Analysis of Evusheld safety and efficacy in multiple sclerosis patients.

BACKGROUND: In December 2021, the U.S. Food and Drug Administration issued emergency use authorization for the combination monoclonal antibodies tixagevimab and cilgavimab (Evusheld - AstraZeneca) for COVID-19 pre-exposure prophylaxis. While COVID-19 vaccination is recommended for multiple sclerosis (MS) patients, there is concern for insufficient antibody response in patients receiving B-cell depleting therapies. The literature is sparse regarding the safety and efficacy of Evusheld use in MS patients. OBJECTIVE: We sought to investigate the administration, safety, and efficacy of Evusheld in MS patients. METHODS: Participants were consecutively recruited from the UCSD MS Center from July 2022 to October 2022. We conducted both a review of medical records and a prospective cohort study. Inclusion criteria included prior diagnosis of MS and eligibility for Evusheld injection due to use of B-cell depleting disease modifying therapy (DMT). All eligible patients were evaluated to determine uptake of Evusheld use. Participant surveys were distributed to Evusheld recipients that evaluated for potential Evusheld side effects and COVID-19 vaccination and infection history. The proportion of COVID-19 infections among participants with or without Evusheld use were compared using Fisher's exact test, and a negative binomial regression analysis was used to evaluate risk for COVID-19 infection after Evusheld administration. RESULTS: A review of medical records showed that 79 MS patients were offered Evusheld by their clinicians during the recruitment period; 48 patients ultimately received the injection. Forty-two participants consented to the prospective cross-sectional study (mean age 46.4 years, 71.8 % female), of which 33 individuals received Evusheld. All participants received at least one COVID-19 vaccination dose, with 92.3 % receiving the initial series and at least one booster dose. One-third (30.8 %) of participants had a previous COVID-19 infection. DMTs included ocrelizumab, rituximab, and ofatumumab. Of the 33 participants who received Evusheld, 10 (30.3 %) reported experiencing at least one side effect. Injection site reactions included pain (most common), itchiness, and redness. General side effects included fatigue (most common), headache, muscle pain, and weakness. Of the 33 participants who received Evusheld, seven participants (21.2 %) tested positive for COVID-19 within 6 months of Evusheld injection. In an unadjusted binomial regression analysis, Evusheld administration was associated with a reduction in COVID-19 infection risk (OR 0.22, 95 % CI 0.05 - 1.02, p = 0.05). After adjusting for age and sex, Evusheld administration was still associated with a lower COVID-19 infection risk though it did not achieve nominal significance (OR 0.21, 95 % CI 0.04 - 1.09, p = 0.06). Of the 9 participants who were offered but did not receive Evusheld, five (55.6 %) tested positive for COVID-19 (p = 0.04 with Pearson's chi square test and p = 0.09 on Fisher's exact test). CONCLUSIONS: Our medical records data demonstrated that only 61 % of MS patients offered Evusheld received the injection. Evusheld seems to be largely well-tolerated. No serious adverse effects were reported. The use of Evusheld was associated with fewer COVID-19 infections, but this did not reach nominal statistical significance in the modest sample size. The lessons learned from the initial Evusheld experience may be applied to future interventions directed at infection prevention in MS patients on immunomodulatory therapies.

Senescence marker p16INK4a expression in patients with multiple sclerosis.

OBJECTIVES: Telomere attrition is associated with disability accumulation and brain atrophy in multiple sclerosis (MS). Downstream of telomere attrition is cellular senescence. We sought to determine differences in the cellular senescence marker p16INK4a expression between MS and healthy control participants and the association of p16INK4a expression with MS disability and treatment exposure. METHODS: Patients meeting diagnostic criteria for MS and healthy controls were recruited for a cross-sectional pilot study. RNA was extracted from peripheral blood mononuclear cells (PBMCs) and p16INK4a expression levels were measured using qRT PCR. Spearman correlation coefficients and regression models were applied to compare expression levels to chronological age, assess case control differences, and determine associations with clinical outcome measures. RESULTS: Fifty-two participants with MS (67 % female, ages 25-70) and 38 healthy controls (66 % female, ages 23-65) were included. p16INK4a levels were not linearly correlated with chronological age in MS (rhos = -0.01, p = 0.94) or control participants (rhos = 0.02, p = 0.92). Higher median p16INK4a levels were observed in the >50-year age group for MS (0.25, IQR 0.14-0.35) vs. controls (0.12, IQR 0.05-0.15) and in this age group B cell depletion therapy was associated with lower expression levels. p16INK4a expression was not associated with any of the measured MS disability outcomes. DISCUSSION: Caution is needed with using p16INK4a expression level from PBMCs as an aging biomarker in MS participants, given lack of correlation with chronological age or large associations with clinical outcomes.

