Below are selected research articles and presentations supported in part by grants from The Siegel Rare Neuroimmune Association for research faculty and staff support, or written with input from The Siegel Rare Neuroimmune Association.
2024
Validation of the international MOGAD panel proposed criteria: a single-centre US study
Abstract
BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a demyelinating disorder of the central nervous system. We aimed to evaluate the diagnostic performance of recently proposed MOGAD diagnostic criteria in a real-world patient cohort at a tertiary referral centre.
METHODS: We identified all patients who were evaluated at Johns Hopkins and were MOG-IgG seropositive by cell-based assay. We retrospectively applied the proposed MOGAD diagnostic criteria.
RESULTS: Among the 122 patients included in this study, 109 fulfilled the diagnostic criteria. Of 64 patients with clear positive MOG-IgG titre, 63 patients also satisfied the supporting clinical or MRI features. Of 58 patients with low positive or unknown MOG-IgG titre, 46 met criteria by fulfilment of the supporting features. The medical records were independently reviewed by two investigators with expertise in demyelinating disease, and patients were assigned empirical clinical diagnoses, with agreement with the application of the MOGAD diagnostic criteria in the majority of cases (90%).
CONCLUSIONS: Our findings support the diagnostic utility of the proposed MOGAD diagnostic criteria. Patients with MOGAD met the supporting clinical or MRI features almost universally, which suggests that the criteria can be used to accurately differentiate MOGAD from mimics with low-titre MOG-IgG seropositivity.
Mapping myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD) global registries: A comprehensive review of publicly listed patient disease registries
Abstract
INTRODUCTION: Understanding of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) pathophysiology, diagnosis, and management is rapidly evolving. Delayed diagnosis or misdiagnosis are common due to symptom overlap with aquaporin-4 (AQP4) neuromyelitis optica spectrum disorder (NMOSD), NMO, and multiple sclerosis. Real-world data from patient databases/registries is crucial to understand the natural history and address unmet needs in rare diseases.
OBJECTIVES/AIMS: This study developed the first global map of MOGAD, NMO and NMOSD patient databases/registries.
METHODS: Databases/registries were identified through searching rare disease portals and websites of known registries, patient advocacy groups, government agencies, academic institutions, reviewing scientific literature and consultation with project partners. Purpose, participants, types of data collected, development plans and challenges were recorded. A 10-question survey, addressing purpose, set-up, coverage, data collected, plans for growth and challenges, was sent to all databases/registries with public contact details.
RESULTS: Thirty-seven databases/registries were identified. Four have a worldwide footprint, two are Australasian and one covers the USA/Canada. The remaining 30 are specific to the US/Canada (n=11), South America (n=6), Europe (n=6), Asia (n=6) and Africa (n=1). The survey was completed by 25 databases/registries; 24/25 (96%) include patients with MOGAD, and 21/25 (84%) with NMO/NMOSD. Support for scientific research and advancing disease understanding was described as a major objective for all 25 (100%). Almost all collect information on diagnosis (n=25, 100%), clinical characteristics (24, 96%), AQP4 tests (22, 88%), MOG antibody tests (22, 88%), details of laboratory findings (21, 84%), radiological results (20, 80%), disability status (20, 80%) and visual acuity (18, 72%). In the next 3–5 years, around one-third of databases/registries plan to include more data (e.g. biomarkers, genetic data; n=8, 32%) or more patients (7, 28%). Challenges related to cost, time, resources and data quality remain.
CONCLUSION: Patient databases/registries including MOGAD, NMO and NMOSD patients have been established in many countries, collecting valuable clinical and laboratory data, and seeking to advance research into these conditions. Despite cost, time, resource and quality challenges, they are an increasingly important source of real-world information to address unmet patient needs in these rare diseases. Survey funded by UCB Pharma.
Palace J, Marignier R , Abend A et al. Poster presented at ECTRIMS 2024.
Correlates of sociodemographic features, healthcare access, and disability in NMOSD
Abstract
INTRODUCTION: Knowledge gaps exist regarding social determinants of health in NMOSD. Here we assessed available parameters of healthcare access with demographics and disability in CIRCLES.
OBJECTIVES/AIMS: Assess potential associations with foreign born status, rural living and safe water access, time to diagnosis, rituximab accessibility, race and ethnicity, and baseline NMOSD disability.
METHODS: Implementation of the longitudinal CIRCLES study is previously described; this cohort was limited to United States and Canada. Race and ethnicity were self-identified. Univariate analyses used chi-squared, ANOVA, and Wilcoxon rank sum testing, and multivariate analyses used logistic regression.
