Publications by authors named "Jeffrey M Gelfand"

91 Publications

Neurosarcoidosis: Pathophysiology, Diagnosis, and Treatment.

Neurol Neuroimmunol Neuroinflamm 2021 Nov 4;8(6). Epub 2021 Oct 4.

From the University of Washington and Billings Clinic, (M.J.B.); Vanderbilt University Medical Center (S.P.), Nashville, TN; Division of Pulmonary and Critical Care (L.L.K.), Department of Medicine, University of California, San Francisco; Division of Pulmonary and Critical Care, Department of Medicine; Univeristy of Iowa (T.A.C.), Iowa City; Department of Neurology (J.M.G.), Division of Neuroimmunology and Glial Biology, University of California, San Francisco.

Although often regarded as a protean illness with myriad clinical and imaging manifestations, neurosarcoidosis typically presents as recognizable syndromes that can be approached in a rational, systematic fashion. Understanding of neurosarcoidosis has progressed significantly in recent years, including updated diagnostic criteria and advances in treatment. The diagnosis of neurosarcoidosis is established by the clinical syndrome, imaging and histopathological findings, and exclusion of other causes. Mounting evidence supports the use of tumor necrosis factor inhibitors as an important addition to the therapeutic armamentarium, along with glucocorticoids and steroid-sparing cytotoxic immunosuppressants. In this narrative review, we summarize recent advances in the diagnosis and treatment of neurosarcoidosis.
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http://dx.doi.org/10.1212/NXI.0000000000001084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495503PMC
November 2021

ANA Investigates Therapeutic Advancements in Neuroimmunology.

Ann Neurol 2021 Nov 7;90(5):720-721. Epub 2021 Oct 7.

Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

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http://dx.doi.org/10.1002/ana.26222DOI Listing
November 2021

Detection of Neoplasms by Metagenomic Next-Generation Sequencing of Cerebrospinal Fluid.

JAMA Neurol 2021 Sep 13. Epub 2021 Sep 13.

Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco.

Importance: Cerebrospinal fluid (CSF) cytologic testing and flow cytometry are insensitive for diagnosing neoplasms of the central nervous system (CNS). Such clinical phenotypes can mimic infectious and autoimmune causes of meningoencephalitis.

Objective: To ascertain whether CSF metagenomic next-generation sequencing (mNGS) can identify aneuploidy, a hallmark of malignant neoplasms, in difficult-to-diagnose cases of CNS malignant neoplasm.

Design, Setting, And Participants: Two case-control studies were performed at the University of California, San Francisco (UCSF). The first study used CSF specimens collected at the UCSF Clinical Laboratories between July 1, 2017, and December 31, 2019, and evaluated test performance in specimens from patients with a CNS malignant neoplasm (positive controls) or without (negative controls). The results were compared with those from CSF cytologic testing and/or flow cytometry. The second study evaluated patients who were enrolled in an ongoing prospective study between April 1, 2014, and July 31, 2019, with presentations that were suggestive of neuroinflammatory disease but who were ultimately diagnosed with a CNS malignant neoplasm. Cases of individuals whose tumors could have been detected earlier without additional invasive testing are discussed.

Main Outcomes And Measures: The primary outcome measures were the sensitivity and specificity of aneuploidy detection by CSF mNGS. Secondary subset analyses included a comparison of CSF and tumor tissue chromosomal abnormalities and the identification of neuroimaging characteristics that were associated with test performance.

Results: Across both studies, 130 participants were included (median [interquartile range] age, 57.5 [43.3-68.0] years; 72 men [55.4%]). The test performance study used 125 residual laboratory CSF specimens from 47 patients with a CNS malignant neoplasm and 56 patients with other neurological diseases. The neuroinflammatory disease study enrolled 12 patients and 17 matched control participants. The sensitivity of the CSF mNGS assay was 75% (95% CI, 63%-85%), and the specificity was 100% (95% CI, 96%-100%). Aneuploidy was detected in 64% (95% CI, 41%-83%) of the patients in the test performance study with nondiagnostic cytologic testing and/or flow cytometry, and in 55% (95% CI, 23%-83%) of patients in the neuroinflammatory disease study who were ultimately diagnosed with a CNS malignant neoplasm. Of the patients in whom aneuploidy was detected, 38 (90.5%) had multiple copy number variations with tumor fractions ranging from 31% to 49%.

Conclusions And Relevance: This case-control study showed that CSF mNGS, which has low specimen volume requirements, does not require the preservation of cell integrity, and was orginally developed to diagnose neurologic infections, can also detect genetic evidence of a CNS malignant neoplasm in patients in whom CSF cytologic testing and/or flow cytometry yielded negative results with a low risk of false-positive results.
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http://dx.doi.org/10.1001/jamaneurol.2021.3088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438621PMC
September 2021

Consensus Curriculum for Fellowship Training in Multiple Sclerosis and Neuroimmunology.

Neurol Clin Pract 2021 Aug;11(4):352-357

Cleveland Clinic Lou Ruvo Center for Brain Health (LHH), Las Vegas, NV; Department of Neurology (AZO), Medical College of Wisconsin, Milwaukee; Keck School of Medicine at University of Southern California (LA), Los Angeles; Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research (JAC), OH; National Multiple Sclerosis Society (KC), New York, NY; Department of Neurology (JD), Stanford University School of Medicine, CA; Department of Neurology (JMG), University of California, San Francisco; Virginia Commonwealth University (MDG), Richmond; Children's Hospital of Philadelphia (SH), University of Pennsylvania Perelman School of Medicine; Piedmont Healthcare (DJ), Mooresville, NC; Corinne Goldsmith Dickinson Center for Multiple Sclerosis (SK), Icahn School of Medicine at Mount Sinai, New York, NY; Johns Hopkins School of Medicine (SDN), Baltimore, MD; Duke University School of Medicine (SS), Durham, NC; Department of Neurology (NLS), Cedars-Sinai Medical Center, Los Angeles, CA; Oregon Health and Science University (VY), Portland VA Medical Center, Portland; Veterans Affairs Multiple Sclerosis Centers of Excellence (VY); and Yale School of Medicine (EEL), Yale University, New Haven, CT.

