Addressing LGBTQ+ health equity and disparities in multiple sclerosis: A call for research and action.

Multiple sclerosis (MS) research has largely overlooked the experiences of the LGBTQ+ community, leaving significant gaps in understanding and addressing their unique health equity challenges. Despite widespread recognition of LGBTQ+ health disparities, particularly in neurology, research at the intersection of sexual orientation, gender identity, and MS remains limited. LGBTQ+ individuals encounter systemic barriers such as discrimination and lack of culturally competent care, exacerbating disparities in MS management and outcomes. Existing studies are scarce, highlighting the urgent need for increased funding and support for research initiatives. By prioritizing LGBTQ+ inclusivity in research, healthcare, and advocacy, we can strive for a more equitable future in MS care.

Podcast on the Challenges and Recommendations to Address Unmet Needs in MS for LGBTQ+ Populations in the United States.

In general, individuals who are lesbian, gay, bisexual, transgender, queer or questioning, plus other identities (LGBTQ+) living with multiple sclerosis (MS) have less favorable healthcare experiences and poorer overall health than cisgendered heterosexual individuals. They may experience further challenges in addition to managing their MS, including psychological or emotional problems, and an increased risk of comorbid diseases and substance abuse. Transgender individuals specifically face additional unique challenges, including high rates of mental health distress and effects from long-term exogenous hormone use and gender affirmation surgery. These findings highlight disparities in both quality of care and health outcomes of LGBTQ+ individuals. Unmet needs and drivers of these disparities relate to a lack of inclusivity in healthcare environments, poor communication between healthcare professionals (HCPs) and LGBTQ+ patients, inadequate HCP knowledge of LGBTQ+ health issues, and gaps in research into the impact of sexual orientation and gender identity in MS. Although data are limited, recommendations to improve the experience and care of LGBTQ+ individuals with MS include increasing HCP awareness of the challenges LGBTQ+ individuals face and provision of inclusive care, with the overarching goal for HCPs to be allies to the LGBTQ+ community. Improvements may be achieved through diversity and cultural awareness training of HCPs on sexual orientation and gender identity, and ensuring a friendly, open, and supportive healthcare environment. Use of sensitive and gender-neutral language by HCPs, representation of LGBTQ+ individuals in patient materials, and access to LGBTQ+ MS support groups are also recommended. HCPs should aim to integrate discussion of sexual orientation and gender identity and sexual and mental health into routine assessments and collaborate with other HCPs as needed. By addressing the challenges and unmet needs of LGBTQ+ individuals with MS, this should help resolve disparities in their quality of care and improve their overall health.

Tixagevimab and Cilgavimab (Evusheld) boosts antibody levels to SARS-CoV-2 in patients with multiple sclerosis on b-cell depleters.

BACKGROUND AND OBJECTIVES: B-cell-depleting therapies may affect the development of a protective immune response following vaccination against SARS-CoV-2. It is important to have a different strategy for creating immunity in this patient population. The objective of this study was to evaluate whether Evusheld (tixagevimab co-packaged with cilgavimab) affects the antibody response to SARS-CoV-2 following an attenuated response to the vaccines against SARS-CoV-2 in patients on b-cell depleters who have multiple sclerosis. METHODS: This was a single-center cohort study performed at Methodist Hospitals in Merrillville, IN, USA. It included patients with multiple sclerosis treated with ocrelizumab and ofatumumab. Patients had already received the mRNA vaccinations against SARS-CoV-2 and had demonstrated an attenuated response on baseline antibody testing. All participants received 150 mg of Evusheld. Follow-up antibody levels were measured at least two weeks following Evusheld injections. RESULTS: All patients (100%) developed the highest level of antibodies possible at least two weeks following Evusheld injections. DISCUSSION: In this study, patients with MS who had an attenuated antibody response to the COVID-19 vaccines due to exposure to b-cell depleters now had the highest antibody response possible after receiving Evusheld. This is important as it provides a different strategy for protection against COVID-19.

B-cell depleters attenuate the humoral response to SARS-CoV-2 vaccines in multiple sclerosis patients: A case-control study.

