Ongoing Healthcare Disparities in neuroHIV: Addressing Gaps in the Care Continuum.

PURPOSE OF REVIEW: We aim to review the neurological complications of HIV and the social, cultural, and economic inequalities that contribute to disparities in neuroHIV care. RECENT FINDINGS: Disparities in diagnostics and care of patients with neurological infections and non-infectious conditions associated with HIV in both high-income and low-to-middle-income countries (LMIC) are common. The COVID-19 pandemic has exacerbated these disparities. Factors, such as HIV-related stigma, may deter people from accessing HIV treatment. First-line recommended treatments for neurological infections are not available in many LMICs, leading to inadequate treatment and exposure to agents with more harmful side effect profiles. Access-related factors, such as lack of transportation, lack of health insurance, and inadequate telehealth access, may increase the risk of HIV-related neurological complications. Further research is needed to increase awareness of neurological complications among providers and PWH, and regional guidelines should be considered to better address these complications.

Diffusion Restriction in the Splenium: A Comparative Study of Cytotoxic Lesions of the Corpus Callosum (CLOCCs) versus Lesions of Vascular Etiology.

Cytotoxic lesions of the corpus callosum (CLOCCs) have broad differential diagnoses. Differentiating these lesions from lesions of vascular etiology is of high clinical significance. We compared the clinical and radiological characteristics and outcomes between vascular splenial lesions and CLOCCs in a retrospective cohort study. We examined the clinical and radiologic characteristics and outcomes in 155 patients with diffusion restriction in the splenium of the corpus callosum. Patients with lesions attributed to a vascular etiology (N = 124) were older (64.1 vs. 34.6 years old, p < 0.001) and had >1 vascular risk factor (91.1% vs. 45.2%, p < 0.001), higher LDL and A1c levels, and echocardiographic abnormalities (all p ≤ 0.05). CLOCCs (N = 31) more commonly had midline splenial involvement (p < 0.001) with only splenial diffusion restriction (p < 0.001), whereas vascular etiology lesions were more likely to have multifocal areas of diffusion restriction (p = 0.002). The rate of in-hospital mortality was significantly higher in patients with vascular etiology lesions (p = 0.04). Across vascular etiology lesions, cardio-embolism was the most frequent stroke mechanism (29.8%). Our study shows that corpus callosum diffusion restricted lesions of vascular etiology and CLOCCs are associated with different baseline, clinical, and radiological characteristics and outcomes. Accurately differentiating these lesions is important for appropriate treatment and secondary prevention.

Diffusion-Restricted Lesions of the Splenium: Clinical Presentation, Radiographic Patterns, and Patient Outcomes.

Background and Objectives: Diffusion-restricted (DR) lesions of the splenium are encountered in a wide variety of pathologies, and their significance is often unclear. We sought to report the spectrum of clinical presentations, neuroimaging patterns, and the predictors of radiographic and clinical outcomes from DR splenial lesions. Methods: This was a single-center, retrospective cohort study from January 1, 2009, to August 1, 2020. A consecutive sample of 3,490 individuals who underwent brain MRI with reported corpus callosum lesions during the study period were evaluated for DR lesions in the corpus callosum. DR lesions were defined as increased signal intensity on diffusion-weighted imaging sequences with decreased signal intensity on apparent diffusion coefficient. Patients with prior neurosurgical procedures, hemorrhage-associated DR, anoxic brain injury, and chronic or previously known or characterized disease processes in the corpus callosum were excluded. Clinical and radiologic outcomes were ascertained, including readmissions within 1 year, in-hospital mortality rates, and resolution of DR at first follow-up imaging. Outcomes were defined a priori. Results: Two hundred patients met criteria for inclusion. The average age was 57 years (standard deviation 19 years). Near half of the patients were women (47%). Encephalopathy (55%), focal weakness (46.5%), and cortical signs (44%) were the most common presenting clinical features. Thirty-five cases (17.5%) had features consistent with cytotoxic lesions of the corpus callosum (CLOCCs). Vascular causes were most frequent (61%), followed by malignancy-related (15%) and trauma (8%). In-hospital mortality occurred in 8.5% of cases, 46.5% were readmitted to the hospital within 1 year, and 49.1% of patients had resolution of the splenial DR at the next scan. Backward stepwise regression models showed that mass effect was negatively associated with splenial DR resolution (odds ratio [OR]: 0.12, confidence interval [CI] 0.03-0.46, p = 0.002). Encephalopathy was significantly associated with in-hospital mortality (OR: 4.50, CI 1.48-17.95, p = 0.007). Patients with a CLOCC had less frequent readmissions at 1-year compared with patients without a CLOCC, p = 0.015. Discussion: Vascular DR lesions of the splenium were more common than CLOCCs and other etiologies in this cohort. While splenial DR lesions can present a clinical challenge, their associated clinical and radiographic characteristics may predict outcome and guide prognosis.