Management of multiple sclerosis and neuroimmunologic disorders has become increasingly complex because of the expanding number of recognized neuroimmune disorders, increased number of therapeutic options, and multidisciplinary care management needs of people with multiple sclerosis and neuroimmunologic disorders. More subspecialists are needed to optimize care of these patients, and many fellowship programs have been created or expanded to increase the subspecialty workforce. Consequently, defining the scope and standardizing fellowship training is essential to ensure that trainees receive high-quality training. A workgroup was created to develop a consensus fellowship curriculum to serve as a resource for all current and future training programs. This curriculum may also serve as a basis for future accreditation efforts.
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http://dx.doi.org/10.1212/CPJ.0000000000001040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382436PMC
August 2021

Identifying falls remotely in people with multiple sclerosis.

J Neurol 2021 Aug 17. Epub 2021 Aug 17.

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, 1651 4th Street, Box 3126, San Francisco, CA, 94143, USA.

Background: Falling is common in people with multiple sclerosis (MS) but tends to be under-ascertained and under-treated.

Objective: To evaluate fall risk in people with MS.

Methods: Ninety-four people with MS, able to walk > 2 min with or without an assistive device (Expanded Disability Status Scale (EDSS ≤ 6.5) were recruited. Clinic-based measures were recorded at baseline and 1 year. Patient-reported outcomes (PROs), including a fall survey and the MS Walking Scale (MSWS-12), were completed at baseline, 1.5, 3, 6, 9, and 12 months. Average daily step counts (STEPS) were recorded using a wrist-worn accelerometer.

Results: 50/94 participants (53.2%) reported falling at least once. Only 56% of participants who reported a fall on research questionnaires had medical-record documented falls. Fallers had greater disability [median EDSS 5.5 (IQR 4.0-6.0) versus 2.5 (IQR 1.5-4.0), p < 0.001], were more likely to have progressive MS (p = 0.003), and took fewer STEPS (mean difference - 1,979, p = 0.007) than Non-Fallers. Stepwise regression revealed MSWS-12 as a major predictor of future falls.

Conclusions: Falling is common in people with MS, under-reported, and under-ascertained by neurologists in clinic. Multimodal fall screening in clinic and remotely may help improve patient care by identifying those at greatest risk, allowing for timely intervention and referral to specialized physical rehabilitation.
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http://dx.doi.org/10.1007/s00415-021-10743-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370664PMC
August 2021

Foundational Telemedicine Workshop for First-Year Medical Students Developed During a Pandemic.

MedEdPORTAL 2021 16;17:11171. Epub 2021 Jul 16.

Associate Professor, Division of Palliative Medicine, Department of Medicine, University of California, San Francisco, School of Medicine.

Introduction: In response to the COVID-19 pandemic and the need for social distancing, medical education curricula across the country had to be quickly transitioned from in-person experiences to remote sessions. Simultaneously, use of telemedicine in clinical practice skyrocketed. Despite telemedicine expansion and the opportunity afforded to teach these skills virtually, many institutions lacked telemedicine curricula.

Methods: We developed and evaluated a foundational telemedicine workshop during a pandemic (158 students in 28 groups) guided by principles to maximize learner engagement during remote learning, including use of discrete, time-limited activities (self-assessment, templated group exercises, review of brief multimedia, and active role-play.).

Results: Students completed pre- and postsession surveys to assess session impact. Of 158 students, 92 (58%) completed the presession survey, and 36 (23%) completed the postsession survey. There was an increase in confidence in all areas, particularly in skills related to starting the encounter, minimizing barriers, and taking the medical history. Learners reported the physical examination content as more useful than any other area and valued the exemplar videos provided.

Discussion: The pandemic highlighted our own institution's need to develop telemedicine curricula to prepare medical students to provide this increasingly essential service. We developed a foundational telemedicine skills session that increased students' reported confidence in their telemedicine knowledge and skills. The session could be easily adapted by other schools interested in incorporating telemedicine into their preclerkship curriculum. Additional experiences providing opportunities to practice and receive feedback on telemedicine skills with standardized and real patients are warranted.
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http://dx.doi.org/10.15766/mep_2374-8265.11171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282677PMC
August 2021

Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors.

J Immunother Cancer 2021 07;9(7)

Harvard Medical School, Boston, Massachusetts, USA.

Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.
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http://dx.doi.org/10.1136/jitc-2021-002890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291304PMC
July 2021

Effects of COVID-19 "Sheltering in Place" on Activity in People With Multiple Sclerosis.

Neurol Clin Pract 2021 Apr;11(2):e216-e218

Department of Neurology, Weill Institute for Neurosciences, MS and Neuroinflammation Clinic, University of California San Francisco.

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http://dx.doi.org/10.1212/CPJ.0000000000000982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032435PMC
April 2021

CoachMS, an innovative closed-loop, interdisciplinary platform to monitor and proactively treat MS symptoms: A pilot study.

Mult Scler J Exp Transl Clin 2021 Jan-Mar;7(1):2055217321988937. Epub 2021 Feb 2.

UCSF Weill Institute for Neurosciences, MS and Neuroinflammation Clinic, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.

