Publications by authors named "Benjamin Greenberg"

288 Publications

Double blind randomized controlled trial of deep brain stimulation for obsessive-compulsive disorder: Clinical trial design.

Contemp Clin Trials Commun 2021 Jun 5;22:100785. Epub 2021 Jun 5.

Butler Hospital, 345 Blackstone Blvd, Providence, RI, 02906, USA.

Obsessive-compulsive disorder (OCD), a leading cause of disability, affects ~1-2% of the population, and can be distressing and disabling. About 1/3 of individuals demonstrate poor responsiveness to conventional treatments. A small proportion of these individuals may be deep brain stimulation (DBS) candidates. Candidacy is assessed through a multidisciplinary process including assessment of illness severity, chronicity, and functional impact. Optimization failure, despite multiple treatments, is critical during screening. Few patients nationwide are eligible for OCD DBS and thus a multi-center approach was necessary to obtain adequate sample size. The study was conducted over a six-year period and was a NIH-funded, eight-center sham-controlled trial of DBS targeting the ventral capsule/ventral striatum (VC/VS) region. There were 269 individuals who initially contacted the sites, in order to achieve 27 participants enrolled. Study enrollment required extensive review for eligibility, which was overseen by an independent advisory board. Disabling OCD had to be persistent for ≥5 years despite exhaustive medication and behavioral treatment. The final cohort was derived from a detailed consent process that included consent monitoring. Mean illness duration was 27.2 years. OCD symptom subtypes and psychiatric comorbidities varied, but all had severe disability with impaired quality of life and functioning. Participants were randomized to receive sham or active DBS for three months. Following this period, all participants received active DBS. Treatment assignment was masked to participants and raters and assessments were blinded. The final sample was consistent in demographic characteristics and clinical features when compared to other contemporary published prospective studies of OCD DBS. We report the clinical trial design, methods, and general demographics of this OCD DBS sample.
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http://dx.doi.org/10.1016/j.conctc.2021.100785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219641PMC
June 2021

Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants.

Nat Neurosci 2021 Jun 28. Epub 2021 Jun 28.

Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA.

Obsessive-compulsive disorder (OCD) affects 1-2% of the population, and, as with other complex neuropsychiatric disorders, it is thought that rare variation contributes to its genetic risk. In this study, we performed exome sequencing in the largest OCD cohort to date (1,313 total cases, consisting of 587 trios, 41 quartets and 644 singletons of affected individuals) and describe contributions to disease risk from rare damaging coding variants. In case-control analyses (n = 1,263/11,580), the most significant single-gene result was observed in SLITRK5 (odds ratio (OR) = 8.8, 95% confidence interval 3.4-22.5, P = 2.3 × 10). Across the exome, there was an excess of loss of function (LoF) variation specifically within genes that are LoF-intolerant (OR = 1.33, P = 0.01). In an analysis of trios, we observed an excess of de novo missense predicted damaging variants relative to controls (OR = 1.22, P = 0.02), alongside an excess of de novo LoF mutations in LoF-intolerant genes (OR = 2.55, P = 7.33 × 10). These data support a contribution of rare coding variants to OCD genetic risk.
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http://dx.doi.org/10.1038/s41593-021-00876-8DOI Listing
June 2021

Utilization and Treatment Patterns of Disease-Modifying Therapy in Pediatric Patients with Multiple Sclerosis in the United States.

Int J MS Care 2021 May-Jun;23(3):101-105. Epub 2020 Jun 2.

Background: The current landscape and treatment patterns of disease-modifying therapy (DMT) use in pediatric patients with multiple sclerosis (MS) are not yet well understood. This study examined DMT utilization and treatment patterns in pediatric patients newly diagnosed as having MS.

Methods: Pediatric patients (<18 years old) with two MS diagnosis claims from January 1, 2010, to December 31, 2016, were identified from the MarketScan Commercial Database. The index date was defined as the date of first MS diagnosis, and patients were followed up for 1 year post-index date. Outcomes evaluated included percentage of patients who initiated treatment after MS diagnosis, different DMTs initiated, treatment discontinuation, and switching treatment during follow-up.

Results: Of 182,057 patients newly diagnosed as having MS, 288 pediatric patients (mean age, 14 years; 61% female) were identified. Within the first year of diagnosis, 188 patients (65.3%) did not receive any DMT. The most common first-initiated treatments were interferons and glatiramer acetate (83%), but 28% of patients switched or discontinued from first-initiated treatment within 6 months of treatment initiation.

Conclusions: This study suggests that a considerable proportion of pediatric patients with MS remain untreated within 1 year of diagnosis. Patients most commonly initiated injectables as their first DMT. Overall, therapy failed early in approximately one in three patients. Thus, the study warrants urgency in treating these patients with currently approved treatment options.
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http://dx.doi.org/10.7224/1537-2073.2019-095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218586PMC
June 2020

Molecular Level Characterization of Circulating Aquaporin-4 Antibodies in Neuromyelitis Optica Spectrum Disorder.

Neurol Neuroimmunol Neuroinflamm 2021 07 24;8(5). Epub 2021 Jun 24.

