Associations of Systemic Inflammation and Senescent Cell Biomarkers with Clinical Outcomes in Older Adults with Schizophrenia.

Individuals with schizophrenia suffer from higher morbidity and mortality throughout life partly due to acceleration of aging-related diseases and conditions. Systemic inflammation is a hallmark of aging and is also observed in schizophrenia. An improved understanding of how inflammation and accelerated aging contribute to long-term health outcomes in schizophrenia could provide more effective treatments to preserve long-term cognitive and physical function. In this pilot cross-sectional study, 24 older adults (≥55 years old) with schizophrenia were assessed on symptoms (Positive and Negative Syndrome Scale), neurocognition (Matrics Consensus Cognitive Battery), mobility (Timed Get Up and Go), and general health (SF-12). Serum levels of 112 different cytokines were measured, from which we derived estimated senescence-associated secretory phenotype (SASP) scores for each participant. Two-tailed Pearson's bivariate correlations were computed to test the associations between schizophrenia clinical outcomes with individual cytokines, and SASP. Higher levels of eotaxin, IL-1α, IL-1ß, and IFNα are associated with both worse PANSS negative and depressive symptoms scores. IL-1α and IL-1ß negatively associated with general physical health whereas eotaxin negatively associated with mobility and global cognition. Overall, we found that specific inflammatory cytokines, but not composite measurements of SASP, are associated with clinical outcomes in older adults with schizophrenia.

Emerging Subspecialties in Neurology: Women's Neurology.

The influence of sex and gender on neurologic disease has become increasingly recognized in science and medicine. This is evident across a woman's lifespan especially during periods of hormonal transitions. Leaders in neurology have advocated for the importance of sex and gender-enriched clinical care, education, and research. The scope of women's neurology spans across a woman's life including puberty, adolescence, peripartum care, menopause, and aging. Women's neurology is a new subspecialty that aligns with a specific patient population and intersects with established neurology subspecialties and other specialties such as obstetrics, maternal fetal medicine, endocrinology, and psychiatry. Its establishment and collaboration with existing and emerging fields enables a more comprehensive approach to neurologic illness through the lens of sex and gender. Women's neurology is rapidly evolving through increased focus at academic centers, including expanded women's neurology curricula, dedicated women's neurology fellowship programs, improved understanding of sex and gender issues in neurosciences, and expansion of therapeutic options. Herein, we describe the history of the women's neurology field, emerging need for women's neurology specialists, information about training and career opportunities, and future directions.

Association of biological aging with frailty and post-transplant outcomes among adults with cirrhosis.

Frailty is classically associated with advanced age but is also an important predictor of clinical outcomes in comparatively young adults with cirrhosis. We examined the association of biological aging with frailty and post-transplant outcomes in a pilot of adults with cirrhosis undergoing liver transplantation (LT). Frailty was measured via the Liver Frailty Index (LFI). The primary epigenetic clock DNA methylation (DNAm) PhenoAge was calculated from banked peripheral blood mononuclear cells; we secondarily explored two first-generation clocks (Hannum; Horvath) and two additional second-generation clocks (GrimAge; GrimAge2). Twelve adults were included: seven frail (LFI ≥ 4.4, mean age 55 years) and five robust (LFI < 3.2, mean age 55 years). Mean PhenoAge age acceleration (AgeAccel) was + 2.5 years (P = 0.23) for frail versus robust subjects. Mean PhenoAge AgeAccel was + 2.7 years (P = 0.19) for subjects who were readmitted or died within 30 days of discharge post-LT versus those without this outcome. When compared with first-generation clocks, the second-generation clocks demonstrated greater average AgeAccel for subjects with frailty or poor post-LT outcomes. Measuring biological age using DNAm-derived epigenetic clocks is feasible in adults undergoing LT. While frail and robust subjects had the same average chronological age, average biological age as measured by second-generation epigenetic clocks tended to be accelerated among those who were frail or experienced a poor post-LT outcome. These results suggest that frailty in these relatively young subjects with cirrhosis may involve similar aging mechanisms as frailty classically observed in chronologically older adults and warrant validation in a larger cohort.