HER2+ esophageal carcinoma leptomeningeal metastases treated with intrathecal trastuzumab regimen.

Materials & methods: We recently reported the largest trial of breast cancer patients with HER2 positive leptomeningeal metastases (LM) treated with trastuzumab. An additional treatment indication was explored as part of a single institution retrospective case series of HER2 positive esophageal adenocarcinoma LM (n = 2). Results: One patient received intrathecal trastuzumab (80 mg twice weekly) as part of their treatment regimen with durable long-term response and clearance of circulating tumor cells in the cerebral spinal fluid. The other patient demonstrated rapid progression and death as previously described in the literature. Conclusion: Intrathecal trastuzumab is a well-tolerated and reasonable therapeutic option worthy of further exploration for patients with HER2 positive esophageal carcinoma LM. An associative, but not a causal relationship, can be made regarding therapeutic intervention.

Cancer of the esophagus, the tube that connects the mouth to the stomach, tends to be aggressive. Very rarely, this cancer can spread to the lining that surrounds your brain, called the leptomeninges. Previous reports of patients who have experienced this specific spreading pattern of esophageal cancer to the leptomeninges are quite grim, with patients experiencing rapid decline and death within weeks to months. However, we write with two cases of esophageal cancer with this leptomeningeal spreading pattern, one of which involves a patient treated with a medication known as trastuzumab. As part of his long and complex course of treatment, this patient was given trastuzumab through a tube traveling directly to the area of the leptomeninges. This patient, now almost 2 years out from his initial diagnosis, has responded well to the treatment. As such, we believe that this specific treatment regimen as well as the ways in which our clinical team tracked this patient's response to medications are worth exploring further.

Clinical use of steroids in viral central nervous system (CNS) infections: three challenging cases.

The role of adjunctive corticosteroids in reducing morbidity and mortality of viral CNS infections remains poorly defined. Clinicians are often left in a quagmire regarding steroid use in complex and rapidly evolving viral CNS infections. Limited studies have explored the underlying mechanisms behind the potential benefit of steroids. Here, we describe steroid use in three cases of viral CNS disease: varicella zoster virus (VZV), Powassan virus, and influenza A-associated acute necrotizing encephalopathy.

The Spinal Dural Arteriovenous Fistula in a Patient With Metastatic Renal Cell Carcinoma.

Spinal dural arteriovenous fistula (SDAVF) is an elusive and underdiagnosed disease. Congestive myelopathy occurs from increased venous pressure transmitted by the fistula between a radiculomeningeal artery and the spinal venous plexus. While its cause remains unknown, associations between SDAVF and hyper-vascular states have been reported. We present the first documented case report of a de novo SDAVF diagnosis in a patient with active renal cell carcinoma (RCC) metastasis to the spinal epidural space and review the literature.

Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 "long haulers".