RESULTS: Of the 669 participants, 85% were female and 81% were anti-aquaporin-4 seropositive (AQP4+). The median age at onset was 37.6 years (SD 14.74) with median disease duration 5 years (SD 7.3) and time to diagnosis of 0.57 years (SD 6.33). Black and Hispanic patients (34% and 31%) were twice as likely to be legally blind at baseline compared to White and Asian patients (16.5% and 8.7%). Black patients were less likely to be independently mobile than White patients (48.4% vs. 68.8%). Fewer Black and Hispanic patients (67.9% and 72.6%) reported independence in activities of daily living (ADLs) compared to White and Asian patients (86.7% and 80.7%). Rural status and safe water access were not associated with worse disability. Immigrant status was not associated with baseline visual/motor disability, but foreign born patients were less likely to report independence with ADLs compared to native born patients (p=0.03). Increased time to diagnosis was associated with worse visual (p=.005) and motor disability (p=.003). Baseline rituximab use was associated with worse motor disability (p=0.03). Multivariate models found increased age at onset (p=.0003) and Black race (<.0001) significantly correlated with motor disability. Black race (p=.0026), Hispanic ethnicity (p=.035), and AQP4+ serostatus (p=.04) significantly correlated with visual disability.
CONCLUSION: Black and Hispanic patients were more likely than White or Asian patients to be disabled in baseline motor, visual, and functional outcomes. Foreign born patients were less likely to be functionally independent than native born patients. Rural living, longer time to diagnosis, and baseline rituximab use did not correlate with visual or motor disability in multivariate models. More research is needed to better understand the SDOH behind health disparities in NMOSD
Satyanarayan S, Behne M , Behne J et al. Poster presented at ECTRIMS 2024.
2023
Understanding treatment decisions in neuromyelitis optica spectrum disorder: a global clinical record review with patient interviews
Abstract
INTRODUCTION: We sought insights into neuromyelitis optica spectrum disorder (NMOSD) treatment practices worldwide.
METHODS: Neurologists from the USA, Germany, Italy, Brazil, South Korea, and China completed an online survey, contributing clinical records for aquaporin-4 (AQP4) immunoglobulin G (IgG)-seropositive adults with NMOSD, which included patient demographics, diagnosis, maintenance treatment history, relapse occurrence, and severity. Interviewed patients receiving NMOSD maintenance therapy provided information about their diagnosis, treatment, perceptions about relapse severity or disease stability, and treatment switches.
RESULTS: A total of 389 neurologists submitted clinical records for 1185 patients with AQP4-IgG-seropositive NMOSD; 33 patients with NMOSD were interviewed. Approximately 25% (228/910) of patients from the clinical record review (CRR) were initially misdiagnosed; 24% (8/33) of patients interviewed reported formal misdiagnosis. Misdiagnosis was associated with treatment delay and more relapses compared with correct diagnosis (mean 3.3 vs 2.8). Maintenance therapy was not initiated within 2 months for 47% (221/472) of patients from the CRR and 24% (8/33) of interviewed patients. Oral corticosteroids/immunosuppressive therapies were typically the first maintenance treatment initiated, except for the USA, where monoclonal antibodies were equally likely to be prescribed. Relapse severity influenced the decision to initiate/change therapy and use monoclonal antibodies. Of interviewed patients, 76% (25/33) did not recall having a choice of treatment and many did not know the rationale for treatment choice.
CONCLUSION: Misdiagnosis of NMOSD appears to be common and is associated with a delay in initiation of maintenance therapy, with decisions influenced by relapse severity. Further real-world studies assessing relapse severity in treatment initiation/switch are required to revise NMOSD treatment recommendations.
Characterisation of disease severity and stability in neuromyelitis optica spectrum disorder: a global clinical record review with patient interviews
Abstract
INTRODUCTION: We sought insights into the classification of and factors associated with relapse severity and disease stability in neuromyelitis optica spectrum disorder (NMOSD) clinical practice worldwide.
METHODS: Neurologists recruited from six countries (the USA, Germany, Italy, Brazil, South Korea, and China) participated in a 30-60 minute online survey and submitted two to four clinical records for aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive adults with NMOSD, which included patient demographics, diagnosis, maintenance treatment history, relapse occurrence, and severity. Separately, patients with NMOSD receiving maintenance therapy were interviewed over the telephone about their treatment journey, as well as perceptions of relapse severity and disease stability, and their potential influence on treatment decisions.
RESULTS: Clinical records for 1185 patients with AQP4-IgG-seropositive NMOSD were provided by 389 neurologists (July-August 2020); 33 patients were interviewed (October-November 2020). There was no clear consensus on how relapse severity was defined in clinical practice, with geographical variations in relapse classification also found. Neurologists tended to rely on clinical assessments when determining severity, viewing each relapse in isolation, whereas patients had a more subjective view based on the changes in their daily lives and comparisons with prior relapses. Similarly, there was a disconnect in the definition of disease stability: the complete absence of relapses was more important for patients than for neurologists.
CONCLUSION: A clear consensus on how to assess relapse severity and disease stability is needed to ensure that patients receive appropriate and timely treatment. In the future, clinical measures should be combined with patient-focused assessments.
2022
Identification of specific causes of myelopathy in a large cohort of patients initially diagnosed with transverse myelitis
Abstract
BACKGROUND AND OBJECTIVES: Identifying the etiologic diagnosis in patients presenting with myelopathy is essential in order to guide appropriate treatment and follow-up. We set out to examine the etiologic diagnosis after comprehensive clinical evaluation and diagnostic work-up in a large cohort of patients referred to our specialized myelopathy clinic, and to explore the demographic profiles and symptomatic evolution of specific etiologic diagnoses.
