Compassionate-use pocapavir and immunoglobulin therapy for treatment of rituximab-associated enterovirus meningoencephalitis.

A 71-year-old woman previously on rituximab treatment for rheumatoid arthritis presented with 2 years of progressive neurologic symptoms. She was found to have persistent hypogammaglobulinemia and B cell depletion despite rituximab discontinuation a year prior. MRI revealed diffuse meningeal enhancement along the entire neuroaxis. LP showed a CSF lymphocytic pleocytosis, elevated protein, and presence of enterovirus by PCR. The patient was hospitalized several times for progressive clinical and radiologic decline, though she had transient improvements following treatment with immunoglobulin therapy. Her CSF remained positive for enterovirus PCR for at least 12 months. Though two brain biopsies were non-diagnostic, pan-Enterovirus was ultimately identified using a high-throughput next-generation sequencing technique. She was treated with compassionate-use pocapavir with clinical stabilization at 4-month follow-up; however, she expired 8 months later from a bacterial pneumonia.

Outcomes of COVID-19 infection in multiple sclerosis and related conditions: One-year pandemic experience of the multicenter New York COVID-19 Neuroimmunology Consortium (NYCNIC).

OBJECTIVE: To determine outcomes of COVID-19 in patients with Multiple Sclerosis (MS) and related conditions, and to determine predictors of these outcomes. METHODS: This was a multicenter, observational cohort study of patients with MS or related CNS autoimmune disorders who developed confirmed or highly suspected COVID-19 infection from 2/1/2020 to 12/31/2020. MAIN OUTCOME AND MEASURE: The primary outcome measure was hospitalization status due to COVID-19. Severity of infection was measured using a 4-point ordinal scale: 1. home care; 2. hospitalization without mechanical ventilation; 3. hospitalization and mechanical ventilation, and 4. death. RESULTS: Of 474 patients in the study, 63.3% had confirmed COVID-19 infection and 93.9% were diagnosed with an MS phenotype. Mean age was 45 ± 13 (mean±SD) years, 72% were female, and 86% were treated with a DMT at the time of infection. 58 patients (12.2%) were hospitalized. 24 patients (5.1%) were critically ill (requiring ICU care or outcome of death), of which 15 patients (3.2%) died. Higher neurological disability and older age independently predicted hospitalization. 85% (102/120) of patients with known antibody results not treated with anti-CD20 therapies were seropositive while only 39.5% (17/43) of patients treated with anti-CD20 demonstrated seropositivity (p < 0.0001). Only 25% (2/8) of patients with PCR-confirmed COVID-19 being treated with anti-CD20 therapies demonstrated seropositivity. CONCLUSIONS: Neurological disability and older age independently predicted hospitalization due to COVID-19. Additionally, the results demonstrate that anti-CD20 therapies significantly blunt humoral responses post-infection, a finding that carries implications with regards to natural or vaccine-mediated immunity.

Evaluation of ocrelizumab in older progressive multiple sclerosis patients.

BACKGROUND: Seminal trials evaluating anti-CD20 therapy in progressive MS primarily found benefit in younger, less-disabled patients with more inflammatory disease activity. The risks and benefits of ocrelizumab use in older patients with progressive froms of MS are not known. METHODS: Retrospective chart review was performed for patients older than 55 with primary or secondary progressive MS at the time of ocrelizumab initiation. Clinical endpoints from 2 years prior to anti-CD20 therapy served as a within-subject control. RESULTS: Data was reviewed for 56 patients older than the age of 55 at the time of ocrelizumab initiation. Of 37 patients with 2-years of follow up on ocrelizumab, 40%(n=15) experienced confirmed disability progression (CDP) while 60% (n=22) remained stable or improved. 24 patients had data available for the within-subject control; for these patients, median age was 67, baseline EDSS 6.3, and disease duration 20.5 years. Prior to anti-CD20 therapy, 58% (n=14) of patients remained stable and 42% (n=10) experienced CDP. After ocrelizumab initiation, 71% (n=17) remained stable and 29% (n=7) experienced CDP. There was no difference between CDP (p=0.54) or change in EDSS (p=0.09) between time periods. Ocrelizumab was well tolerated and no difference in infection rate was seen using the within-subject control. CONCLUSIONS: We found no difference in clinical endpoints for patients on ocrelizumab compared to prior to anti-CD20 therapy; however, we could not exclude a modest effect given our sample size. Larger trials are needed to evaluate ocrelizumab use in this understudied MS subpopulation.