OBJECTIVE: Most SARS-CoV-2-infected individuals never require hospitalization. However, some develop prolonged symptoms. We sought to characterize the spectrum of neurologic manifestations in non-hospitalized Covid-19 "long haulers". METHODS: This is a prospective study of the first 100 consecutive patients (50 SARS-CoV-2 laboratory-positive (SARS-CoV-2+ ) and 50 laboratory-negative (SARS-CoV-2- ) individuals) presenting to our Neuro-Covid-19 clinic between May and November 2020. Due to early pandemic testing limitations, patients were included if they met Infectious Diseases Society of America symptoms of Covid-19, were never hospitalized for pneumonia or hypoxemia, and had neurologic symptoms lasting over 6 weeks. We recorded the frequency of neurologic symptoms and analyzed patient-reported quality of life measures and standardized cognitive assessments. RESULTS: Mean age was 43.2 ± 11.3 years, 70% were female, and 48% were evaluated in televisits. The most frequent comorbidities were depression/anxiety (42%) and autoimmune disease (16%). The main neurologic manifestations were: "brain fog" (81%), headache (68%), numbness/tingling (60%), dysgeusia (59%), anosmia (55%), and myalgias (55%), with only anosmia being more frequent in SARS-CoV-2+ than SARS-CoV-2- patients (37/50 [74%] vs. 18/50 [36%]; p < 0.001). Moreover, 85% also experienced fatigue. There was no correlation between time from disease onset and subjective impression of recovery. Both groups exhibited impaired quality of life in cognitive and fatigue domains. SARS-CoV-2+ patients performed worse in attention and working memory cognitive tasks compared to a demographic-matched US population (T-score 41.5 [37, 48.25] and 43 [37.5, 48.75], respectively; both p < 0.01). INTERPRETATION: Non-hospitalized Covid-19 "long haulers" experience prominent and persistent "brain fog" and fatigue that affect their cognition and quality of life.

Central nervous system disease with JC virus infection in adults with congenital HIV.

OBJECTIVE: The aim of this study was to describe the natural history of individuals with congenital HIV who develop JC virus (JCV) infection of the central nervous system (CNS). METHODS: We retrospectively evaluated individuals with congenital HIV who met criteria for progressive multifocal leukoencephalopathy (PML) or JCV granule cell neuronopathy (JCV GCN) at three major healthcare centres in the northeast USA. Data on adherence to combined antiretroviral therapy (cART), neurologic symptoms, serum markers of immunity and HIV infection, cerebrospinal fluid (CSF) analyses, radiographic features, modified Rankin Scale (mRS) scores and survival were collected from the electronic medical record up to a censoring date of 1 August 2020. RESULTS: Among 10 adults with congenitally acquired HIV, nine were diagnosed with definitive PML and one was diagnosed with probable JCV GCN. Individuals presented at the time of their PML or JCV GCN diagnosis with a mean mRS of 2.0 (standard deviation 1.0). A premorbid mRS was documented for six patients and was zero in all cases. The most common risk factor was confirmed cART nonadherence in nine individuals. Five individuals with PML and one with JCV GCN died, with a latency from symptom onset to death of approximately 3 months for three individuals, and approximately 2 years for the remaining two. CONCLUSION: Youth-adulthood transition is a high-risk point for dropping off from medical care. The study of this timepoint in people living with HIV could help inform effective care in these individuals.

Central nervous system (CNS) enterovirus infections: A single center retrospective study on clinical features, diagnostic studies, and outcome.

Enteroviruses (EV) are responsible for a large number of meningoencephalitis cases, especially in children. The objective of this study was to identify modes of diagnosis including the significance of respiratory and cerebrospinal fluid samples, associated clinical characteristics, inpatient management, and outcome of individuals with EV infections of the central nervous system (CNS). Electronic medical records of individuals with enterovirus infections of the CNS who presented to the Columbia University Irving Medical Center and Children's Hospital of New York between January 1, 2012 and December 31, 2017 were reviewed retrospectively for demographic, epidemiological, and clinical data. The median age overall was 1.7 months (interquartile range 14 years) and most (62.4%) were male. The majority of CNS infections presented as meningitis (95.7%) and occurred in the summer (45.2%) and fall seasons (37.6%). Eighty-five cases (91.4%) demonstrated EV positivity in cerebrospinal fluid, thirty cases (32.3%) exhibited both cerebrospinal fluid and respiratory positivity, and eight cases (8.6%) exhibited respiratory positivity with coinciding neurological findings. Eighty-nine individuals overall (95.7%) received antibiotics and 37 (39.8%) received antiviral treatment. All surviving individuals had favorable Modified Rankin Scores (MRS) within the zero to two ranges upon discharge. Testing respiratory samples in addition to cerebrospinal fluid was found to be an important diagnostic tool in EV-associated cases. While clinical outcomes were favorable for an overwhelming majority of cases, etiological understanding of CNS infections is essential for identifying ongoing and changing epidemiological patterns and aid in improving the diagnosis and treatment.

NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats.