Refractory Status Epilepticus Associated With a Pathogenic Variant in TNFRSF13B.

Febrile infection-related epilepsy syndrome (FIRES) is a rare epileptic syndrome characterized by new-onset refractory status epilepticus preceded by a febrile illness. Limited literature exists regarding the relationship between primary immunodeficiencies and immune-mediated epilepsy, and the relationship between new-onset refractory status epilepticus and common variable immunodeficiency (CVID) is not well-understood. We present a case of a 21-year-old female with a history of recurrent sinus infections, asthma, thrombocytopenia, atrioventricular nodal reentrant tachycardia, and neonatal seizures who presented with fever and new-onset status epilepticus. She was ultimately diagnosed with a heterozygous variant in TNFRSF13B c.311G>A (p.Cys104Tyr), which encodes for a tumor necrosis factor receptor implicated in CVID.

Survival Analysis of Immunotherapy Effects on Relapse Rate in Pediatric and Adult Autoimmune Encephalitis.

BACKGROUND AND OBJECTIVES: Prior observational studies for autoimmune encephalitis (AE) have mostly focused on outcomes after acute immunotherapies with better outcomes associated with earlier immunotherapy use. However, the impact of long-term immunotherapy and its association with clinical relapse is not well known. METHODS: We conducted a retrospective study of consecutive patients meeting published clinical criteria for AE evaluated at UC San Diego and Rady Children's Hospital from January 2007 to November 2021. Survival analysis and Cox multivariable regression models were used to evaluate relapse risk using rituximab exposure as a time-dependent variable. Pooled and age-stratified analyses were performed. RESULTS: A total of 204 pediatric and 380 adult participants were screened of which 30 pediatric and 75 adult participants were included. The most common antibody subtype in both cohorts was anti-NMDA receptor (76% in pediatric, 34% in adult). Relapses occurred in 31% of pediatric antibody-positive, 40% of adult antibody-positive, and 20% of adult antibody-negative cases. Times to first relapse (TTFR) were 10.6 ± 7.4 months (pediatric antibody-positive), 13.1 ± 24.5 months (adult antibody-positive), and 6.9 ± 3.8 months (adult antibody-negative). Rituximab was the most common second-line immunotherapy used. Combining pediatric and adult data, rituximab use was associated with a 71% lower hazard for time to first relapse (hazard ratio [HR] 0.29, 95% CI 0.09-0.85) and 51% lower hazard for recurring relapses (HR 0.49, 95% CI 0.9-1.26). The HR for TTFR with rituximab use in children was 0.30 (95% CI 0.05-1.69), 0.29 (95% CI 0.07-1.29) in adults, 0.32 in non-NMDA antibody-positive encephalitis (95% CI 0.07-1.39), and 0.42 (95% CI 0.07-2.67) for anti-NMDAR. DISCUSSION: Relapses are common in pediatric and adult patients with AE, although less frequently in anti-NMDARE. Using a rigorous survival model, we demonstrate a substantial benefit of rituximab use for reducing relapse rates in AE, especially for the adult population. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that rituximab is associated with a lower hazard to relapse in patients with AE.

The NHANES Biological Age Index demonstrates accelerated aging in MS patients.

