neuropsychiatric complications.Disclosure of InterestNone Declared

Morphine and morphine-6-glucuronide (M6G) produce central nervous system (CNS) effects by activating mu-opioid receptors, while naloxone is used mainly for the reversal of opioid overdose, specifically for the fatal complication of respiratory depression, but also for alleviating opioid-induced side effects. In this study we developed a physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model to simultaneously predict pharmacokinetics and CNS effects (miosis, respiratory depression and analgesia) of morphine as well as antagonistic effects of naloxone against morphine. The pharmacokinetic and pharmacodynamic parameters were obtained from in vitro data, in silico, or animals. Pharmacokinetic and pharmacodynamic simulations were conducted using 39 and 36 clinical reports, respectively. The pharmacokinetics of morphine and M6G following oral or intravenous administration were simulated, and the PBPK-PD model was validated using clinical observations. The Emax model correlated CNS effects with free concentrations of morphine and M6G in brain parenchyma. The predicted CNS effects were compared with observations. Most clinical observations fell within the 5th-95th percentiles of simulations based on 1000 virtual individuals. Most of the simulated area under the concentration-time curve or peak concentrations also fell within 0.5-2-fold of observations. The contribution of morphine to CNS effects following intravenous or oral administration was larger than that of M6G. Pharmacokinetics and antagonistic effects of naloxone on CNS effects were also successfully predicted using the developed PBPK-PD model. In conclusion, the pharmacokinetics and pharmacodynamics of morphine and M6G, antagonistic effects of naloxone against morphine-induced CNS effects may be successfully predicted using the developed PBPK-PD model based on the parameters derived from in vitro, in silico, or animal studies.

Refractory Pneumonia in a 12-year-old Girl with Hemoglobin SS Disease

Background: Sedation in terminally-ill cancer patients is typically used to alleviate symptoms of physical distress during the last week of life, in order to allow patients to achieve serenity. These include pain, as well as respiratory, neuropsychiatric, and gastrointestinal symptoms. The purpose of this study is to investigate the effect of the sedative protocol containing ketamine, midazolam, and morphine (KMM) on symptoms of terminally-ill cancer patients at the end-of-life, as well as on consciousness level, and overall survival. Methods and Findings: This retrospective study included terminally-ill cancer patients (>18 years) who completed cancer-specific treatment and received KMM upon hospitalization. Medical records were reviewed. The symptoms were classified according to their severity before and during treatment. Control of debilitating symptoms and level of consciousness during the hospitalization was clinically evaluated. Results: The study included 30 patients (10 males; mean age, 55 years). Range doses were: 0.1-1 mg/kg, 0.05-0.5 mg/kg, and 0.5-5 mg/kg daily, for ketamine, midazolam, and morphine, respectively. The mean survival was 4.6 days (therefore, analyses focused on the first 3 days). A statistically significant decrease in pain was achieved on the first day of treatment (P<0.0001). Further improvement was sustained through the following 2 days (P=0.022). An improvement in respiratory, gastrointestinal, and neuropsychiatric symptoms was reported (P=0.033). A significant decline in consciousness level was observed with time. The initial pain level (before administrating KMM) was negatively associated with survival. Conclusions: The KMM protocol is an effective method in controlling pain and providing relief from respiratory, neuropsychiatric, and gastrointestinal symptoms. No KMMassociated complications were identified. Further research is warranted.