Background: There are numerous challenges to treating co-occurring symptoms in multiple sclerosis (MS).

Objective: To pilot the feasibility of a novel symptom management platform, CoachMS, to monitor MS symptoms (bladder function, ambulation, and mood: BAM) and respond to changes in real-time.

Methods: In this 12-week randomized controlled pilot trial, participants' symptoms were monitored using weekly questionnaires and remote ambulatory monitoring (Fitbit Flex2®). Behavioral change principles used included shared goal setting at 2 weeks. Between weeks 2-12, the CoachMS group received targeted contact and interventions if symptoms worsened; the control group were treated through usual clinic practice. Our outcomes were feasibility (retention, adherence and acceptability; primary) and proportion of recommended treatments pursued (secondary); efficacy was explored.

Results: Of 21 participants enrolled, 13 (62%) completed the study; protocol adherence was excellent. CoachMS participants demonstrated greater follow-through with clinical recommendations than controls (OR 9.3, 95% CI (0.9, 97.6)). As a cohort, each BAM symptom tended to improve. Suicidality was detected in one control participant, resulting in urgent evaluation and hospitalization.

Conclusions: The innovative CoachMS platform was feasible and acceptable in this cohort with baseline BAM symptoms. It could represent an accessible, cost-effective tool to monitor MS symptoms in real-time; a larger trial is planned.
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http://dx.doi.org/10.1177/2055217321988937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970691PMC
February 2021

Development of a Low-Resource Operating Room and a Wide-Awake Orthopedic Surgery Program During the COVID-19 Pandemic.

Surg Innov 2021 Apr 29;28(2):183-188. Epub 2021 Mar 29.

Department of Surgery, Fortney Breast Center, Anne Arundel Medical Center, Annapolis, MD, USA.

The COVID-19 pandemic resulted in significant medication, supply and equipment, and provider shortages, limiting the resources available for provision of surgical care. In response to mandates restricting surgery to high-acuity procedures during this period, our institution developed a multidisciplinary Low-Resource Operating Room (LROR) Taskforce in April 2020. This study describes our institutional experience developing an LROR to maintain access to urgent surgical procedures during the peak of the COVID-19 pandemic. A delineation of available resources and resource replacement strategies was conducted, and a final institution-wide plan for operationalizing the LROR was formed. Specialty-specific subgroups then convened to determine best practices and opportunities for LROR utilization. Orthopedic surgery performed in the LROR using wide-awake local anesthesia no tourniquet (WALANT) is presented as a use case. . Overall, 19 limited resources were identified, spanning across the domains of physical space, drugs, devices and equipment, and personnel. Based on the assessment, the decision to proceed with creation of an LROR was made. Sixteen urgent orthopedic surgeries were successfully performed using WALANT without conversion to general anesthesia. In response to the COVID-19 pandemic, a LROR was successfully designed and operationalized. The process for development of a LROR and recommended strategies for operating in a resource-constrained environment may serve as a model for other institutions and facilitate rapid implementation of this care model should the need arise in future pandemic or disaster situations.
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http://dx.doi.org/10.1177/15533506211003530DOI Listing
April 2021

Underutilization of physical therapy for symptomatic women with MS during and following pregnancy.

Mult Scler Relat Disord 2021 Feb 19;48:102703. Epub 2020 Dec 19.

Weill Institute for Neurosciences, MS and Neuroinflammation Clinic, University of California San Francisco, Department of Neurology. Electronic address:

Background: Many patients with MS continue to have symptoms of their disease even when inflammatory activity is reduced by DMTs. Although disease activity tends to be reduced during pregnancy - especially in the third trimester - women with MS can experience ongoing symptoms during pregnancy, or new ones in the immediate postpartum period, that degrade quality of life. While many MS-related and postpartum symptoms can be improved with physical therapy (PT), there are currently no guidelines on pregnancy-related rehabilitation in MS. In this analysis, we evaluated the prevalence of PT-amenable symptoms and patterns of PT referrals in a cohort of UCSF MS Clinic patients who became pregnant.

Methods: We extracted electronic medical records (EMR) data for the year before conception, during pregnancy, and year postpartum for women with MS cared for at UCSF between 09-2005 and 08-2019. This included clinical visits, MS therapies and symptoms (as defined by the National MS Society). PT and pelvic floor PT orders and notes were also extracted.

Results: We included 142 live birth pregnancies from 118 women. During the course of their pregnancy and within the year postpartum, 107 women (75.4%) reported at least one PT-amenable symptom. A total of 30 (28.0%) referrals were made to PT, with attendance confirmed for 10 (33.3% of referrals). Symptoms most commonly triggering a referral for PT evaluation were numbness and urinary incontinence. Falls were reported after 10 of the pregnancies; 4 resulted in a referral to PT. Forty-one women reported urinary incontinence: 11 (26.8%) were referred to PT, and 2 to pelvic floor PT. Nineteen women experienced a documented relapse during pregnancy and/or postpartum: 11 received a PT referral, and 4 attended PT.

Conclusions: While women with MS recorded at least 1 PT-amenable symptom during or following 75.4% of their pregnancies, only 28% of these were referred to PT - and only a third attended PT. Of significance was the 4.9% referral rate for pelvic floor PT in postpartum women with a record of urinary incontinence. Pelvic floor PT is a mainstay of general postpartum care in many European countries. These data illustrate critical gaps in rehabilitation referral, access and use at the intersection of neurological conditions and pregnancy in a large US-based MS clinic. They lend support for quality improvement efforts to improve care pathways and for telerehabilitation innovations to reduce barriers to access and improve synergistic care between PT, MD and urologic care.
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http://dx.doi.org/10.1016/j.msard.2020.102703DOI Listing
February 2021

Maintaining Access to Orthopaedic Surgery During Periods of Operating Room Resource Constraint: Expanded Use of Wide-Awake Surgery During the COVID-19 Pandemic.