From the Department of Chemical Engineering (J.L., H.T., J.R.M., C.-H.L.), University of Texas at Austin, TX; Department of Neurology (S.A.B., E.M.), Dell Medical School, University of Texas at Austin, TX; Department of Chemistry & Molecular Biology (F.S., K.H.), University of Gothenburg, Sweden; Department of Neurology and Neurotherapeutics (C.J., N.M., B.M.G.), University of Texas Southwestern Medical Center, Dallas, TX; Department of Biomedical Engineering (J.E.K.), University of Texas at Austin, TX; and Department of Molecular Biosciences (G.C.I.), University of Texas at Austin, TX.

Objective: To determine whether distinct aquaporin-4 (AQP4)-IgG lineages play a role in neuromyelitis optica spectrum disorder (NMOSD) pathogenesis, we profiled the AQP4-IgG polyclonal serum repertoire and identified, quantified, and functionally characterized distinct AQP4-IgG lineages circulating in 2 patients with NMOSD.

Methods: We combined high-throughput sequencing and quantitative immunoproteomics to simultaneously determine the constituents of both the B-cell receptor (BCR) and the serologic (IgG) anti-AQP4 antibody repertoires in the peripheral blood of patients with NMOSD. The monoclonal antibodies identified by this platform were recombinantly expressed and functionally characterized in vitro.

Results: Multiple antibody lineages comprise serum AQP4-IgG repertoires. Their distribution, however, can be strikingly different in polarization (polyclonal vs pauciclonal). Among the 4 serum AQP4-IgG monoclonal antibodies we identified in 2 patients, 3 induced complement-dependent cytotoxicity in a model mammalian cell line ( < 0.01).

Conclusions: The composition and polarization of AQP4-IgG antibody repertoires may play an important role in NMOSD pathogenesis and clinical presentation. Here, we present a means of coupling both cellular (BCR) and serologic (IgG) antibody repertoire analysis, which has not previously been performed in NMOSD. Our analysis could be applied in the future to clinical management of patients with NMOSD to monitor disease activity over time as well as applied to other autoimmune diseases to facilitate a deeper understanding of disease pathogenesis relative to autoantibody clones.
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http://dx.doi.org/10.1212/NXI.0000000000001034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225010PMC
July 2021

Reconstituting T cell receptor selection in-silico.

Genes Immun 2021 Jul 14;22(3):187-193. Epub 2021 Jun 14.

Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, USA.

Each T cell receptor (TCR) gene is created without regard for which substances (antigens) the receptor can recognize. T cell selection culls developing T cells when their TCRs (i) fail to recognize major histocompatibility complexes (MHCs) that act as antigen presenting platforms or (ii) recognize with high affinity self-antigens derived from healthy cells and tissue. While T cell selection has been thoroughly studied, little is known about which TCRs are retained or removed by this process. Therefore, we develop an approach using TCR gene sequencing and machine learning to identify patterns in TCR protein sequences influencing the outcome of T cell receptor selection. We verify the trained models classify TCRs from developing T cells as being before selection and TCRs from mature T cells as being after selection. Our approach may provide future avenues for studying the relationship between T cell selection and conditions like autoimmune diseases.
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http://dx.doi.org/10.1038/s41435-021-00141-9DOI Listing
July 2021

Acute flaccid myelitis: long-term outcomes recorded in the CAPTURE study compared with paediatric transverse myelitis.

BMJ Neurol Open 2021 19;3(1):e000127. Epub 2021 May 19.

Neurology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Background: Since 2014, the USA has documented three outbreaks of acute flaccid myelitis (AFM). Unique features and treatment responses of this myelitis variant have not been prospectively studied. This study prospectively measured outcomes in paediatric myelitis patients relative to treatments.

Methods: This was a prospective, multicentre, non-randomised, observational cohort study. The study duration was 5 years and the length of follow-up was 1 year. This study collected data from children and families in North America. Patients were enrolled at academic centres with expertise in myelitis or online via a web portal. Paediatric patients diagnosed with myelitis were eligible for enrolment in the study within 6 months of onset of symptoms. Patients were characterised as transverse myelitis (TM) or the AFM variant based on clinical and radiographic findings.

Results: The cohort of 90 patients included patients with AFM and TM. Of the 51 patients with AFM there was evidence of two clinically relevant patterns. This included a grey matter restricted form of AFM and a cohort with concomitant white matter that could explain lower extremity motor deficits in patients with lesions restricted to the cervical spine. The improvement in deficits with the use of corticosteroids was similar to what was observed in the TM cohort (p=0.97).

Conclusions: Clinicians should consider on a case by case basis the approach to therapy for AFM patients. Prospective controlled studies of long-term outcomes would be useful in this growing patient population.
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http://dx.doi.org/10.1136/bmjno-2021-000127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137186PMC
May 2021

Bladder management in children with transverse myelitis.

J Pediatr Urol 2021 Apr 21. Epub 2021 Apr 21.

Department of Pediatric Urology, Children's Medical Center, Dallas, TX, USA. Electronic address:

Background: Patients with transverse myelitis (TM) often present with urinary retention. While many recover their bladder function, some have persistent voiding dysfunction, and both intermediate and long-term outcomes are variable.

Objective: In patients who develop urinary retention requiring clean intermittent catheterization (CIC) at onset of TM, we sought to assess factors associated with improved voiding function and the risk of requiring persistent CIC over time.