Advancing specificity in delirium: The delirium subtyping initiative.

BACKGROUND: Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long-term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology. METHODS: The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts. RESULTS: Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium-spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations. DISCUSSION: The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes. HIGHLIGHTS: Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning.

Clinical Reasoning: A 22-Year-Old Man With Multifocal Brain and Osseous Lesions.

The evaluation of patients with disseminated processes with CNS and osseous involvement is often challenging. A 22-year-old healthy man developed left-sided weakness, paresthesias, and neck pain over several weeks. On clinical examination, he was noted to have decreased right eye visual acuity, left-sided pyramidal weakness and numbness, and bilateral hyperreflexia. MRI revealed multifocal widespread abnormalities: nonenhancing lesions throughout the infratentorial brain, pituitary gland, right frontal lobe, and optic nerves, in addition to an enhancing intramedullary cervical spinal cord lesion, extensive nodular leptomeningeal enhancement of the spine, and numerous enhancing bony lesions throughout the vertebrae and iliac bones. CSF analysis was notable for normal opening pressure, protein 465 mg/dL, glucose 21 mg/dL, and normal cell count. Extensive serum and CSF analysis for infectious, inflammatory, and neoplastic etiologies was unrevealing, and the diagnosis was ultimately revealed after additional staining of tissue biopsy specimen from sacral and cerebellar biopsies. This case highlights the differential diagnoses for widely disseminated disease affecting the CNS and bones and informs pediatric and adult clinicians of important recent developments regarding this diagnostic entity.

Anti-CD20 monoclonal antibody therapy in postpartum women with neurological conditions.

OBJECTIVE: Postpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti-CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease-modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti-CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes. METHODS: Fifty-seven cis-women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post-infusion. Breastmilk was collected pre-infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients' questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes. RESULTS: The median average concentration of mAb in breastmilk was low (OCR: 0.08 µg/mL, range 0.05-0.4; RTX: 0.03 µg/mL, range 0.005-0.3). Concentration peaked 1-7 days post-infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was <1% (OCR: 0.1%, range 0.07-0.7; RTX: 0.04%, range 0.005-0.3). Forty-three participants continued to breastfeed post-infusion. At 8-12 months, the proportion of infants' growth between the 3rd and 97th World Health Organization percentiles did not differ for breastfed (36/40) and non-breastfed (14/16, p > 0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non-breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse. INTERPRETATION: These confirm minimal transfer of mAb into breastmilk. Anti-CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well-tolerated for both mother and infant.

Jugular Foramen Syndrome Caused by Varicella Zoster Virus Infection.

Jugular foramen syndrome (JFS) is a lower cranial neuropathy syndrome characterized by dysphonia and dysphagia. The syndrome is caused by dysfunction of the glossopharyngeal, vagus, and spinal accessory nerves at the level of the pars nervosa and pars vascularis within the jugular foramen. There are numerous etiologies for JFS, including malignancy, trauma, vascular, and infection. Here, we present the case of a healthy adult man who developed JFS secondary to an atypical presentation of Varicella Zoster meningitis, and was promptly diagnosed and treated with rapid symptom resolution. We diagnosed the patient using specialized skull-based imaging which detailed the jugular foramen, as well as CSF analysis. This case highlights the clinical value of detailed structural evaluation, consideration for infection in the absence of systemic symptoms, and favorable outcomes following early identification and treatment.

Clinical and Radiographic Characteristics of Nocardia vs Non-Nocardia Brain Abscesses.