J Am Acad Orthop Surg Glob Res Rev 2020 12 15;4(12):e20.00100. Epub 2020 Dec 15.

From the Department of Orthopedics, Anne Arundel Medical Center, Annapolis, MD.

Introduction: Wide-awake local anesthesia no tourniquet (WALANT) presents a nonstandard anesthetic approach initially described for use in hand surgery that has gained interest and utilization across a variety of orthopaedic procedures. In response to operating room resource constraints imposed by the COVID-19 pandemic, our orthopaedic service rapidly adopted and expanded its use of WALANT.

Methods: A retrospective review of 16 consecutive cases performed by 7 surgeons was conducted. Patient demographics, surgical details, and perioperative outcomes were assessed. The primary end point was WALANT failure, defined as intraoperative conversion to general anesthesia.

Results: No instances of WALANT failure requiring conversion to general anesthesia occurred. In recovery, one patient (6%) required narcotics for pain control, and the average postoperative pain numeric rating scale was 0.6. The maximum pain score experienced was 4 in the patient requiring postoperative narcotics. The average time in recovery was 42 minutes and ranged from 8 to 118 minutes.

Conclusion: The WALANT technique was safely and effectively used in 16 cases across multiple orthopaedic subspecialties, including three procedures not previously described in the literature. WALANT techniques hold promise for use in future disaster scenarios and should be evaluated for potential incorporation into routine orthopaedic surgical care.
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http://dx.doi.org/10.5435/JAAOSGlobal-D-20-00100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743835PMC
December 2020

An electronic, unsupervised patient-reported Expanded Disability Status Scale for multiple sclerosis.

Mult Scler 2021 08 25;27(9):1432-1441. Epub 2020 Nov 25.

UCSF MS and Neuroinflammation Center, Weill Institute for Neurosciences, Department of Neurology, Division of Neuroinflammation and Glial Biology, University of California San Francisco, San Francisco, CA, USA.

Background: In persons with multiple sclerosis (MS), the Expanded Disability Status Scale (EDSS) is the criterion standard for assessing disability, but its in-person nature constrains patient participation in research and clinical assessments.

Objective: The aim of this study was to develop and validate a scalable, electronic, unsupervised patient-reported EDSS (ePR-EDSS) that would capture MS-related disability across the spectrum of severity.

Methods: We enrolled 136 adult MS patients, split into a preliminary testing Cohort 1 ( = 50), and a validation Cohort 2 ( = 86), which was evenly distributed across EDSS groups. Each patient completed an ePR-EDSS either immediately before or after a MS clinician's Neurostatus EDSS evaluation.

Results: In Cohort 2, mean age was 50.6 years (range = 26-80) and median EDSS was 3.5 (interquartile range (IQR) = [1.5, 5.5]). The ePR-EDSS and EDSS agreed within 1-point for 86% of examinations; kappa for agreement within 1-point was 0.85 ( < 0.001). The correlation coefficient between the two measures was 0.91 (<0.001).

Discussion: The ePR-EDSS was highly correlated with EDSS, with good agreement even at lower EDSS levels. For clinical care, the ePR-EDSS could enable the longitudinal monitoring of a patient's disability. For research, it provides a valid and rapid measure across the entire spectrum of disability and permits broader participation with fewer in-person assessments.
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http://dx.doi.org/10.1177/1352458520968814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144241PMC
August 2021

Gut microbiota-specific IgA B cells traffic to the CNS in active multiple sclerosis.

Sci Immunol 2020 11;5(53)

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA.

Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed CNS, resulting in a strong, compartmentalized IgA enrichment in active MS and other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue. These findings establish gut microbiota-specific IgA cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.
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http://dx.doi.org/10.1126/sciimmunol.abc7191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043673PMC
November 2020

Retinal INL Thickness in Multiple Sclerosis: A Mere Marker of Neurodegeneration?

Ann Neurol 2021 01 11;89(1):192-193. Epub 2020 Nov 11.

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA.

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http://dx.doi.org/10.1002/ana.25933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990472PMC
January 2021

Early postoperative pain and opioid consumption after arthroscopic shoulder surgery with or without open subpectoral biceps tenodesis and interscalene block.

J Orthop 2020 Nov-Dec;22:372-376. Epub 2020 Aug 26.

Anne Arundel Medical Center Orthopedics, United States.

Objective: The addition of open subpectoral biceps tenodesis to arthroscopic shoulder surgery with interscalene block has been anecdotally observed to result in increased postoperative pain. This study aims to evaluate the impact of tenodesis on early postoperative pain and recovery.

Methods: A retrospective review of patients undergoing arthroscopic shoulder surgery with general anesthesia and interscalene block was conducted.

Results: Patients undergoing tenodesis experienced longer OR time, pain numeric rating scale (NRS), and consumed more morphine milligram equivalents (MME) in PACU. After controlling for confounding factors, tenodesis was significantly associated with increased opioid MME consumption in the PACU (β = 1.045, p = .028) and last PACU pain NRS (β = 0.541, p = .009).

Conclusion: Overall, pain scores and narcotic consumption were low after surgery, making these differences potentially clinically insignificant. Further study is required to evaluate whether these trends are consistent among this population.
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http://dx.doi.org/10.1016/j.jor.2020.08.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486418PMC
August 2020

A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis.

Proc Natl Acad Sci U S A 2020 09 28;117(37):22932-22943. Epub 2020 Aug 28.