Study Design: We reviewed children evaluated at our institution for TM from April 1998 to October 2018. Patients were included if they required CIC at initial presentation of TM. Demographics, initial and follow up neurologic exams were evaluated for their association with a return to baseline volitional voiding after requiring catheterization upon diagnosis of TM, with or without medical therapy.

Results: Among the 78 patients who presented with TM during the study period, 43 patients required CIC, with median follow up of 2.7 years. When evaluating for demographic or sensorimotor features associated with improvement to baseline voiding function in patients who initially required CIC, preserved lower extremity reflexes at presentation was the only significant prognostic factor (p < 0.05). Additionally, having complete lower motor neurologic recovery was associated with volitional voiding (p < 0.05). Among the 43 patients who were initially catheterizing, 27/43 (62%) were volitionally voiding at median follow up of 7 months from initial presentation, while the remaining 16/43 remained on CIC for a median follow up of 3.6 years. The cumulative risk of remaining on CIC was 60%, 47%, and 42% at 1, 5, and 10 year follow up, respectively, though there was not a significant difference in the rate of bladder recovery if patients had preserved reflexes.

Discussion: In children with TM who initially developed urinary retention, intact reflexes at presentation were associated with urologic recovery. Additionally, complete neurologic recovery was associated with volitional voiding. While 62% were volitionally voiding at most recent follow-up, the cumulative incidence of dependence on CIC within the first year of diagnosis was 60%, with a relatively few patients regaining volitional voiding by 10 years of follow-up.

Conclusion: Among those initially evaluated for urinary retention in the setting of transverse myelitis, intact lower extremity reflexes on physical exam was associated with improved voiding function at most recent follow-up. However, more than half the patients on CIC at initial presentation required CIC at one year of follow-up. Careful, long-term monitoring of voiding status in patients with TM is recommended, even with improvement of neurological status.
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http://dx.doi.org/10.1016/j.jpurol.2021.04.003DOI Listing
April 2021

Is Persistent Motor or Vocal Tic Disorder a Milder Form of Tourette Syndrome?

Mov Disord 2021 May 4. Epub 2021 May 4.

Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation.

Objective: The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT.

Methods: We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta-analyses, incorporating data from previously published literature.

Results: Rates of obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta-analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First-degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates.

Conclusions: Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28593DOI Listing
May 2021

Magnetic Resonance Imaging-Guided Laser Thermal Ventral Capsulotomy for Intractable Obsessive-Compulsive Disorder.

Neurosurgery 2021 05;88(6):1128-1135

Robert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence, Rhode Island, USA.

Background: Obsessive-compulsive disorder (OCD) is a disabling condition characterized by intrusive thoughts and repetitive behaviors. A subset of individuals have severe, treatment-resistant illness and are nonresponsive to medication or behavioral therapies. Without response to conventional therapeutic options, surgical intervention becomes an appropriate consideration.

Objective: To report clinical outcomes and the safety profile of bilateral ventral anterior capsulotomy for OCD using magnetic resonance (MR)-guided laser interstitial thermal therapy (LITT) in 10 patients followed for 6 to 24 mo.

Methods: A total of 10 patients underwent LITT for severe OCD; 1 patient withdrew prior to follow-up. LITT is a minimally invasive ablative technique performed with precise targeting and use of thermography under MR guidance. Lesions of the ventral anterior limb of the internal capsule by other techniques have been shown to be efficacious in prior studies.

Results: A total of 7 of the 9 patients were considered full responders (77.8%; Yale-Brown Obsessive-Compulsive Scale change ≥35%). Adverse effects included transient apathy/amotivation postsurgery (2 patients). One patient had a small tract hemorrhage where the laser fiber traversed the cerebral cortex as well as persistent insomnia postsurgery. One individual died after a drug overdose 7 mo postsurgery, which was judged unrelated to the surgery.

Conclusion: LITT ventral capsulotomy was generally well tolerated, with promising evidence of effectiveness in the largest such series to date. Results were comparable to those after gamma knife ventral capsulotomy, as well as ventral anterior limb deep brain stimulation.
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http://dx.doi.org/10.1093/neuros/nyab050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223246PMC
May 2021

Magnetic Resonance Imaging-Guided Laser Thermal Ventral Capsulotomy for Intractable Obsessive-Compulsive Disorder.

Neurosurgery 2021 05;88(6):1128-1135

Robert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence, Rhode Island, USA.

Background: Obsessive-compulsive disorder (OCD) is a disabling condition characterized by intrusive thoughts and repetitive behaviors. A subset of individuals have severe, treatment-resistant illness and are nonresponsive to medication or behavioral therapies. Without response to conventional therapeutic options, surgical intervention becomes an appropriate consideration.

Objective: To report clinical outcomes and the safety profile of bilateral ventral anterior capsulotomy for OCD using magnetic resonance (MR)-guided laser interstitial thermal therapy (LITT) in 10 patients followed for 6 to 24 mo.

Methods: A total of 10 patients underwent LITT for severe OCD; 1 patient withdrew prior to follow-up. LITT is a minimally invasive ablative technique performed with precise targeting and use of thermography under MR guidance. Lesions of the ventral anterior limb of the internal capsule by other techniques have been shown to be efficacious in prior studies.