Background and Objectives: Diagnosis and treatment of CNS nocardiosis is challenging and often delayed, which increases morbidity and mortality. The primary objective was to compare the clinical and radiographic characteristics of patients with CNS nocardiosis with non-Nocardia bacterial brain abscesses. Methods: We performed a case-control study of patients with brain abscesses diagnosed between 1998 and 2018 at a tertiary academic center. We identified 56 patients with brain MRI demonstrating brain abscess from the institutional imaging database: 14 with culture-confirmed nocardiosis and 42 randomly selected prevalent controls with culture-confirmed non-Nocardia bacterial infection. The primary outcomes were the diagnosis of concomitant lung infection and history of immunosuppression. Secondary outcomes included abscess radiographic characteristics: multifocality, occipital lobe and/or infratentorial location, and bilobed morphology. Results: Compared with patients with non-Nocardia brain abscesses, patients with CNS nocardiosis were older (median 61 years [IQR 59-69] vs 48 years [IQR 34-61]; p = 0.03), more likely to be immunosuppressed [71% (10) vs 19% (8); p < 0.001), have diabetes (36% (5) vs 10% [4]; p = 0.03), or a concomitant lung infection (86% [12] vs 2% [1]; p < 0.001). Radiographically, more cases of CNS nocardiosis exhibited multifocal abscesses (29% [4] vs 2% [1]; p = 0.01), which were located in the infratentorial (43% [6] vs 10% (4); p = 0.01) or occipital (36% [5] vs 5% [2]; p = 0.008) regions and had a bilobed (as opposed to unilobed) morphology (79% [11] vs 19% [8]; p < 0.001). Blood and CSF cultures were negative in most of the cases and controls, whereas neurosurgical specimen culture yielded a diagnosis in 100% of specimens. Discussion: Patients with CNS nocardiosis were more likely to be older, have a history of diabetes or immunosuppression, or have a concomitant lung infection compared with those with non-Nocardia brain abscesses. Abscesses because of CNS nocardiosis were more likely to be multifocal, affect the infratentorial region or occipital lobe, or have a bilobed appearance. Neurosurgical specimen culture was most likely to yield a diagnosis for both Nocardia and non-Nocardia abscesses. The combination of clinical and imaging findings may suggest CNS nocardiosis and inform early initiation of targeted empiric treatment.

Spinal epidural arteriovenous fistula with nerve root enhancement mimicking myeloradiculitis: a case report.

BACKGROUND: Gadolinium enhancement of spinal nerve roots on magnetic resonance imaging (MRI) has rarely been reported in spinal dural arteriovenous fistula (SDAVF). Nerve root enhancement and cerebrospinal fluid (CSF) pleocytosis can be deceptive and lead to a misdiagnosis of myeloradiculitis. We report a patient who was initially diagnosed with neurosarcoid myeloradiculitis due to spinal nerve root enhancement, mildly inflammatory cerebrospinal fluid, and pulmonary granulomas, who ultimately was found to have an extensive symptomatic SDAVF. CASE PRESENTATION: A 52-year-old woman presented with a longitudinally extensive spinal cord lesion with associated gadolinium enhancement of the cord and cauda equina nerve roots, and mild lymphocytic pleocytosis. Pulmonary lymph node biopsy revealed non-caseating granulomas and neurosarcoid myeloradiculitis was suspected. She had rapid and profound clinical deterioration after a single dose of steroids. Further work-up with spinal angiography revealed a thoracic SDAVF, which was surgically ligated leading to clinical improvement. CONCLUSIONS: This case highlights an unexpected presentation of SDAVF with nerve root enhancement and concurrent pulmonary non-caseating granulomas, leading to an initial misdiagnosis with neurosarcoidosis. Nerve root enhancement has only rarely been described in cases of SDAVF; however, as this case highlights, it is an important consideration in the differential diagnosis of non-inflammatory causes of longitudinally extensive myeloradiculopathy with nerve root enhancement. This point is highly salient due to the importance of avoiding misdiagnosis of SDAVF, as interventions such as steroids or epidural injections used to treat inflammatory or infiltrative mimics may worsen symptoms in SDAVF. We review the presentation, diagnosis, and management of SDAVF as well as a proposed diagnostic approach to differentiating SDAVF from inflammatory myeloradiculitis.