Weill Institute for Neurosciences, University of California, San Francisco, CA 94158;

Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; = 12), other neurologic diseases (ONDs; = 1), and healthy controls (HCs; = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS ( = 4), clinically isolated syndrome ( = 2), and OND ( = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood-brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein-Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.
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http://dx.doi.org/10.1073/pnas.2008523117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502747PMC
September 2020

Imaging correlates of visual function in multiple sclerosis.

PLoS One 2020 3;15(8):e0235615. Epub 2020 Aug 3.

Division of Neuroimmunology and Glial Biology UCSF, Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, United States of America.

No single neuroimaging technique or sequence is capable of reflecting the functional deficits manifest in MS. Given the interest in imaging biomarkers for short- to medium-term studies, we aimed to assess which imaging metrics might best represent functional impairment for monitoring in clinical trials. Given the complexity of functional impairment in MS, however, it is useful to isolate a particular functionally relevant pathway to understand the relationship between imaging and neurological function. We therefore analyzed existing data, combining multiparametric MRI and OCT to describe MS associated visual impairment. We assessed baseline data from fifty MS patients enrolled in ReBUILD, a prospective trial assessing the effect of a remyelinating drug (clemastine). Subjects underwent 3T MRI imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI), myelin content quantification, and retinal imaging, using OCT. Visual function was assessed, using low-contrast letter acuity. MRI and OCT data were studied to model visual function in MS, using a partial, least-squares, regression analysis. Measures of neurodegeneration along the entire visual pathway, described most of the observed variance in visual disability, measured by low contrast letter acuity. In those patients with an identified history of ON, however, putative myelin measures also showed correlation with visual performance. In the absence of clinically identifiable inflammatory episodes, residual disability correlates with neurodegeneration, whereas after an identifiable exacerbation, putative measures of myelin content are additionally informative.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235615PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398529PMC
September 2020

A Precision Medicine Tool for Patients With Multiple Sclerosis (the Open MS BioScreen): Human-Centered Design and Development.

J Med Internet Res 2020 07 6;22(7):e15605. Epub 2020 Jul 6.

Department of Neurology, UCSF Weill Institute for Neurosciences, San Francisco, CA, United States.

Background: Patients with multiple sclerosis (MS) face several challenges in accessing clinical tools to help them monitor, understand, and make meaningful decisions about their disease course. The University of California San Francisco MS BioScreen is a web-based precision medicine tool initially designed to be clinician facing. We aimed to design a second, openly available tool, Open MS BioScreen, that would be accessible, understandable, and actionable by people with MS.

Objective: This study aimed to describe the human-centered design and development approach (inspiration, ideation, and implementation) for creating the Open MS BioScreen platform.

Methods: We planned an iterative and cyclical development process that included stakeholder engagement and iterative feedback from users. Stakeholders included patients with MS along with their caregivers and family members, MS experts, generalist clinicians, industry representatives, and advocacy experts. Users consisted of anyone who wants to track MS measurements over time and access openly available tools for people with MS. Phase I (inspiration) consisted of empathizing with users and defining the problem. We sought to understand the main challenges faced by patients and clinicians and what they would want to see in a web-based app. In phase II (ideation), our multidisciplinary team discussed approaches to capture, display, and make sense of user data. Then, we prototyped a series of mock-ups to solicit feedback from clinicians and people with MS. In phase III (implementation), we incorporated all concepts to test and iterate a minimally viable product. We then gathered feedback through an agile development process. The design and development were cyclical-many times throughout the process, we went back to the drawing board.

Results: This human-centered approach generated an openly available, web-based app through which patients with MS, their clinicians, and their caregivers can access the site and create an account. Users can enter information about their MS (basic level as well as more advanced concepts), visualize their data longitudinally, access a series of algorithms designed to empower them to make decisions about their treatments, and enter data from wearable devices to encourage realistic goal setting about their ambulatory activity. Agile development will allow us to continue to incorporate precision medicine tools, as these are validated in the clinical research arena.

Conclusions: After engaging intended users into the iterative human-centered design of the Open MS BioScreen, we will now monitor the adaptation and dissemination of the tool as we expand its functionality and reach. The insights generated from this approach can be applied to the development of a number of self-tracking, self-management, and user engagement tools for patients with chronic conditions.
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http://dx.doi.org/10.2196/15605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381029PMC
July 2020

Risk of Neuroinflammatory Adverse Events With Tumor Necrosis Factor Inhibitor Treatment.

JAMA Neurol 2020 08;77(8):933-935

Rheumatology, Zuckerberg San Francisco General Hospital, University of California, San Francisco, San Francisco.

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http://dx.doi.org/10.1001/jamaneurol.2020.1160DOI Listing
August 2020

Anti-gamma-aminobutyric acid receptor type A encephalitis: a review.

Curr Opin Neurol 2020 06;33(3):372-380

Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

Purpose Of Review: To systematically review the clinical features, diagnosis, and management of anti-gamma-aminobutyric acid receptor Type A (GABAA) autoimmune encephalitis with a focus on recent data.

Recent Findings: In a review of published reports, we identified 50 cases of anti-GABAA receptor encephalitis with clinical features reported. The median age at presentation was 47 years old (range, 2.5 months-88 years old), 64% were adults, 36% were children and it occurred in both males and females. Eight-two percent (41/50) presented with seizures, 72% (36/50) with encephalopathy, and 58% (29/50) with both. Of those presenting with seizures, 42% developed status epilepticus during their disease course. Ninety-six percent (48/50) had MRI results reported, with 83% of these cases having abnormal findings, most commonly multifocal/diffuse cortical and subcortical T2/FLAIR hyperintense lesions without associated gadolinium enhancement. Almost one-third, 28% (14/50), had an associated malignancy detected by the time of diagnosis, 64% (9/14) of which was thymoma. Of 44 patients with outcomes reported, 80% had partial or complete recovery, whereas 20% had poor outcomes including 11% (5/44) who died. Of the 42 patients with type of treatment(s) and outcomes reported, 54% (23/42) received only first-line immunotherapy and 31% (13/42) received first-line and second-line immunotherapy. Receiving a combination of first-line and second-line immunotherapy may be associated with higher likelihood of complete recovery. When follow-up MRIs were reported, all showed improvement, and sometimes complete resolution, of T2/FLAIR hyperintensities.