Results: A total of 7 of the 9 patients were considered full responders (77.8%; Yale-Brown Obsessive-Compulsive Scale change ≥35%). Adverse effects included transient apathy/amotivation postsurgery (2 patients). One patient had a small tract hemorrhage where the laser fiber traversed the cerebral cortex as well as persistent insomnia postsurgery. One individual died after a drug overdose 7 mo postsurgery, which was judged unrelated to the surgery.

Conclusion: LITT ventral capsulotomy was generally well tolerated, with promising evidence of effectiveness in the largest such series to date. Results were comparable to those after gamma knife ventral capsulotomy, as well as ventral anterior limb deep brain stimulation.
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http://dx.doi.org/10.1093/neuros/nyab050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223246PMC
May 2021

The COBRE Center for Neuromodulation (CCN) at Butler Hospital: Clinical-Translational Research in Human Brain Stimulation.

R I Med J (2013) 2021 Mar 1;104(2):30-33. Epub 2021 Mar 1.

Butler Hospital, Providence RI; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University.

The COBRE Center for Neuromodulation (CCN) at Butler Hospital supports clinical research in neuromodulation and investigators' career development in this field. The work couples brain stimulation methods with readouts of brain activity (e.g., using various neuroimaging, behavioral, and physiological assessment methods) in clinical or clinically relevant populations. Its guiding principle is that for noninvasive brain stimulation to gain efficacy and implementation, it is essential to better characterize clinically relevant target circuits and mechanisms of action. The CCN includes a Design and Analysis Core (DAC) to support rigorous and innovative experimental design and data analytic strategies and a Neuromodulation and Neuroimaging Core (NNC) to facilitate the acquisition and processing of high-quality data using noninvasive neurostimulation and neuroimaging methods. This article will describe the CCN's research focus and how it enhances research capacity in neuromodulation in our state. It will introduce our current investigator Project Leaders, their projects, and our pilot project program. It will also detail the CCN's links to Centers and research cores in Rhode Island researching allied areas of clinical neuroscience, neurology, psychiatry, and psychology, current collaborative efforts across those centers, and opportunities to collaborate in research and training.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211205PMC
March 2021

Physician Compensation in the United States - Through the Lens of the MS Neurologist.

Mult Scler Relat Disord 2021 May 17;50:102847. Epub 2021 Feb 17.

Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

Purpose Of Review: To explore the elements that are typically considered when determining physician compensation in the United States and to examine if the compensation of neurologists with expertise in multiple sclerosis (MS) care is commensurate with that for other neurological specialists and medical specialists that also employ complex therapies, e.g., oncology.

Recent Findings: The complexity in the diagnosis and management of MS requires increasing specialization. Additionally, changing models for the delivery of MS care has resulted in the MS neurologist generating significant contribution margins. In fact, the revenue to compensation ratio for the MS neurologist may be significantly higher than that of any other discipline in neuroscience service lines. However, while the contribution margin is often a key justification of compensation of interventional and intensive care practitioners in neuroscience service lines, it is generally not considered in the MS neurologist's compensation. Compensation models for MS neurologists typically depend heavily on the absolute number of relative value units associated with evaluation and management (E&M) codes making other fields of neurology financially more attractive to trainees.

Summary: In considering the shortage of MS specialists, the demands of their discipline, and the revenue to compensation ratios, the MS neurologist is significantly undercompensated relative to other neurological specialists and to physicians in other disciplines. Compensating the MS neurologist appropriately and supporting the necessary infrastructure for MS care will likely attract more trainees to this discipline and help reverse the current scarcity of MS neurologists in the United States.
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http://dx.doi.org/10.1016/j.msard.2021.102847DOI Listing
May 2021

Clinical Features, Treatment Strategies, and Outcomes in Hospitalized Children With Immune-Mediated Encephalopathies.

Pediatr Neurol 2021 03 28;116:20-26. Epub 2020 Nov 28.

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.

Background: Autoimmune encephalitis (AE) and acute disseminated encephalomyelitis (ADEM) are immune-mediated brain conditions that can cause substantial neurological sequalae. Data describing the clinical characteristics, treatments, and neurological outcomes for these conditions are needed.

Methods: This is a single-center retrospective review of children diagnosed with AE or ADEM over a nine-year period with discharge outcomes measured by the Modified Rankin Score.

Results: Seventy-five patients (23 with ADEM and 52 with AE) were identified. Patients with ADEM had a higher percentage of abnormal magnetic resonance imaging findings (100% vs 60.8%; P < 0.001) and a shorter time from symptom onset to diagnosis (6 vs 14 days; P = 0.024). Oligoclonal bands and serum and cerebrospinal fluid inflammatory indices were higher in patients with AE. Nearly all patients received corticosteroids followed by plasmapheresis or intravenous immunoglobulin, and treatment strategies did not differ significantly between groups. Second-line immune therapies were commonly used in patients with AE. Finally, patients with AE had trends toward longer hospital lengths of stay (21 vs 13 days) and a higher percentage of neurological disability at hospital discharge (59.6% vs 34.8%).