BACKGROUND: Chronological age is associated with disability accumulation in multiple sclerosis (MS). Biological age may give more precise estimates of aging pathways associations with MS severity. Both normal aging and accelerated aging from MS may negatively impact disease course. Multi-marker indices of aging, such as the NHANES biological age index (BAI), may be more robust than single biomarkers in capturing biological age and are strongly associated with mortality risk and aging-related diseases. OBJECTIVE: We sought to investigate whether the NHANES BAI, utilizing readily available measures in the clinic, captures accelerating aging and correlates with disability in MS participants. METHODS: We conducted a prospective, cross-sectional case-control pilot study. Consecutive patients who met the 2017 McDonald's Criteria for MS were recruited from May 2020 to May 2022 along with age-similar healthy controls. BAI components included blood pressure, FEV1, serum creatinine, C-reactive protein, blood-urea nitrogen, albumin, alkaline phosphatase, cholesterol, CMV IgG, and hemoglobin A1c. The index was calculated using the Klemara and Doubal method. Spearman correlation and multivariable linear regression models were used to assess the association between BAI and MS clinical outcomes. RESULTS: A total of 51 MS (68.6% female) and 38 control (68.4% female) participants were recruited. BAI correlated with chronological age (CA) in MS (r2=0.90,p<0.0001) and control participants (r2 =0.87,p<0.0001). The mean BAI was 1.4 years older than CA in MS participants (range +15 to -10.5 years) and 2.2 years younger in control participants (range +11.2 to -14.1 years). In unadjusted Spearman analyses, BAI correlated with the timed 25-foot walk (T25FW, rhos=0.31, p = 0.045) and symbol digit modalities test (SDMT rhos = 0.35, p = 0.018). In a multivariable regression model, a 5-year older BAI was associated with a 1.2-point lower score on SDMT (95%CI -2.2 to -0.25, p = 0.014). CONCLUSIONS: MS participants were biologically older than their own chronological age and age-similar controls. In this modest-sized pilot sample, there was strongest correlation for MS outcome measures between BAI and the SDMT. These results support further study of the BAI as a marker of biological age variability in MS.

Longitudinal analysis and treatment of neuropsychiatric symptoms in post-acute sequelae of COVID-19.

BACKGROUND: Persistent neuropsychiatric symptoms following acute COVID-19 infection are frequently reported. These include anxiety, depression, difficulty concentrating, fatigue, and insomnia. The longitudinal evolution of this neuropsychiatric burden is poorly understood and clinical guidelines concerning treatment are lacking. OBJECTIVE: We sought to describe the longitudinal evolution of neuropsychiatric symptoms in the post-acute sequelae of COVID-19 (PASC) syndrome and examine symptom treatment at a single center. METHODS: Consecutive participants experiencing persistent neurologic symptoms after acute COVID-19 infection were recruited from October 2020 to July 2022. Data collected included COVID-19 infection history, neurological exam and review of systems, Montreal Cognitive Assessment (MoCA), and self-reported surveys concerning neuropsychiatric symptoms and treatment. Data were collected at baseline and at 1-year follow-up. RESULTS: A total of 106 participants (mean age 48.6, females 67%) were included in the study. At 1-year follow-up, 72.5% of participants reported at least one neuropsychiatric symptom. Over half (52.5%) of participants reported persistent fatigue. At baseline, 38.8% of all participants had met the established MoCA cut-off score of < 26 for mild cognitive impairment; this decreased to 20.0% at 1 year. COVID-19 infection severity was associated with neuro-PASC symptoms (including fatigue and anxiety) at 1 year. Overall, 29% of participants started at least one new medication for COVID-19-associated neuropsychiatric symptoms. Of the participants who started new medications, fatigue was the most common indication (44.8%) followed by insomnia (27.6%). CONCLUSIONS: Neuropsychiatric symptoms related to neuro-PASC improve over time but can persist for over a year post-recovery. Most treatment modalities targeted neuro-PASC fatigue.

MRI Features and Their Association With Outcomes in Children With Anti-NMDA Receptor Encephalitis.