Epidemiological, preclinical, and clinical studies have suggested a role for microdose lithium in reducing Alzheimer's disease (AD) risk by modulating key mechanisms associated with AD pathology. The novel microdose lithium formulation, NP03, has disease-modifying effects in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis at pre-plaque stages, before frank amyloid-ß (Aß) plaque deposition, during which Aß is primarily intraneuronal. Here, we are interested in determining whether the positive effects of microdose lithium extend into early Aß post-plaque stages. We administered NP03 (40µg Li/kg; 1 ml/kg body weight) to McGill-R-Thy1-APP transgenic rats for 12 weeks spanning the transition phase from plaque-free to plaque-bearing. The effect of NP03 on remote working memory was assessed using the novel object recognition task. Levels of human Aß38, Aß40, and Aß42 as well as levels of pro-inflammatory mediators were measured in brain-extracts and plasma using electrochemiluminescent assays. Mature Aß plaques were visualized with a thioflavin-S staining. Vesicular acetylcholine transporter (VAChT) bouton density and levels of chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-6 (IL-6), and 4-hydroxynonenal (4-HNE) were probed using quantitative immunohistochemistry. During the early Aß post-plaque stage, we find that NP03 rescues functional deficits in object recognition, reduces loss of cholinergic boutons in the hippocampus, reduces levels of soluble and insoluble cortical Aß42 and reduces hippocampal Aß plaque number. In addition, NP03 reduces markers of neuroinflammation and cellular oxidative stress. Together these results indicate that microdose lithium NP03 is effective at later stages of amyloid pathology, after appearance of Aß plaques.

Fungal Infections of the Central Nervous System.

Fungal central nervous system infections present in a myriad of clinical manifestation and remain a significant diagnostic challenge. Presenting symptoms, cerebrospinal fluid analysis, conventional fungal serum markers and imaging correlates of disease are seldom sensitive or specific; fungal culture growth or histopathologic analysis are often required for definitive diagnoses but limited by feasibility. Novel diagnostic tools (such as the cryptococcal antigen and next-generation sequencing) have increased diagnostic potency when available but require further studies to define their utility.Invasive fungal infections are an emerging health threat in the setting of increased immunomodulatory treatments, advancements in transplant medicine and increased world-wide travel. Therefore, strong clinical suspicion from epidemiologic clues, clinical progression and presence of CNS dissemination risk factors must be exercised to pursue broad diagnostic workups and rapidly initiate medical and surgical management. This article will describe the epidemiology, clinical presentations, diagnostic approach and therapeutic interventions for fungal infections in the central nervous system.

Quantitative Analysis of Immune Infiltrates in Primary Melanoma.

Novel methods to analyze the tumor microenvironment (TME) are urgently needed to stratify melanoma patients for adjuvant immunotherapy. Tumor-infiltrating lymphocyte (TIL) analysis, by conventional pathologic methods, is predictive but is insufficiently precise for clinical application. Quantitative multiplex immunofluorescence (qmIF) allows for evaluation of the TME using multiparameter phenotyping, tissue segmentation, and quantitative spatial analysis (qSA). Given that CD3+CD8+ cytotoxic lymphocytes (CTLs) promote antitumor immunity, whereas CD68+ macrophages impair immunity, we hypothesized that quantification and spatial analysis of macrophages and CTLs would correlate with clinical outcome. We applied qmIF to 104 primary stage II to III melanoma tumors and found that CTLs were closer in proximity to activated (CD68+HLA-DR+) macrophages than nonactivated (CD68+HLA-DR-) macrophages (P < 0.0001). CTLs were further in proximity from proliferating SOX10+ melanoma cells than nonproliferating ones (P < 0.0001). In 64 patients with known cause of death, we found that high CTL and low macrophage density in the stroma (P = 0.0038 and P = 0.0006, respectively) correlated with disease-specific survival (DSS), but the correlation was less significant for CTL and macrophage density in the tumor (P = 0.0147 and P = 0.0426, respectively). DSS correlation was strongest for stromal HLA-DR+ CTLs (P = 0.0005). CTL distance to HLA-DR- macrophages associated with poor DSS (P = 0.0016), whereas distance to Ki67- tumor cells associated inversely with DSS (P = 0.0006). A low CTL/macrophage ratio in the stroma conferred a hazard ratio (HR) of 3.719 for death from melanoma and correlated with shortened overall survival (OS) in the complete 104 patient cohort by Cox analysis (P = 0.009) and merits further development as a biomarker for clinical application. Cancer Immunol Res; 6(4); 481-93. ©2018 AACR.