Conclusions: Although patients with ADEM and AE may have similar presenting symptoms, we found significant differences in the frequency of imaging findings, symptom duration, and laboratory and cerebrospinal fluid profiles, which can assist in distinguishing between the diagnoses. Patients in both groups were treated with a combination of immunomodulating therapies, and neurological disability was common at hospital discharge.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.11.014DOI Listing
March 2021

Acute flaccid myelitis: cause, diagnosis, and management.

Lancet 2021 01 23;397(10271):334-346. Epub 2020 Dec 23.

Department of Infectious Diseases, Hospital de Niños "Ricardo Gutiérrez", Buenos Aires, Argentina.

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.
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http://dx.doi.org/10.1016/S0140-6736(20)32723-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909727PMC
January 2021

Neurological infections in 2020: COVID-19 takes centre stage.

Lancet Neurol 2021 01;20(1):17-18

UT Southwestern Medical Center, University of Texas, Dallas, TX 75390, USA.

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http://dx.doi.org/10.1016/S1474-4422(20)30451-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833034PMC
January 2021

Selective Depletion of Antigen-Specific Antibodies for the Treatment of Demyelinating Disease.

Mol Ther 2021 03 17;29(3):1312-1323. Epub 2020 Nov 17.

Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, 469 Joe H. Reynolds Medical Sciences Building, 1114 TAMU, College Station, TX 77843, USA; Cancer Sciences Unit, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, 3107 Medical Research & Education Building, 8447 State Highway 47, Bryan, TX 77807, USA. Electronic address:

Current treatments for antibody-mediated autoimmunity are associated with lack of specificity, leading to immunosuppressive effects. To overcome this limitation, we have developed a class of antibody-based therapeutics for the treatment of autoimmunity involving antibodies that recognize the autoantigen, myelin oligodendrocyte glycoprotein (MOG). These agents ("Seldegs," for selective degradation) selectively eliminate antigen (MOG)-specific antibodies without affecting the levels of antibodies of other specificities. Seldeg treatment of mice during antibody-mediated exacerbation of experimental autoimmune encephalomyelitis by patient-derived MOG-specific antibodies results in disease amelioration. Consistent with their therapeutic effects, Seldegs deliver their targeted antibodies to Kupffer and liver sinusoidal endothelial cells that are known to have tolerogenic effects. Our results show that Seldegs can ameliorate disease mediated by MOG-specific antibodies and indicate that this approach also has the potential to treat other autoimmune diseases where the specific clearance of antibodies is required.
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http://dx.doi.org/10.1016/j.ymthe.2020.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934575PMC
March 2021

Home-Based Pediatric Teleneuropsychology: A validation study.

Arch Clin Neuropsychol 2020 Nov;35(8):1266-1275

Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Objective: To evaluate home-based teleneuropsychology in a pediatric cohort to determine if assessment via in-person and home-based videoconference yield similar results. The second objective was to determine the level of satisfaction with videoconference-based assessment among participants and caregivers.

Method: Fifty-eight participants, aged 6-20 years, were recruited through specialty programs for pediatric demyelinating disorders. Each participant was administered the same brief neuropsychological battery of common measures twice, once during an in-person session and once during a remote home-based videoconference session. Order of sessions was counterbalanced and time between assessments ranged from 1 to 50 days. It was hypothesized that results obtained through in-person vs. remote videoconference sessions would not be significantly different and that most participants and caregivers would rate the experience with teleneuropsychology as satisfactory.

Results: Mann-Whitney U tests showed no significant differences in results obtained in the in-person first vs. remote videoconference first sessions or the change in performance across sessions. Satisfaction ratings by participants and caregivers were largely favorable for the use of the videoconference testing format.

Conclusions: The current study is the first to validate home-based teleneuropsychology and is the first to validate teleneuropsychological assessment in a pediatric sample. Future studies should replicate these findings as well as expand on sample size, diversity of populations evaluated, and the assessment tools administered. Careful consideration of ethical and practical factors should be given before providing pediatric teleneuropsychology services.
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http://dx.doi.org/10.1093/arclin/acaa070DOI Listing
November 2020

Interocular Difference in Retinal Nerve Fiber Layer Thickness Predicts Optic Neuritis in Pediatric-Onset Multiple Sclerosis.

J Neuroophthalmol 2020 Oct 22. Epub 2020 Oct 22.

Division of Neurology (ATW, JRS, AML, GWL), Children's Hospital of Philadelphia and Departments of Neurology and Pediatrics (ATW), Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Departments of Neurology (LB) and Ophthalmology (GH), Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; Division of Neuroimmunology and Glial Biology (AJG, EW), Department of Neurology, Weill Institute of Neurosciences, University of California San Francisco, San Francisco, California; Department of Neurology and Neurotherapeutics (DC, BG), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Neurology, University of California San Diego, San Diego, California; and Department of Ophthalmology (AJG), University of California San Francisco, San Francisco, California.

Background: Optical coherence tomography (OCT) is capable of quantifying retinal damage. Defining the extent of anterior visual pathway injury is important in multiple sclerosis (MS) as a way to document evidence of prior disease, including subclinical injury, and setting a baseline for patients early in the course of disease. Retinal nerve fiber layer (RNFL) thickness is typically classified as low if values fall outside of a predefined range for a healthy population. In adults, an interocular difference (IOD) in RNFL thickness greater than 5 μm identified a history of unilateral optic neuritis (ON). Through our PERCEPTION (PEdiatric Research Collaboration ExPloring Tests in Ocular Neuroimmunology) study, we explored whether RNFL IOD informs on remote ON in a multicenter pediatric-onset MS (POMS) cohort.