BACKGROUND: B-cell depleting agents are FDA approved for the treatment of RRMS (ocrelizumab (OCR) and ofatumumab (OFA)) and PPMS (OCR).  In the case of OCR, prior studies have raised concerns about patients' ability to form antibodies in response to various antigens, especially SARS-CoV-2. In addition, emerging data have shown an attenuated humoral response to vaccines against SARS-CoV-2. The objective of this study is to determine whether b-cell depleters or sphingosine 1-phosphate (S1P) modulators attenuate the antibody response to various SARS-CoV-2 vaccines in patients with MS as compared with other MS disease modifying therapies (DMTs). METHODS: This is a case-control study looking at the odds of developing antibodies to three SARS-CoV-2 vaccines (Pfizer-BioNTech, Moderna, and Johnson & Johnson) in patients treated with b-cell depleters or S1P modulators versus other disease modifying therapies.  Patients were recruited at the Comprehensive MS Center at Methodist Hospitals. Patients who did not have a prior COVID-19 infection and received one of the three vaccines were tested for antibodies against the SARS-CoV-2 spike protein (Labcorp, semi-quantitative total antibody) at least two weeks following the final dose of the vaccine. Groups (B-cell, S1P modulators, other DMT, and no DMT) were compared on antibody level. The main outcome was whether or not a humoral response was detected by antibody testing. Dichotomous antibody response was tested using logistic regression models, and the quantitative response was tested using ANCOVA adjusted for covariates (age, sex, race, MS type, disease duration, vaccine, and lymphocyte count). P-values <0.05 were considered significant. RESULTS: Sixty-seven patients were enrolled in the study, with 17 on OCR, 3 on OFA, 12 on S1P modulators, 29 on other DMT, and 6 not currently on any DMT. Patients who received OCR or OFA had decreased odds of forming antibodies (OR 0.031, p < 0.001, 95% CI (0.003-0.268)). Patients who received S1P modulators did not have decreased odds of forming antibodies (OR 0.413, p = 0.413, 95% CI (0.28-21.7). However, when analyzing the antibody response as a continuous variable, patients on S1P modulators showed lower absolute levels of antibodies (p = 0.024). CONCLUSIONS: Patients who received B-cell depleters within the prior 6 months of SARS-CoV-2 vaccination had decreased odds of developing antibodies compared with other DMTs.  In line with other similar research, this suggests that b-cell depleters attenuate the antibody response to SARS-CoV-2 vaccines.  Although S1P modulators had an attenuation of the absolute antibody level, the odds of being negative did not differ from those on other DMTs.

Attenuation of antibody response to SARS-CoV-2 infection in patients with multiple sclerosis on ocrelizumab: A case-control study.

OBJECTIVE: Ocrelizumab (OCR) is a monoclonal antibody directed at B-cells that is FDA approved for treatment of RRMS and PPMS. Prior studies have raised concerns about patients' ability to form antibodies in response to various antigens, especially SARS-CoV-2. The objective of this study is to determine whether OCR attenuates the antibody response to SARS-CoV-2 in patients with MS as compared with other disease modifying therapies. METHODS: This is a case-control study looking at the odds of developing antibodies to SARS-CoV-2 in patients treated with OCR versus other disease modifying therapies. From May 13, 2020 through March 1, 2021, patients with a RT-PCR-confirmed infection to SARS-CoV-2 were tested for presence of antibodies and the data was recorded. Outpatients with MS at the Methodist Hospitals Comprehensive MS Center were selected who had a prior infection with COVID-19 as demonstrated by RT-PCR in the electronic health records. Odds ratios were calculated to compare rates of antibody formation with OCR exposure vs other DMT. RESULTS: 24 patients had evidence of COVID-19 and had antibody testing available at the time of analysis. Patients who received OCR had decreased odds of forming antibodies (OR 0.045, p = 0.011, 95% CI (0.004,0.488)). CONCLUSIONS: Patients who received OCR within the prior 6 months of COVID-19 infection had decreased odds of developing antibodies as compared with other DMTs. This suggests that OCR may attenuate the antibody response to SARS-CoV-2. Additional studies should analyze the odds of spike protein antibody formation in response to SARS-CoV-2 vaccines for patients on OCR.

Herpes Simplex Virus 2 Meningoencephalitis-Associated Bilateral Optic Neuritis and Radiculitis.

The most common ocular complication of herpes simplex virus (HSV) is acute retinal necrosis. We present a rare case of a patient with HSV-2 meningoencephalitis that developed severe vision-threatening optic neuritis. The patient was treated with steroids and IVIG, which allowed a rapid improvement in her vision.

Reduction in ocrelizumab-induced infusion reactions by a modified premedication protocol.

BACKGROUND: Ocrelizumab is a monoclonal antibody directed against CD20+ B cells that is approved for MS. The most common side effect is infusion-associated reactions (IARs). This study examines whether a modified premedication protocol reduces incidence of IARs and further examines predictors of IARs. METHODS: Patients took cetirizine 10 mg, ranitidine 75 mg, and increased hydration the night before the ocrelizumab infusion. This regimen was repeated the next day prior to arrival. Just prior to the infusion, patients were pretreated with IV diphenhydramine 50 mg, IV methylprednisolone 125 mg, and oral acetaminophen 650 mg. Rates of IARs with this modified protocol were compared to patients who had received only pretreatment medications. RESULTS: 207 patients received ocrelizumab. With the modified premedication protocol, we found significant decreased odds of IARs (OR 0.40, p = 0.024, 95% CI (0.18, 0.88). Among the baseline characteristics, there was a significant reduction of IARs with increasing age (OR 0.94, p = 0.001) and male sex (OR 0.34, p = 0.034). Body mass index (BMI) increased the odds of IARs (OR 1.07, p = 0.029). Race and smoking status did not affect IARs. CONCLUSION: The modified premedication protocol described herein significantly decreases rates of IARs by 60% and suggests that the additional premedication regimen is beneficial. Age and male sex are protective for IARs while BMI is a risk factor for IARs.