OBJECTIVES: How brain MRI lesions associate with outcomes in pediatric anti-NMDA receptor encephalitis (pNMDARE) is unknown. In this study, we correlate T2-hyperintense MRI brain lesions with clinical outcomes in pNMDARE. METHODS: This was a multicenter retrospective cohort study from 11 institutions. Children younger than 18 years with pNMDARE were included. One-year outcomes were assessed by the modified Rankin Score (mRS) with good (mRS ≤2) and poor (mRS ≥3) outcomes. RESULTS: A total of 175 pNMDARE subjects were included, with 1-year mRS available in 142/175 (81%) and 60/175 (34%) had abnormal brain MRIs. The most common T2-hyperintense lesion locations were frontal, temporal, and parietal. MRI features that predicted poor 1-year outcomes included abnormal MRI, particularly T2 lesions in the frontal and occipital lobes. After adjusting for treatment within 4 weeks of onset, improvement within 4 weeks, and intensive care unit admission, MRI features were no longer associated with poor outcomes, but after multiple imputation for missing data, T2 frontal and occipital lesions associated with poor outcomes. DISCUSSION: Abnormal frontal and occipital lesions on MRI may associate with 1-year mRS in pNMDARE. MRI of the brain may be a helpful prognostication tool that should be examined in future studies.

Therapeutic Advances in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system that causes significant disability and healthcare burden. The treatment of MS has evolved over the past three decades with development of new, high efficacy disease modifying therapies targeting various mechanisms including immune modulation, immune cell suppression or depletion and enhanced immune cell sequestration. Emerging therapies include CNS-penetrant Bruton's tyrosine kinase inhibitors and autologous hematopoietic stem cell transplantation as well as therapies aimed at remyelination or neuroprotection. Therapy development for progressive MS has been more challenging with limited efficacy of current approved agents for inactive disease and older patients with MS. The aim of this review is to provide a broad overview of the current therapeutic landscape for MS.

Longitudinal evaluation of neurologic-post acute sequelae SARS-CoV-2 infection symptoms.

OBJECTIVE: To assess the initial features and evolution of neurologic Postacute Sequelae of SARS-CoV-2 infection (neuro-PASC) in patients with and without prior neurologic disease. METHODS: Participants with neurologic symptoms following acute SARS-CoV-2 infection were recruited from October 9, 2020 to October 11, 2021. Clinical data included a SARS-CoV-2 infection history, neurologic review of systems, neurologic exam, Montreal cognitive assessment (MoCA), and symptom-based self-reported surveys at baseline (conducted after acute infection) and 6-month follow-up assessments. RESULTS: Fifty-six participants (69% female, mean age 50 years, 29% with prior neurologic disease such as multiple sclerosis) were enrolled, of which 27 had completed the 6-month follow-up visit in this ongoing study. SARS-CoV-2 infection severity was largely described as mild (39.3%) or moderate (42.9%). At baseline, following acute infection, the most common neurologic symptoms were fatigue (89.3%) and headaches (80.4%). At the 6-month follow-up, memory impairment (68.8%) and decreased concentration (61.5%) were the most prevalent, though on average all symptoms showed a reduction in reported severity score at the follow-up. Complete symptom resolution was reported in 33.3% of participants by 6 months. From baseline to 6 months, average MoCA scores improved overall though 26.3% of participants' scores decreased. A syndrome consisting of tremor, ataxia, and cognitive dysfunction (PASC-TAC) was observed in 7.1% of patients. INTERPRETATION: Early in the neuro-PASC syndrome, fatigue and headache are the most commonly reported symptoms. At 6 months, memory impairment and decreased concentration were most prominent. Only one-third of participants had completed resolution of neuro-PASC at 6 months, although persistent symptoms trended toward improvement at follow-up.

Evaluation of the Educational Impact of the Urology Collaborative Online Video Didactics Lecture Series.