Methods: POMS (defined using consensus criteria and first attack <18 years) patients were recruited from 4 academic centers. A clinical history of ON (>6 months prior to an OCT scan) was confirmed by medical record review. RNFL thickness was measured on Spectralis machines (Heidelberg, Germany). Using a cohort of healthy controls from our centers tested on the same machines, RNFL thickness <86 μm (<2 SDs below the mean) was defined as abnormal. Based on previously published findings in adults, an RNFL IOD >5 μm was defined as abnormal. The proportions of POMS participants with RNFL thinning (<86 μm) and abnormal IOD (>5 μm) were calculated. Logistic regression was used to determine whether IOD was associated with remote ON.

Results: A total of 157 participants with POMS (mean age 15.2 years, SD 3.2; 67 [43%] with remote ON) were enrolled. RNFL thinning occurred in 45 of 90 (50%) ON eyes and 24 of 224 (11%) non-ON eyes. An IOD >5 μm was associated with a history of remote ON (P < 0.001). An IOD >5 μm occurred in 62 participants, 40 (65%) with remote ON. Among 33 participants with remote ON but normal RNFL values (≥86 μm in both eyes), 14 (42%) were confirmed to have ON by IOD criteria (>5 μm).

Conclusions: In POMS, the diagnostic yield of OCT in confirming remote ON is enhanced by considering RNFL IOD, especially for those patients with RNFL thickness for each eye in the normal range. An IOD >5 μm in patients with previous visual symptoms suggests a history of remote ON.
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http://dx.doi.org/10.1097/WNO.0000000000001070DOI Listing
October 2020

Revisiting Transverse Myelitis: Moving Toward a New Nomenclature.

Front Neurol 2020 23;11:519468. Epub 2020 Sep 23.

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States.

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http://dx.doi.org/10.3389/fneur.2020.519468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546824PMC
September 2020

Heterozygous Cystic Fibrosis Transmembrane Regulator Gene Missense Variants Are Associated With Worse Cardiac Function in Patients With Duchenne Muscular Dystrophy.

J Am Heart Assoc 2020 10 2;9(19):e016799. Epub 2020 Oct 2.

Department of Internal Medicine UT Southwestern Medical Center Dallas TX.

Background Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by mutations within the dystrophin gene. DMD is characterized by progressive skeletal muscle degeneration and atrophy and progressive cardiomyopathy. It has been observed the severity of cardiomyopathy varies in patients with DMD. Methods and Results A cohort of male patients with DMD and female DMD carriers underwent whole exome sequencing. Potential risk factor variants were identified according to their functional annotations and frequencies. Cardiac function of 15 male patients with DMD was assessed by cardiac magnetic resonance imaging, and various cardiac magnetic resonance imaging parameters and circulating biomarkers were compared between genotype groups. Five subjects carrying potential risk factor variants in the cystic fibrosis transmembrane regulator gene demonstrated lower left ventricular ejection fraction, larger left ventricular end-diastolic volume, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels compared with 10 subjects who did not carry the potential risk factor variants (=0.023, 0.019 and 0.028, respectively). Conclusions This study revealed heterozygous cystic fibrosis transmembrane regulator gene missense variants were associated with worse cardiac function in patients with DMD. The cystic fibrosis transmembrane regulator gene may serve as a genetic modifier that accounts for more severe cardiomyopathy in patients with DMD, who would require more aggressive management of the cardiomyopathy.
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http://dx.doi.org/10.1161/JAHA.120.016799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792368PMC
October 2020

A Secondary Analysis on Effects of Theta Burst Transcranial Magnetic Stimulation to Reduce Anger in Veterans With Posttraumatic Stress Disorder.

Neuromodulation 2021 Jul 17;24(5):870-878. Epub 2020 Sep 17.

VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center and Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02906, USA.

Introduction: Anger is an important clinical feature of posttraumatic stress disorder (PTSD) that can hamper recovery. We recently reported that intermittent theta burst stimulation (iTBS) demonstrated preliminary efficacy to reduce symptoms of posttraumatic stress disorder and major depression; here, we performed a secondary analysis testing whether iTBS reduced symptoms of anger over the course of iTBS treatment and compared to sham stimulation.

Materials And Methods: Fifty veterans with chronic PTSD received ten daily sessions of sham-controlled, double-blind iTBS (1800 pulses/session, once per weekday) targeting the right dorsolateral prefrontal cortex (intent-to-treat = 25 per group). Participants who completed the double-blind phase were offered another ten sessions of unblinded iTBS. Participants completed the Dimensions of Anger Reactions scale at pre-iTBS baseline, treatment midpoints, and endpoints of the blinded and unblinded phases, and at one-month after the last stimulation session. Correlations between anger, PTSD, depression, and sleep were also explored.

Results: After the first week, during the double-blind phase, participants randomized to active stimulation reported significantly reduced anger compared to sham stimulation (p = 0.04). Participants initially randomized to sham appeared to catch-up to the point they no longer differed from those initially randomized to active iTBS when they received iTBS during the unblinded phase (p = 0.14). Anger reduction was maintained at one-month after iTBS in participants initially randomized to active stimulation (i.e., total of four weeks of iTBS).