Summary: Anti-GABAA receptor encephalitis can present across the age spectrum and should be considered in patients who present with rapidly progressive encephalopathy and/or seizures. Brain MRI often shows a distinctive pattern of multifocal cortical and subcortical T2/FLAIR hyperintense lesions, generally not typical of other known central nervous system autoantibody associated encephalitis syndromes. High clinical suspicion and early diagnosis are important given the potential for clinical improvement with immunotherapy.
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http://dx.doi.org/10.1097/WCO.0000000000000814DOI Listing
June 2020

Fixational microsaccades: A quantitative and objective measure of disability in multiple sclerosis.

Mult Scler 2020 03 7;26(3):343-353. Epub 2020 Feb 7.

Department of Neurology, University of California, San Francisco, San Francisco, CA, USA/Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA.

Background: Objective tools for prognosis and disease progression monitoring in multiple sclerosis (MS) are lacking. The visuomotor system could be used to track motor dysfunction at the micron scale through the monitoring of fixational microsaccades.

Aims: The aim of this study was to evaluate whether microsaccades are correlated with standard MS disability metrics and to assess whether these methods play a predictive role in MS disability.

Method: We used a custom-built retinal eye tracker, the tracking scanning laser ophthalmoscope (TSLO), to record fixation in 111 participants with MS and 100 unaffected controls.

Results: In MS participants, a greater number of microsaccades showed significant association with higher Expanded Disability Status Scale score (EDSS,  < 0.001), nine-hole peg test (non-dominant:  = 0.006), Symbol Digit Modalities Test (SMDT,  = 0.014), and Functional Systems Scores (FSS) including brainstem ( = 0.005), cerebellar ( = 0.011), and pyramidal ( = 0.009). Both brainstem FSS and patient-reported fatigue showed significant associations with microsaccade number, amplitude, and peak acceleration. Participants with MS showed a statistically different average number ( = 0.020), peak vertical acceleration ( = 0.003), and vertical amplitude ( < 0.001) versus controls. Logistic regression models for MS disability were created using TSLO microsaccade metrics and paraclinical tests with ⩾80% accuracy.

Conclusion: Microsaccades provide objective measurements of MS disability level and disease worsening.
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http://dx.doi.org/10.1177/1352458519894712DOI Listing
March 2020

Intrathecal B-cell activation in LGI1 antibody encephalitis.

Neurol Neuroimmunol Neuroinflamm 2020 03 6;7(2). Epub 2020 Feb 6.

From the Department of Neurology (K.L.-H., S.W., A.P., S.J., A.L.G., R.D., J.M.G., M.D.G., M.R.W., S.S.Z., H.-C.v.B.), UCSF Weill Institute for Neurosciences; Program in Immunology (K.L.-H., S.S.Z.), UCSF, San Francisco, CA; Department of Neurology (K.L.-H., G.L.), Klinikum rechts der Isar, Technische Universität München, Germany; and Oxford Autoimmune Neurology Group (S.R.I., S.M.), John Radcliffe Hospital, University of Oxford, UK.

Objective: To study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis.

Methods: Paired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB.

Results: Serum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls.

Conclusions: Our results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies.
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http://dx.doi.org/10.1212/NXI.0000000000000669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051206PMC
March 2020

Exploratory analysis of the potential for advanced diagnostic testing to reduce healthcare expenditures of patients hospitalized with meningitis or encephalitis.

PLoS One 2020 15;15(1):e0226895. Epub 2020 Jan 15.

Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California, United States of America.

Objective: To estimate healthcare expenditures that could be impacted by advanced diagnostic testing for patients hospitalized with meningitis or encephalitis.

Methods: Patients hospitalized with meningitis (N = 23,933) or encephalitis (N = 7,858) in the U.S. were identified in the 2010-2014 Truven Health MarketScan Commercial Claims and Encounters Database using ICD-9-CM diagnostic codes. The database included an average of 40.8 million commercially insured enrollees under age 65 per year. Clinical, demographic and healthcare utilization criteria were used to identify patient subgroups early in their episode who were at risk to have high inpatient expenditures. Healthcare expenditures of patients within each subgroup were bifurcated: those expenditures that remained five days after the patient could be classified into the subgroup versus those that had occurred previously.

Results: The hospitalization episode rate per 100,000 enrollee-years for meningitis was 13.0 (95% CI: 12.9-13.2) and for encephalitis was 4.3 (95% CI: 4.2-4.4), with mean inpatient expenditures of $36,891 (SD = $92,636) and $60,181 (SD = $130,276), respectively. If advanced diagnostic testing had been administered on the day that a patient could be classified into a subgroup, then a test with a five-day turnaround time could impact the following mean inpatient expenditures that remained by subgroup for patients with meningitis or encephalitis, respectively: had a neurosurgical procedure ($83,337 and $56,020), had an ICU stay ($34,221 and $46,051), had HIV-1 infection or a previous organ transplant ($37,702 and $62,222), were age <1 year ($35,371 and $52,812), or had a hospital length of stay >2 days ($18,325 and $30,244).