Potential Neurologic Manifestations of COVID-19.

PURPOSE OF REVIEW: Neurologic complications are increasingly recognized in the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This coronavirus is related to severe acute respiratory syndrome coronavirus (SARS-CoV) and other human coronavirus-related illnesses that are associated with neurologic symptoms. These symptoms raise the question of a neuroinvasive potential of SARS-CoV-2. RECENT FINDINGS: Potential neurologic symptoms and syndromes of SARS-CoV-2 include headache, fatigue, dizziness, anosmia, ageusia, anorexia, myalgias, meningoencephalitis, hemorrhage, altered consciousness, Guillain-Barré syndrome, syncope, seizure, and stroke. In addition, we discuss neurologic effects of other coronaviruses, special considerations for management of neurologic patients, and possible long-term neurologic and public health sequelae. SUMMARY: As SARS-CoV-2 is projected to infect a large part of the world's population, understanding the potential neurologic implications of COVID-19 will help neurologists and others recognize and intervene in neurologic morbidity during and after the pandemic of 2020.

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.

General dentists' use of diagnostic equipment and methods.

An accurate diagnosis is essential for making treatment decisions in dentistry. However, little research is available as to which tests are done routinely and how commonly they are performed. The purpose of this study was to investigate diagnostic methods and equipment used by general dentists in private practice in Perth. The study involved a retrospective audit of 30 patient records from seven individual general dentists working in private practices in the Perth Metropolitan area. De-identification of patient records was done prior to the researchers' visit. Radiographs were the most commonly used diagnostic tool. Percussion was also commonly employed, followed by cold pulp testing and mobility. The most commonly used tests were radiographs, percussion, periodontal probing and visual examination. The frequency of these tests differed depending on whether the patient presented with or without pain, with percussion and cold tests used more frequently when the patient presented with pain.

Median Arcuate Ligament Syndrome Is Not a Vascular Disease.

BACKGROUND: Median arcuate ligament syndrome (MALS) is a rare disorder characterized by postprandial abdominal pain, weight loss, and celiac stenosis. Diagnosis can be challenging, leading to a delay in treatment. We report on our continued experience using a laparoscopic approach for this uncommon diagnosis. METHODS: This is an Institutional Review Board-approved, prospectively collected retrospective analysis of patients treated with laparoscopic MAL release at our institution. Data collected included patient demographics, preoperative symptoms, operative approach, and postoperative outcomes. Patients were then contacted to complete a postoperative survey designed to assess the improvement of symptoms and overall patient satisfaction. RESULTS: A total of 39 patients (33 women and 6 men) underwent laparoscopic MAL release from March 2007 to July 2014. Mean age was 40.6 years (range, 17-77 years). Thirty of 39 patients had a postoperative celiac axis ultrasound. Twenty-three had a patent celiac axis on postoperative duplex. Of the remaining 7, 5 with residual celiac axis stenosis and 1 with occlusion, reported complete resolution of their symptoms. One remaining patient with occlusion remained symptomatic. Thirty-three of 39 (84.6%) reported symptom relief after surgery. Nine of 33 (27.3%) responders had cardiovascular risk factors versus 4 of 6 (67%) nonresponders. Five patients with atypical presentations underwent preoperative diagnostic celiac plexus block using local anesthetic, with 4 reporting symptom reliefs after block. These 4 patients also reported postoperative symptom relief. One patient of 39 received a postoperative celiac stent placement and remained symptomatic. There were 4 conversions to open surgery (10.3%) and no deaths. CONCLUSIONS: Laparoscopic MAL release continues to be a safe and effective means of managing MALS. Our data suggest that the symptoms associated with MALS are not related to vascular compromise, and atherosclerotic risk factors may predict poorer outcomes. Symptomatic relief is seen in the vast majority of patients undergoing this procedure. However, patient selection remains critically important in obtaining optimal results.

Abnormal hip physical examination findings in asymptomatic female soccer athletes.