Conclusions: This secondary analysis suggests that iTBS might reduce anger in veterans with PTSD. Future studies focused on more granular level anger outcomes and effects of number of stimulation sessions are needed.
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http://dx.doi.org/10.1111/ner.13256DOI Listing
July 2021

Utilization of Visual Acuity Retroilluminated Charts for the Assessment of Afferent Visual System Dysfunction in a Pediatric Neuroimmunology Population.

J Neuroophthalmol 2021 03;41(1):19-23

Multiple Sclerosis Division (PVS, MM, DC, BMG), Department of Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, Texas; Department of Neurology (JG), University of California San Diego, San Diego, California; Department of Neurology and Pediatrics (LB), Boston Children's Hospital, Boston, Massachusetts; Division of Neurology (ATW), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and Departments of Neurology and Pediatrics (ATW), Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Visual acuity has been a significant outcome measure in clinical trials for patients suffering from neuro-ophthalmological diseases and multiple sclerosis; however, there are limited data on the comparison of various testing strategies in pediatric patients with these disorders. Clinical trials using vision as an outcome could include a variety of tools to assess the acuity, including 2-m and 4-m standardized retroilluminated charts.

Methods: We investigated the difference in Early Treatment Diabetic Retinopathy Study (ETDRS) scores obtained using 2-m and 4-m charts, as well as the impact of optic neuritis, use of vision correction, age, and gender on visual acuity data from 71 patients with pediatric neuroimmunological conditions in a cross-sectional study.

Results: We determine that the ETDRS letter scores obtained using 4-m charts are on average 3.43 points less (P = 0.0034) when testing monocular ETDRS letter scores and on average 4.14 points less (P = 0.0008) when testing binocular ETDRS letter scores, relative to that obtained using the 2-m charts. However, we find that when performing monocular testing, optic neuritis in the eye being tested did not result in a statistically significant difference between 2-m and 4-m ETDRS letter scores.

Conclusions: Although visual acuity charts are formatted by the distance, there are significant differences in the number of letters correctly identified between 2-m and 4-m charts. Although the differences may not impact the clinical acuity, research protocols should consider these differences before collapsing data across disparate studies.
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http://dx.doi.org/10.1097/WNO.0000000000001001DOI Listing
March 2021

A Brief Report on an 8-Week Course of Mindfulness-based Care for Chronic Pain in the Treatment of Veterans With Back Pain: Barriers Encountered to Treatment Engagement and Lessons Learned.

Med Care 2020 09;58 Suppl 2 9S:S94-S100

Mental Health and Behavioral Sciences Service, Department of Veteran Affairs Medical Center, Providence VA Medical Center.

Background: Chronic pain and associated symptoms are debilitating for veterans. Medical costs of treatments are high and current treatment options, most notably with opioid medications, have been associated with significant risk. Mindfulness-based interventions appear promising for chronic pain, but require additional testing in veteran care settings.

Objective: This project was designed to test the feasibility of engaging and retaining veterans with chronic lower back pain in a new mindfulness protocol tailored for veterans, mindfulness-based care for chronic pain (MBCP). Clinical outcomes were also assessed.

Design: An open pilot trial of an 8-week MBCP course that included meditation, gentle yoga, and psychoeducation.

Subjects: Twenty-two veterans (mean age=49.77; 18% women) were recruited from a VA Medical Center in the Northeastern US. After screening for inclusion/exclusion criteria, 20 were eligible at baseline.

Measures: Veterans were assessed at baseline and postintervention for functional impairment, pain intensity and bothersomeness, depression, and mindfulness.

Results: The average number of sessions completed was 5; only 4 (20%) attended all sessions. Eleven of the 20 participants (55%) attended 5 or more sessions and had complete preintervention and postintervention visits. Five of the 11 had a clinically meaningful decrease in pain intensity and in depressive symptoms, while 6 of 11 had a meaningful decrease in pain bothersomeness and functional impairment.

Conclusions: It was challenging to enroll and retain participants in this study, even with our intervention designed for veterans. We discuss possible adaptations and refinements in MBCP for veterans with chronic pain to enhance feasibility and improve upon these interventions.
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http://dx.doi.org/10.1097/MLR.0000000000001377DOI Listing
September 2020

Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy in paediatric patients with multiple sclerosis: Results from the PARADIG study.

Mult Scler 2021 May 7;27(6):922-932. Epub 2020 Jul 7.

Division of Paediatric Neurology, Department of Paediatrics and Adolescent Medicine, University Medical Centre Göttingen, Georg August University Göttingen, Göttingen, Germany.

Background: Reduction in absolute lymphocyte count (ALC) is expected with fingolimod treatment.

Objective: To evaluate the effect of fingolimod 0.5 mg versus intramuscular interferon β-1a (30 μg) on ALC and its relationship with infections in paediatric-onset multiple sclerosis (POMS) up to 4 years.

Methods: We assessed ALC at baseline, monthly till 3 months, and every 3 months (core phase) and with variable periodicity (extension phase) of Phase 3 PARADIG study ( = 215). Incidence rates (IRs) of infection-related adverse events (AEs)/100 patient-years were analysed by on-study nadir ALC.