Multiple neuroanatomical tract-tracing using fluorescent Alexa Fluor conjugates of cholera toxin subunit B in rats.

Cholera toxin subunit B (CTB) is a highly sensitive retrograde neuroanatomical tracer. With the new availability of fluorescent Alexa Fluor (AF) conjugates of CTB, multiple neuroanatomical connections can be reliably studied and compared in the same animal. Here we provide a protocol that describes the use of AF-CTB for studying connections in the central nervous system of rats. The viscous properties of CTB allow small and discreet injection sites yet still show robust retrograde labeling. Furthermore, the AF conjugates are extremely bright and photostable, compared with other conventional fluorescent tracers. This protocol can also be adapted for use with other neuroanatomical tracers. Including a 7-d survival period, this protocol takes approximately 11 to 12 d to complete in its entirety.

The efficacy of the fluorescent conjugates of cholera toxin subunit B for multiple retrograde tract tracing in the central nervous system.

Cholera toxin subunit B (CTB) is a sensitive neuroanatomical tracer that generally transports retrogradely in the nervous system, and has been used extensively in brightfield microscopy. Recently, Alexa Fluor (AF) conjugates of CTB have been made available, which now allows multiple tracing with CTB. In this study, we examined the efficacy of these new AF-CTB conjugates when injected into the brain, and compared the results to our previous experiences using fluorescent 3k dextran amines. To test this, we injected AF 488 and AF 594 CTB into the anterior cingulate cortex and the medial agranular cortex in the rat, and examined the retrograde transport to the lateral posterior nucleus of the thalamus. We found that CTB was very viscous but yet very sensitive: small injection sites revealed very intense and detailed retrograde labeling. Anterograde transport was seen only when tissue at the injection site was damaged. These findings suggest that AF-CTB is a very reliable and sensitive retrograde tracer, and should be the first choice retrograde tracer for experiments examining multiple pathways within the same brain.

Cortical connections of the rat lateral posterior thalamic nucleus.

Spatial processing related to directed attention is thought to be mediated by a specific cortical-basal ganglia-thalamic-cortical network in the rat. Key components of this network are associative cortical areas medial agranular cortex (AGm) and posterior parietal cortex (PPC), dorsocentral striatum (DCS), and lateral posterior (LP) thalamic nucleus, all of which are interconnected. Previously, we found that thalamostriatal projections reaching DCS arise from separate populations of neurons of the mediorostral part of LP (LPMR). The far medial LPMR (fmLPMR) terminates in central DCS, a projection area of AGm, whereas central LPMR terminates in dorsal DCS, a projection area of PPC. This represents segregated regional convergence in DCS from different sources of thalamic and cortical inputs. In the present study, thalamocortical and corticothalamic projections arising from and terminating in LPMR and neighboring thalamic nuclei were studied by anterograde and retrograde tracing techniques in order to further understand the anatomical basis of this neural circuitry. A significant finding was that within LPMR, separate neuronal populations provide thalamic inputs to AGm or PPC and that these cortical areas project to separate regions in LPMR, from which they receive thalamic inputs. Other cortical areas adjacent to AGm or PPC also demonstrated reciprocal connections with LP or surrounding nuclei in a topographic manner. Our findings suggest that the cortical-basal ganglia-thalamic network mediating directed attention in the rat is formed by multiple loops, each having reciprocal connections that are organized in a precise and segregated topographical manner.

Topography in the projections of lateral posterior thalamus with cingulate and medial agranular cortex in relation to circuitry for directed attention and neglect.

In the rat, the lateral posterior thalamic nucleus (LP) has reciprocal connections with areas of the cortex and the striatum involved in directed attention and its dysfunctional counterpart, contralateral neglect. It has also been shown that the medial portion of the mediorostral part of LP (mLPMR) is of special interest because it has connections with the dorsocentral striatum, a key node in this circuitry. In the present study we used neuroanatomical tracers to map the specific connections and topography of LP with the anterior cingulate cortex (ACC) and medial agranular cortex (AGm). We primarily used Alexa Fluor conjugates of the retrograde tracer cholera toxin subunit B, and injected two different colored conjugates into ACC and AGm in the same animal in order to directly compare the differential topography of the thalamocortical connections of mLPMR. The bidirectional tracer, dextran amine, was also used to examine anterograde corticothalamic projections of AGm and ACC. We found that mLPMR consists of two distinct groups of neurons, with the more dorsal group projecting to ACC and the more ventral group projecting to AGm. This is mirrored by a similar corticothalamic topography. These findings suggest that the ventral mLPMR is specifically associated with AGm and dorsocentral striatum, while dorsal mLPMR is associated with ACC. They also suggest that ACC may play a role in the circuitry for directed attention and contralateral neglect, as it is known to do in humans.