Discussion: Inpatient expenditures for patients hospitalized with meningitis or encephalitis were substantial and varied widely. Patient subgroups who had high healthcare expenditures could be identified early in their stay, raising the potential for advanced diagnostic testing to lower these expenditures.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226895PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961903PMC
April 2020

Allogeneic HSCT for adult-onset leukoencephalopathy with spheroids and pigmented glia.

Brain 2020 02;143(2):503-511

Hematology and Blood and Marrow Transplantation, University of California, San Francisco, CA, USA.

Adult-onset leukoencephalopathy with spheroids and pigmented glia (ALSP) is an autosomal dominant leukoencephalopathy caused by mutations in colony stimulating factor 1 receptor (CSF1R). Here we report clinical and imaging outcomes following allogeneic haematopoietic stem cell transplantation (HSCT) in two patients with ALSP at the University of California, San Francisco between January 2016 and December 2017. Patient 1 proceeded to transplantation at age 53 with a haplo-identical sibling donor. Patient 2, whose sister and mother had died of the disease, proceeded to transplantation at age 49 with a 12/12 human leukocyte antigen-matched unrelated donor. Both patients received reduced intensity conditioning regimens. At 28 and 26 months post-HSCT, respectively, both patients were alive, without evidence of graft-versus-host disease, with major infection at 1 year in one and new-onset seizures in the other. In both cases, neurological worsening continued post-HSCT; however, the progression in cognitive deficits, overall functional status and gait impairment gradually stabilized. There was continued progression of parkinsonism in both patients. On brain MRI, within 1 year there was stabilization of T2/FLAIR abnormalities, and after 2 years there was complete resolution of abnormal multifocal reduced diffusion. In summary, after >2 years of follow-up, allogeneic HSCT in ALSP led to interval resolution of diffusion MRI abnormalities, stabilization of T2/FLAIR MRI abnormalities, and partial clinical stabilization, supportive of treatment response. Allogeneic HSCT may be beneficial in ALSP by providing a supply of bone marrow-derived brain-engrafting myeloid cells with donor wild-type CSF1R to repopulate the microglial niche.
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http://dx.doi.org/10.1093/brain/awz390DOI Listing
February 2020

Validation of a consumer-grade activity monitor for continuous daily activity monitoring in individuals with multiple sclerosis.

Mult Scler J Exp Transl Clin 2019 Oct-Dec;5(4):2055217319888660. Epub 2019 Nov 21.

Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, USA.

Background: Technological advancements of remote-monitoring used in clinical-care and research require validation of model updates.

Objectives: To compare the output of a newer consumer-grade accelerometer to a previous model in people with multiple sclerosis (MS) and to the ActiGraph, a waist-worn device widely used in MS research.

Methods: Thirty-one individuals with MS participated in a 7-day validation by the Fitbit Flex (Flex), Fitbit Flex-2 (Flex2) and ActiGraph GT3X. Primary outcome was step count. Valid epochs of 5-min block increments, where there was overlap of ≥1 step/min for both devices were compared and summed to give a for analysis.

Results: Bland-Altman plots showed no systematic difference between the Flex and Flex2; mean step-count difference of 25 more steps-per-day more recorded by Flex2 (95% confidence intervals (CI) = 2, 48;  = 0.04),interclass correlation coefficient (ICC) = 1.00. Compared to the ActiGraph, Flex2 (and Flex) tended to record more steps (808 steps-per-day more than the ActiGraph (95% CI= -2380, 765;  < 0.01), although the ICC was high (0.98) indicating that the devices were likely measuring the same kind of activity.

Conclusions: Steps from Flex and Flex2 can be used interchangeably. Differences in total step count between ActiGraph and Flex devices can make cross-device comparisons of numerical step-counts challenging particularly for faster walkers.
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http://dx.doi.org/10.1177/2055217319888660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876176PMC
November 2019

Progressive Neurological Impairment and an Enhancing Brainstem Lesion in a Middle-aged Man.

JAMA Neurol 2019 Nov;76(11):1397-1398

Division of Neuroinflammation and Glial Biology, Department of Neurology, University of California, San Francisco.

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http://dx.doi.org/10.1001/jamaneurol.2019.3002DOI Listing
November 2019

Multiple sclerosis and sarcoidosis: A case for coexistence.

Neurol Clin Pract 2019 Jun;9(3):218-227

New York University Langone Medical Center (CT, LZR, IK), Multiple Sclerosis Comprehensive Care Center, New York, NY; the Vanderbilt University Medical Center (SP), Neuroimmunology Division, Nashville, TN; the Brigham and Women's Hospital (MJB, DJK, TC), Massachusetts General Hospital, Harvard Medical School, Boston, MA; and the Division of Neuroinflammation and Glial Biology (JMG), UCSF Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA.

Background: Patients with biopsy-proven systemic sarcoidosis who develop a chronic CNS disorder are often presumed to have neurosarcoidosis (NS), however, the possibility of comorbid neurologic disease, such as MS, must be considered if presentation and course are not typical for NS.

Methods: Retrospective chart review across 4 academic MS centers was undertaken to identify patients with diagnosis of MS (2017 McDonald criteria) and biopsy-confirmed extraneural sarcoidosis. Data were abstracted from each chart using a case report form that systematically queried for demographic, clinical, and paraclinical characteristics relevant to NS and MS.

Results: Ten patients met our inclusion criteria (mean age 47.7 [±5.9] years; 80% female). Noncaseating granulomas consistent with sarcoidosis were found on biopsy in all cases (lung 7/10, mediastinum 2/10, liver 1/10, spleen 1/10, and skin 1/10). Diagnosis of MS was based on clinical history of MS-like relapses and MRI findings characteristic of demyelination and typical disease evolution during follow-up (average of 7 years). No patient developed features of NS that could be considered a "red flag" against the diagnosis of MS (such as meningeal enhancement, hydrocephalus, and pituitary involvement). All patients were treated with disease-modifying therapy for MS.