Predisposing and Precipitating Factors Associated With Delirium: A Systematic Review.

Importance: Despite discrete etiologies leading to delirium, it is treated as a common end point in hospital and in clinical trials, and delirium research may be hampered by the attempt to treat all instances of delirium similarly, leaving delirium management as an unmet need. An individualized approach based on unique patterns of delirium pathophysiology, as reflected in predisposing factors and precipitants, may be necessary, but there exists no accepted method of grouping delirium into distinct etiologic subgroups. Objective: To conduct a systematic review to identify potential predisposing and precipitating factors associated with delirium in adult patients agnostic to setting. Evidence Review: A literature search was performed of PubMed, Embase, Web of Science, and PsycINFO from database inception to December 2021 using search Medical Subject Headings (MeSH) terms consciousness disorders, confusion, causality, and disease susceptibility, with constraints of cohort or case-control studies. Two reviewers selected studies that met the following criteria for inclusion: published in English, prospective cohort or case-control study, at least 50 participants, delirium assessment in person by a physician or trained research personnel using a reference standard, and results including a multivariable model to identify independent factors associated with delirium. Findings: A total of 315 studies were included with a mean (SD) Newcastle-Ottawa Scale score of 8.3 (0.8) out of 9. Across 101 144 patients (50 006 [50.0%] male and 49 766 [49.1%] female patients) represented (24 015 with delirium), studies reported 33 predisposing and 112 precipitating factors associated with delirium. There was a diversity of factors associated with delirium, with substantial physiological heterogeneity. Conclusions and Relevance: In this systematic review, a comprehensive list of potential predisposing and precipitating factors associated with delirium was found across all clinical settings. These findings may be used to inform more precise study of delirium's heterogeneous pathophysiology and treatment.

Potential for remote vital sign monitoring to improve hospital patient sleep: A feasibility study.

BACKGROUND: Even low-acuity patients suffer from disrupted sleep in the hospital in part due to routine overnight vital sign (VS) checks. When invasive monitoring is not needed, vital sign monitoring devices (VSMDs) similar to consumer-grade health monitors may play a role in promoting sleep, which can aid healing and recovery. METHODS: We provided one VSMD to neuroscience ward patients during their hospital stays and used surveys to assess patient and nurse attitudes toward the device and the impact of the device on patient comfort. We also compared VSMD-streamed vS data to nurse-recorded vS data in the chart to evaluate the consistency of data streaming and data concordance between the device and nurse-collected vital sign values. FINDINGS: 21 patients and 15 nurses enrolled. Overall, patients and nurses responded positively to the device and patients preferred wearing the device to receiving manual vital checks overnight. The most common device-related cause of sleep disruption per patients was device weight (29%). Device vS were concordant with nurse vS on average but there was significant variance in agreement between nurse and device values. INTERPRETATION: Patients and nurses feel positively about the use of VSMDs and their use in the hospital. The device we tested may be limited in its sleep promotion by its weight and patient comfort assessment. Further research is needed to assess the precision of the device in measuring vital signs when used in a clinical setting. Future studies should compare VSMD models and assess their impacts on patient sleep in the absence of manual vS checks overnight. FUNDING: Funding provided by the Sara & Evan Williams Foundation Endowed Neurohospitalist Chair at UCSF.

Opinion and Special Article: The Need for Specialized Training in Women's Neurology.