PURPOSE: Examination of the hip provides information regarding risk for pre-arthritic hip disorders, knee injuries, and low back pain. The purpose of this study was to report a hip screening examination of asymptomatic female soccer athletes and to test the hypothesis that these findings vary by competition experience. METHODS: Asymptomatic females from a youth soccer club, a college, and a professional team were evaluated. Passive hip range of motion, hip abduction strength, and hip provocative tests were assessed. Data were compared for the grade/middle school, high school, college, and professional athletes. RESULTS: One hundred and seventy-two athletes with a mean age of 16.7 ± 5 years (range 10-30) participated. Professional athletes had less flexion (HF) for both hips (p < 0.0001) and less internal rotation (IR) for the preferred kicking leg (p < 0.05) compared to all other groups. Grade/middle school athletes had more external rotation in both hips as compared to all other groups (p < 0.0001). For the preferred kicking leg, collegiate athletes had less hip abduction strength as compared to other groups (p < 0.01). Positive provocative hip tests were found in 22 % of all players and 36 % of the professionals. In professionals, a positive provocative test was associated with ipsilateral decreased HF (p = 0.04). CONCLUSION: Asymptomatic elite female soccer athletes with the most competition experience had less bilateral hip flexion and preferred kicking leg IR than less-experienced athletes. Positive provocative hip tests were found in 22 % of athletes. Future studies are needed to show whether these findings link to risk for intra-articular hip or lumbar spine and knee disorders. LEVEL OF EVIDENCE: III.

VILIP-1 expression in vivo results in decreased mouse skin keratinocyte proliferation and tumor development.

VILIP-1, a member of the neuronal Ca(2+) sensor protein family, is able to act as a tumor suppressor in carcinoma cells by inhibiting cell proliferation and migration. In order to study the role of VILIP-1 in skin carcinogenesis we generated transgenic mice overexpressing VILIP-1 in epidermis under the control of the bovine keratin K5 promoter (K5-VILIP-1). We studied the susceptibility of FVB wild type and VILIP-1 transgenic mice to chemically mediated carcinogenesis. After 30 weeks of treatment with a two-stage carcinogenesis protocol, all animals showed numerous skin tumors. Nevertheless, K5-VILIP-1 mice showed decreased squamous cell carcinoma (SCC) multiplicity of approximately 49% (p<0.02) with respect to the corresponding SCC multiplicity observed in wild type (WT) mice. In addition, the relative percentage of low-grade cutaneous SCCs grade I (defined by the differentiation pattern according to the Broders grading scale) increased approximately 50% in the K5-VILIP1 mice when compared with SCCs in WT mice. Similar tendency was observed using a complete carcinogenesis protocol for skin carcinogenesis using benzo(a)pyrene (B(a)P). Further studies of tumors and primary epidermal keratinocyte cultures showed that matrix metalloproteinase 9 (MMP-9) levels and cell proliferation decreased in K5-VILIP-1 mice when compared with their wild counterparts. In addition tissue inhibitor of metalloproteinase 1 (TIMP-1) expression was higher in K5-VILIP-1 keratinocytes. These results show that VILIP-1 overexpression decreases the susceptibility to skin carcinogenesis in experimental mouse cancer models, thus supporting its role as a tumor suppressor gene.

VILIP-1 downregulation in non-small cell lung carcinomas: mechanisms and prediction of survival.

VILIP-1, a member of the neuronal Ca++ sensor protein family, acts as a tumor suppressor gene in an experimental animal model by inhibiting cell proliferation, adhesion and invasiveness of squamous cell carcinoma cells. Western Blot analysis of human tumor cells showed that VILIP-1 expression was undetectable in several types of human tumor cells, including 11 out of 12 non-small cell lung carcinoma (NSCLC) cell lines. The down-regulation of VILIP-1 was due to loss of VILIP-1 mRNA transcripts. Rearrangements, large gene deletions or mutations were not found. Hypermethylation of the VILIP-1 promoter played an important role in gene silencing. In most VILIP-1-silent cells the VILIP-1 promoter was methylated. In vitro methylation of the VILIP-1 promoter reduced its activity in a promoter-reporter assay. Transcriptional activity of endogenous VILIP-1 promoter was recovered by treatment with 5'-aza-2'-deoxycytidine (5'-Aza-dC). Trichostatin A (TSA), a histone deacetylase inhibitor, potently induced VILIP-1 expression, indicating that histone deacetylation is an additional mechanism of VILIP-1 silencing. TSA increased histone H3 and H4 acetylation in the region of the VILIP-1 promoter. Furthermore, statistical analysis of expression and promoter methylation (n = 150 primary NSCLC samples) showed a significant relationship between promoter methylation and protein expression downregulation as well as between survival and decreased or absent VILIP-1 expression in lung cancer tissues (p<0.0001). VILIP-1 expression is silenced by promoter hypermethylation and histone deacetylation in aggressive NSCLC cell lines and primary tumors and its clinical evaluation could have a role as a predictor of short-term survival in lung cancer patients.