Conclusions: We propose a rational diagnostic approach to patients with sarcoidosis who may have comorbid MS. When the clinical picture is equivocal, the presence of multiple "MS-typical lesions" and the absence of any "NS-typical lesions" on MRI favor diagnosis of MS. Close follow-up is required to ascertain whether clinical and radiologic disease evolution and response to MS therapies conform to the proposed diagnosis of MS.
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http://dx.doi.org/10.1212/CPJ.0000000000000629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615652PMC
June 2019

Exploratory proteomic analysis implicates the alternative complement cascade in primary CNS vasculitis.

Neurology 2019 07 3;93(5):e433-e444. Epub 2019 Jul 3.

From the Departments of Biochemistry and Biophysics (C.M.-B., H.R., H.A.S., K.C.Z., J.L.D.), Pharmaceutical Chemistry (G.M.K., A.Y.), Pathology and Laboratory Medicine (T.T.), and Neurology (S.A.J., V.C.D., J.M.G., M.R.W.), University of California, San Francisco; Department of Rheumatology/Immunology (R.A.H.-A., L.H.C.), Cleveland Clinic, OH; Department of Neurology (M.P.G.), Boston Children's Hospital, MA; Division of Neurology (J.M.C.), Connecticut Children's Medical Center, Hartford; Division of Rheumatology (A.G.S.), University of Pennsylvania, Philadelphia; Kaiser Permanente (J.F.M.), San Francisco Medical Center; UCSF Weill Institute for Neurosciences (S.A.J., V.C.D., J.M.G., M.R.W.); and Chan Zuckerberg Biohub (J.L.D.), San Francisco, CA.

Objective: To identify molecular correlates of primary angiitis of the CNS (PACNS) through proteomic analysis of CSF from a biopsy-proven patient cohort.

Methods: Using mass spectrometry, we quantitatively compared the CSF proteome of patients with biopsy-proven PACNS (n = 8) to CSF from individuals with noninflammatory conditions (n = 11). Significantly enriched molecular pathways were identified with a gene ontology workflow, and high confidence hits within enriched pathways (fold change >1.5 and concordant Benjamini-Hochberg-adjusted < 0.05 on DeSeq and test) were identified as differentially regulated proteins.

Results: Compared to noninflammatory controls, 283 proteins were differentially expressed in the CSF of patients with PACNS, with significant enrichment of the complement cascade pathway (C4-binding protein, CD55, CD59, properdin, complement C5, complement C8, and complement C9) and neural cell adhesion molecules. A subset of clinically relevant findings were validated by Western blot and commercial ELISA.

Conclusions: In this exploratory study, we found evidence of deregulation of the alternative complement cascade in CSF from biopsy-proven PACNS compared to noninflammatory controls. More specifically, several regulators of the C3 and C5 convertases and components of the terminal cascade were significantly altered. These preliminary findings shed light on a previously unappreciated similarity between PACNS and systemic vasculitides, especially anti-neutrophil cytoplasmic antibody-associated vasculitis. The therapeutic implications of this common biology and the diagnostic and therapeutic utility of individual proteomic findings warrant validation in larger cohorts.
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http://dx.doi.org/10.1212/WNL.0000000000007850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693432PMC
July 2019

Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis.

N Engl J Med 2019 06;380(24):2327-2340

From the Departments of Neurology (M.R.W., V.D., S.A.J., F.C.C., J.M.G.), Biochemistry and Biophysics (H.A.S., K.C.Z., J.L.D.), Laboratory Medicine (S.A., G.Y., S.F., D.S., B.B., B.H., S.M., C.Y.C.), and Epidemiology and Biostatistics (J.N.), the Department of Medicine, Division of Infectious Diseases (C.L., C.Y.C.), the Department of Medicine, Division of Hospital Medicine (A.B.), and Weill Institute for Neurosciences (M.R.W., V.D., S.A.J., F.C.C., J.M.G.), University of California, San Francisco (UCSF), UCSF-Abbott Viral Diagnostics and Discovery Center (S.A., G.Y., S.F., D.S., B.B., C.Y.C.), the Chan Zuckerberg Biohub (C.L., J.L.D.), and Zuckerberg San Francisco General Hospital (B.H.), San Francisco, the School of Public Health, University of California, Berkeley, Berkeley (B.D.F.), Children's Hospital Los Angeles (S.N.N., J.B., J.D.B.), the Department of Medicine, Division of Infectious Diseases (J.M., M.C., T.V., P.R.A., J.D.K.), and the Departments of Neurology (P.M.V.) and Pathology and Laboratory Medicine (S.C., R.M.H.), University of California, Los Angeles, Los Angeles, and the Departments of Pathology and Laboratory Medicine (C.D.G., F.M., N.A.O., C.R.P.) and Neurological Surgery (L.L.Z.) and the Department of Internal Medicine, Division of Infectious Diseases (S.H.C., C.R.P.), University of California, Davis, Davis - all in California; the Children's National Medical Center and George Washington University School of Medicine, Washington, DC (R.L.D.); St. Jude Children's Research Hospital, Memphis, TN (R.D., G.M., R.H.); and Children's Hospital Colorado, Aurora (K.M., S.R.D.).

Background: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test.

Methods: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review.

Results: We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment.

Conclusions: Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).
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http://dx.doi.org/10.1056/NEJMoa1803396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764751PMC
June 2019
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