OBJECTIVE: To assess the impact of the Urology Collaborative Online Video Didactic (COViD) lecture series series on resident knowledge as a supplement to resident education during the coronavirus disease 2019 pandemic. METHODS: One hundred thirty-nine urology residents were voluntarily recruited from 8 institutions. A 20-question test, based on 5 COViD lectures, was administered before and after watching the lectures. Pre- and posttest scores (percent correct) and score changes (posttest minus pretest score) were assessed considering demographic data and number of lectures watched. Multiple linear regression determined predictors of improved scores. RESULTS: Of residents recruited, 95 and 71 took the pre- and posttests. Median number of lectures watched was 3. There was an overall increase in correct scores from pretest to posttest (45% vs 57%, P < .01). Watching any lectures vs none led to higher posttest scores (60% vs 44%, P < .01) and score changes (+16% vs +1%, P < .01). There was an increase in baseline pretest scores by post-graduate year (PGY) (P < .01); however there were no significant differences in posttest or score changes by PGY. When accounting for lectures watched, PGY, and time between lecture and posttest, being a PGY6 (P = .01) and watching 3-5 lectures (P < .01) had higher overall correct posttest scores. Watching 3-5 lectures led to greater score changes (P < .001-.04). Over 65% of residents stated the COViD lectures had a large or very large impact on their education. CONCLUSIONS: COViD lectures improved overall correct posttest scores and increased knowledge base for all resident levels. Furthermore, lectures largely impacted resident education during the coronavirus disease 2019 pandemic.

A systematic review and quantitative synthesis of the long-term psychiatric sequelae of pediatric autoimmune encephalitis.

BACKGROUND: Long-term neuropsychiatric sequelae of autoimmune encephalitis (AE) remain understudied, particularly in pediatric-onset AE. We aimed to synthesize the published data on ongoing psychiatric symptoms in pediatric-onset AE. METHODS: The Pubmed, PyscINFO, Web of Science databases were searched from their inception years to August 23, 2021, and 29 studies were identified and analyzed. We also performed a quantitative synthesis of available patient data from the 29 studies combined with a cohort of anti-NMDA receptor (NMDAR) AE from our institution to examine the associations between acute treatment course and long-term psychiatric outcome. RESULTS: At long-term follow up, 52.4% of the cases with pediatric-onset AE had any persistent symptom and 36.0% had at least one psychiatric symptom. Pooled data found that 36.3% of pediatric-onset anti-NMDAR AE had ongoing psychiatric symptoms. Using a univariate logistic regression analysis, we found that abnormal initial EEG, use of certain immunotherapies, and persistent cognitive impairments were associated with ongoing psychiatric symptoms. LIMITATIONS: Limitations of the existing literature included a significant paucity of outcomes measured using consistent, objective methods. Limitations of the systematic review included the wide variability among the studies reviewed, which rendered a meta-analysis impossible and beyond the scope of the paper. CONCLUSION: Chronic psychiatric and behavioral problems remain present in one-third of children months to years after onset of AE. Larger scaled prospective observational studies with a consistent standardized battery of testing are needed to examine impact of specific clinical features and immunotherapies on long-term mental health outcomes.

Expanding the phenotypic and molecular spectrum of NFS1-related disorders that cause functional deficiencies in mitochondrial and cytosolic iron-sulfur cluster containing enzymes.

Iron-sulfur cluster proteins are involved in critical functions for gene expression regulation and mitochondrial bioenergetics including the oxidative phosphorylation system. The c.215G>A p.(Arg72Gln) variant in NFS1 has been previously reported to cause infantile mitochondrial complex II and III deficiency. We describe three additional unrelated patients with the same missense variant. Two infants with the same homozygous variant presented with hypotonia, weakness and lactic acidosis, and one patient with compound heterozygous p.(Arg72Gln) and p.(Arg412His) variants presented as a young adult with gastrointestinal symptoms and fatigue. Skeletal muscle biopsy from patients 1 and 3 showed abnormal mitochondrial morphology, and functional analyses demonstrated decreased activity in respiratory chain complex II and variably in complexes I and III. We found decreased mitochondrial and cytosolic aconitase activities but only mildly affected lipoylation of pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase enzymes. Our studies expand the phenotypic spectrum and provide further evidence for the pathogenicity and functional sequelae of NFS1-related disorders with disturbances in both mitochondrial and cytosolic iron-sulfur cluster containing enzymes.

To Be or No B2: A Rare Cause of Stridor and Weakness in a Toddler.