Women's Neurology is an emerging subspecialty that focuses on neurologic disorders across a woman's lifetime. This new domain recognizes that both health and disease are directly affected by hormonal and reproductive changes throughout the life span. This field includes neurologic diseases with a higher prevalence in women and diseases that require specialized management during pregnancy, postpartum period, lactation, and menopause. A survey was sent to US neurology residency program directors to understand the state of training in the area. Their responses highlighted an urgent need for additional education in this field for neurology residents. In this study, we discuss the educational gaps in this area, the clinical benefits of a women's neurology discipline, and the instructional gaps in this area and provide practical recommendations for training programs in women's neurology using 2 innovative fellowship programs.

Hepatic and renal function impact concentrations of plasma biomarkers of neuropathology.

Introduction: The impact of hepatorenal function on plasma biomarkers of neuropathology is unknown. Herein, we measured several plasma biomarkers in patients with cirrhosis. Methods: Plasma phosphorylated tau (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau), and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) were measured in 135 adults with cirrhosis and 22 healthy controls using Simoa. Within cirrhosis, associations between biomarkers and hepatorenal function were explored using linear regression. Results: p-tau181, NfL, t-tau, and UCHL1 were increased 2- to 4-fold in cirrhosis, whereas GFAP was not increased. Within cirrhosis, creatinine moderately correlated with p-tau181 (ß = 0.75, P < .01), NfL (ß = 0.32, P < .01), and t-tau (ß = 0.31, P < .01), but not GFAP (ß = -0.01, P = .88) or UCHL1 (ß = -0.05, P = .60), whereas albumin showed weak, inverse correlations: p-tau181 (ß = -0.18, P < .01), NfL (ß = -0.22, P < .01), GFAP (ß = -0.17, P < .05), t-tau (ß = -0.20, P = .02), and UCHL1 (ß = -0.15, P = .09). Conclusions: Elevated p-tau181, NfL, and t-tau in cirrhosis were associated with renal impairment and hypoalbuminemia, suggesting that hepatorenal function may be important when interpreting plasma biomarkers of neuropathology.

Reproductive Rights in Neurology-The Supreme Court's Impact on All of Us.

This Viewpoint discusses how abortion bans will affect the delivery of current standard neurologic care for many patients, specifically standards that depend on planning or preventing pregnancies using individual choice.

Giant cell myositis associated with metastatic thymoma and granulomatous hypercalcaemia.

Giant cell myositis (GCM) is a rare inflammatory myopathy associated with myasthenia gravis and thymoma. Here, we report on a woman in her late 50s with a history of myasthenia gravis, systemic lupus erythematosus and stage IV thymoma with pleural metastases, who presented with proximal weakness, neuromuscular respiratory failure and hypercalcaemia. She was diagnosed with GCM via muscle biopsy and screened for myocarditis but showed no evidence of myocardial involvement. Her hypercalcaemia was consistent with a granulomatous process, likely driven by her GCM. Her strength gradually improved, and her hypercalcaemia did not recur after treatment with high dose steroids, intravenous immune globulin and plasma exchange. Her course was complicated by several opportunistic infections in the setting of her immunosuppression. Despite the high morbidity associated with GCM, she demonstrated clinical improvement after initiating immunosuppressive therapy and continues to be managed in the outpatient setting.

COVID-19 severity and age increase the odds of delirium in hospitalized adults with confirmed SARS-CoV-2 infection: a cohort study.