Results: With fingolimod, ALC rapidly reduced to 29.9%-34.4% of baseline values within 2 weeks and remained stable thereafter; no relevant changes observed with interferon. IRs of AEs were 67.6 with fingolimod and 61.8 with interferon; IR ratios with respect to interferon, overall: 1.09, by nadir ALC 0.2-0.4 × 10/L: 1.13 and >0.4 × 10/L: 0.91. Three patients had a single episode of ALC <0.2 × 10/L (core phase). No opportunistic infections were observed and infection risk did not increase during the extension phase.

Conclusion: In paediatric patients, the overall incidence of infections was comparable between fingolimod and interferon. No association was observed between nadir ALC and infections in POMS, although sample size may have been too small to rule an association.
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http://dx.doi.org/10.1177/1352458520936934DOI Listing
May 2021

Prolonged avoidance training exacerbates OCD-like behaviors in a rodent model.

Transl Psychiatry 2020 07 3;10(1):212. Epub 2020 Jul 3.

Departments of Psychiatry and Anatomy & Neurobiology, School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR, 00936, USA.

Obsessive-compulsive disorder (OCD) is characterized by compulsive behaviors that often resemble avoidance of perceived danger. OCD can be treated with exposure-with-response prevention (ERP) therapy in which patients are exposed to triggers but are encouraged to refrain from compulsions, to extinguish compulsive responses. The compulsions of OCD are strengthened by many repeated exposures to triggers, but little is known about the effects of extended repetition of avoidance behaviors on extinction. Here we assessed the extent to which overtraining of active avoidance affects subsequent extinction-with-response prevention (Ext-RP) as a rodent model of ERP, in which rats are extinguished to triggers, while the avoidance option is prevented. Male rats conditioned for 8d or 20d produced similar avoidance behavior to a tone paired with a shock, however, the 20d group showed a severe impairment of extinction during Ext-RP, as well as heightened anxiety. Furthermore, the majority of overtrained (20d) rats (75%) exhibited persistent avoidance following Ext-RP. In the 8d group, only a minority of rats (37%) exhibited persistent avoidance, and this was associated with elevated activity (c-Fos) in the prelimbic cortex and nucleus accumbens. In the 20d group, the minority of non-persistent rats (25%) showed elevated activity in the insular-orbital cortex and paraventricular thalamus. Lastly, extending the duration of Ext-RP prevented the deleterious effects of overtraining on extinction and avoidance. These rodent findings suggest that repeated expression of compulsion-like behaviors biases individuals toward persistent avoidance and alters avoidance circuits, thereby reducing the effectiveness of current extinction-based therapies.
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http://dx.doi.org/10.1038/s41398-020-00892-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334221PMC
July 2020

Mapping PTSD symptoms to brain networks: a machine learning study.

Transl Psychiatry 2020 06 18;10(1):195. Epub 2020 Jun 18.

Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, 02906, USA.

Posttraumatic Stress Disorder (PTSD) is a prevalent and debilitating condition with complex and variable presentation. While PTSD symptom domains (intrusion, avoidance, cognition/mood, and arousal/reactivity) correlate highly, the relative importance of these symptom subsets often differs across patients. In this study, we used machine learning to derive how PTSD symptom subsets differ based upon brain functional connectivity. We acquired resting-state magnetic resonance imaging in a sample (N = 50) of PTSD patients and characterized clinical features using the PTSD Checklist for DSM-5 (PCL-5). We compared connectivity among 100 cortical and subcortical regions within the default mode, salience, executive, and affective networks. We then used principal component analysis and least-angle regression (LARS) to identify relationships between symptom domain severity and brain networks. We found connectivity predicted PTSD symptom profiles. The goodness of fit (R) for total PCL-5 score was 0.29 and the R for intrusion, avoidance, cognition/mood, and arousal/reactivity symptoms was 0.33, 0.23, -0.01, and 0.06, respectively. The model performed significantly better than chance in predicting total PCL-5 score (p = 0.030) as well as intrusion and avoidance scores (p = 0.002 and p = 0.034). It was not able to predict cognition and arousal scores (p = 0.412 and p = 0.164). While this work requires replication, these findings demonstrate that this computational approach can directly link PTSD symptom domains with neural network connectivity patterns. This line of research provides an important step toward data-driven diagnostic assessments in PTSD, and the use of computational methods to identify individual patterns of network pathology that can be leveraged toward individualized treatment.
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http://dx.doi.org/10.1038/s41398-020-00879-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303205PMC
June 2020

Transient aphasia induced by intermittent theta burst stimulation.

Brain Stimul 2020 Jul - Aug;13(4):941-942. Epub 2020 Mar 25.

VA RR&D Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, RI, 02908, USA; Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Butler Hospital, Providence, RI, USA.

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http://dx.doi.org/10.1016/j.brs.2020.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343258PMC
March 2020

Informing Further Research in the Use of Brain Stimulation in Psychiatric Disorders: Response to Syed and Smith.

Am J Psychiatry 2020 05;177(5):466-467

The Center for Neurorestoration and Neurotechnology, Providence VA Medical Center, Providence, R.I., and the Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, R.I.

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http://dx.doi.org/10.1176/appi.ajp.2019.19101052rDOI Listing
May 2020
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