We present a case of a young child with a rare metabolic disorder whose clinical presentation resembled that of autoimmune myasthenia gravis. The differential diagnosis was expanded when autoantibody testing was negative and the patient did not respond to standard immunomodulatory therapies. Rapid whole genome sequencing identified 2 rare variants of uncertain significance in the SLC52A3 gene shown to be in compound heterozygous state after parental testing. Biallelic mutations in SLC52A3 are associated with Riboflavin Transporter Deficiency, which in its untreated form, results in progressive neurodegeneration and death. Supplementation with oral riboflavin has been shown to limit disease progression and improve symptoms in some patients. When the diagnosis is suspected, patients should be started on supplementation immediately while awaiting results from genetic studies.

A Case of Tuberculosis-Associated Acute Disseminated Encephalomyelitis in a Seven-Month-Old Infant.

A seven-month-old previously healthy female infant presented with acute onset encephalopathy and left focal weakness in the setting of three months of non-productive cough. She was diagnosed with pulmonary tuberculosis (TB), and neuroimaging showed multifocal non-enhancing T2 hyperintensities in the brain and longitudinal T2 hyperintensity in the spinal cord consistent with acute disseminated encephalomyelitis (ADEM). However, her cerebrospinal fluid (CSF) did not show evidence of TB infection. She was treated with high-dose steroids for five days with a steroid taper along with antitubercular medications with a remarkable recovery in gross motor function. This case suggests a previously unreported association between TB and an immune-mediated demyelinating syndrome in children that is clinically distinct from other more common forms of TB-associated central nervous system (CNS) complications.

The Utility of Infectious and Neurodiagnostic Testing in Children With Complex Febrile Seizures Requiring Mechanical Ventilation.

A retrospective cohort analysis was performed on 79 consecutive patients between 6 months and 5 years admitted to a tertiary hospital with a diagnosis of complex febrile seizures requiring mechanical ventilation from 2011 to 2017 to determine the utility of infectious and neurologic diagnostics. Intubation was used as a proxy for severity of illness. The overall intensive care unit stay was short (95% intubated <24 hours, 88% admitted <3 days). No life-threatening infections were identified, and none required surgical interventions. Electroencephalogram (EEG) was obtained on 43%, 26% of which were abnormal. Sixty-six percent of patients were discharged on rescue benzodiazepine and 20% with maintenance antiseizure medications. Duration of follow-up averaged 4 years (range 1 month to 9 years); 8 patients (10%) were subsequently diagnosed with epilepsy. Our findings suggest that extensive diagnostic evaluations may not be necessary for children with complex febrile seizures requiring mechanical ventilation although the role of EEG is less understood.

Multi-Institutional Collaborative Resident Education in the Era of COVID-19.

INTRODUCTION: The 2019-2020 coronavirus pandemic has had a significant impact on all aspects of health care. Decrease in clinical and operative volume and limitations for conferences has drastically decreased educational opportunities for resident trainees. We describe the formation and initial success of the Collaborative Online Video Didactics lecture series, a multi-institutional online video didactics collaboration. METHODS: Zoom data extraction and postlecture evaluation surveys were used to collect data on the impact of the pandemic on local educational activities as well as feedback about the lecture series. Lectures are being given by faculty from 35 institutions. The twice daily, hour-long webinar averages more than 470 live viewers per session with an average of 33.5 questions per session and has over 7,000 YouTube views of the recordings after the first 2 weeks. RESULTS: Viewers reported significant decreases in outpatient (75.2%), inpatient (64.9%) and operating room (77.7%) volumes at local programs, and only half (52.7%) of the survey responders indicated an increase in didactics locally. The lectures have been well-received, with over 90% of respondents giving the lecturers and series above average or excellent ratings. A significant majority of responders indicated that the lecture series has allowed for ongoing education opportunities during the pandemic (95.0%), helped to access faculty experts from other institutions (92.3%) and provided a sense of community connectedness during this period of social isolation (81.7%). CONCLUSIONS: We strongly encourage other institutions and trainees to participate in the didactic series and hope that this series can continue to evolve and be of benefit beyond the pandemic.