BACKGROUND: Despite recognition of the neurologic and psychiatric complications associated with SARS-CoV-2 infection, the relationship between coronavirus disease 19 (COVID-19) severity on hospital admission and delirium in hospitalized patients is poorly understood. This study sought to measure the association between COVID-19 severity and presence of delirium in both intensive care unit (ICU) and acute care patients by leveraging an existing hospital-wide systematic delirium screening protocol. The secondary analyses included measuring the association between age and presence of delirium, as well as the association between delirium and safety attendant use, restraint use, discharge home, and length of stay. METHODS: In this single center retrospective cohort study, we obtained electronic medical record (EMR) data using the institutional Epic Clarity database to identify all adults diagnosed with COVID-19 and hospitalized for at least 48-h from February 1-July 15, 2020. COVID-19 severity was classified into four groups. These EMR data include twice-daily delirium screenings of all patients using the Nursing Delirium Screening Scale (non-ICU) or CAM-ICU (ICU) per existing hospital-wide protocols. RESULTS: A total of 99 patients were diagnosed with COVID-19, of whom 44 patients required ICU care and 17 met criteria for severe disease within 24-h of admission. Forty-three patients (43%) met criteria for delirium at any point in their hospitalization. Of patients with delirium, 24 (56%) were 65 years old or younger. After adjustment, patients meeting criteria for the two highest COVID-19 severity groups within 24-h of admission had 7.2 times the odds of having delirium compared to those in the lowest category [adjusted odds ratio (aOR) 7.2; 95% confidence interval (CI) 1.9, 27.4; P = 0.003]. Patients > 65 years old had increased odds of delirium compared to those < 45 years old (aOR 8.7; 95% CI 2.2, 33.5; P = 0.003). Delirium was associated with increased odds of safety attendant use (aOR 4.5; 95% CI 1.0, 20.7; P = 0.050), decreased odds of discharge home (aOR 0.2; 95% CI 0.06, 0.6; P = 0.005), and increased length of stay (aOR 7.5; 95% CI 2.0, 13; P = 0.008). CONCLUSIONS: While delirium is common in hospitalized patients of all ages with COVID-19, it is especially common in those with severe disease on hospital admission and those who are older. Patients with COVID-19 and delirium, compared to COVID-19 without delirium, are more likely to require safety attendants during hospitalization, less likely to be discharged home, and have a longer length of stay. Individuals with COVID-19, including younger patients, represent an important population to target for delirium screening and management as delirium is associated with important differences in both clinical care and disposition.

KIBRA, MTNR1B, and FKBP5 genotypes are associated with decreased odds of incident delirium in elderly post-surgical patients.

Despite the association between cognitive impairment and delirium, little is known about whether genetic differences that confer cognitive resilience also confer resistance to delirium. To investigate whether older adults without postoperative delirium, compared with those with postoperative delirium, are more likely to have specific single nucleotide polymorphisms (SNPs) in the FKBP5, KIBRA, KLOTHO, MTNR1B, and SIRT1 genes known to be associated with cognition or delirium. This prospective nested matched exploratory case-control study included 94 older adults who underwent orthopedic surgery and screened for postoperative delirium. Forty-seven subjects had incident delirium, and 47 age-matched controls were not delirious. The primary study outcome was genotype frequency for the five SNPs. Compared with participants with delirium, those without delirium had higher adjusted odds of KIBRA SNP rs17070145 CT/TT [vs. CC; adjusted odds ratio (aOR) 2.80, 95% confidence interval (CI) 1.03, 7.54; p = 0.04] and MTNR1B SNP rs10830963 CG/GG (vs. CC; aOR 4.14, 95% CI 1.36, 12.59; p = 0.01). FKBP5 SNP rs1360780 CT/TT (vs. CC) demonstrated borderline increased adjusted odds of not developing delirium (aOR 2.51, 95% CI 1.00, 7.34; p = 0.05). Our results highlight the relevance of KIBRA, MTNR1B, and FKBP5 in understanding the complex relationship between delirium, cognition, and sleep, which warrant further study in larger, more diverse populations.

Approach to Altered Mental Status and Inpatient Delirium.

Altered mental status is a nonspecific diagnosis that encompasses a wide spectrum of disease and is frequently cited as a reason for both hospital admission and inpatient neurologic consultation. There are numerous etiologies of altered mental status, and so although many are facile with the workup of this potentially life-threatening entity, it can nevertheless be overwhelming. Our goal was to provide a practical framework embedded in a current, comprehensive review of the epidemiology, clinical evaluation, and management of undifferentiated altered mental status. We pay particular attention to the management of a critical yet underdiagnosed subtype of altered mental status: delirium.