METHODS: In this retrospective study of patients referred to the Johns Hopkins Myelitis and Myelopathy Center between 2006 and 2021 for evaluation of “transverse myelitis”, the final etiologic diagnosis determined after comprehensive evaluation in each patient was reviewed and validated. Demographic characteristics and temporal profile of symptom evolution were recorded.
RESULTS: Of 1193 included patients, 772 (65%) were determined to have an inflammatory myelopathy and 421 (35%) were determined to have a non-inflammatory myelopathy. Multiple sclerosis/clinically isolated syndrome (n = 221, 29%) and idiopathic myelitis (n = 149, 19%) were the most frequent inflammatory diagnoses, while spinal cord infarction (n = 197, 47%) and structural causes of myelopathy (n = 108, 26%) were the most frequent non-inflammatory diagnoses. Compared to patients with inflammatory myelopathies, patients with non-inflammatory myelopathies were more likely to be older, male and experience chronic symptom evolution (p < 0.001 for all). Hyperacute symptom evolution was most frequent in patients with spinal cord infarction (74%), while chronic symptom evolution was most frequent in patients with structural causes of myelopathy (81%), arteriovenous fistula or arteriovenous malformation (81%), myelopathy associated with rheumatologic disorder (71%), and sarcoidosis-associated myelopathy (61%). CONCLUSIONS: Patients initially diagnosed with “transverse myelitis” are eventually found to have a more specific inflammatory or even non-inflammatory cause, potentially resulting in inappropriate treatment and follow-up. Demographic characteristics and temporal profile of symptom evolution may help inform a differential diagnosis in these patients. Etiological diagnosis of myelopathies would provide better therapeutic decisions. Murphy OC, Barreras P, Villabona-Rueda A, Mealy M, Pardo C. Identification of specific causes of myelopathy in a large cohort of patients initially diagnosed with transverse myelitis. J Neurol Sci . 2022 Nov 15;442:120425. doi: 10.1016/j.jns.2022.120425. Epub 2022 Sep 29.
Understanding treatment decisions in neuromyelitis optica spectrum disorder: a global clinical record review with patient interviews
Min J-H (1), Capobianco M (2), Welsh C (3), Lobo P (4), deFiebre G (5), Lana-Peixoto M (6), Wingerchuk DM (7), Wang J (8), Ringelstein M (9,10)
1. Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of
2. Neurology Department, San Luigi Gonzaga University Hospital, Orbassano, Italy
3. Blueprint Partnership, Manchester, United Kingdom
4. ApotheCom, London, United Kingdom
5. Siegel Rare Neuroimmune Association, Columbus, Ohio, United States
6. Federal University of Minas Gerais Medical School, Belo Horizonte, Brazil
7. Department of Neurology, Mayo Clinic, Scottsdale, Arizona, United States
8. Beijing Tongren Hospital, Capital Medical University, Beijing, China
9. Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
10. Department of Neurology, Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
Abstract presented virtually at ECTRIMS 2022.
Characterisation of disease severity and stability in neuromyelitis optica spectrum disorder: a global clinical record review with patient interviews
Capobianco M (1), Ringelstein M (2, 3), Welsh C (3), Lobo P (4), deFiebre G (5), Lana-Peixoto M (6), Wang J (8), Min J-H (1), , Wingerchuk DM (7),
1. Neurology Department, San Luigi Gonzaga University Hospital, Orbassano, Italy
2. Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
3. Department of Neurology, Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
4. Blueprint Partnership, Manchester, United Kingdom
5. ApotheCom, London, United Kingdom
6. Siegel Rare Neuroimmune Association, Columbus, Ohio, United States
7. Federal University of Minas Gerais Medical School, Belo Horizonte, Brazil
8. Beijing Tongren Hospital, Capital Medical University, Beijing, China
9. Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of
10. Department of Neurology, Mayo Clinic, Scottsdale, Arizona, United States
Abstract presented virtually at ECTRIMS 2022.
2021
Modern Look at Transverse Myelitis and Inflammatory Myelopathy: Epidemiology of the National Veterans Health Administration Population
Abstract
BACKGROUND AND OBJECTIVES: To characterize population-level data associated with transverse myelitis (TM) within the US Veterans Health Administration (VHA).
METHODS: This retrospective review used VHA electronic medical record from 1999 to 2015. We analyzed prevalence, disease characteristics, modified Rankin Scale (mRS) scores, and mortality data in patients with TM based on the 2002 Diagnostic Criteria.
RESULTS: We identified 4,084 patients with an International Classification of Diseases (ICD) code consistent with TM and confirmed the diagnosis in 1,001 individuals (90.7% males, median age 64.2, 67.7% Caucasian, and 31.4% smokers). The point prevalence was 7.86 cases per 100,000 people. Less than half of the cohort underwent a lumbar puncture, whereas only 31.8% had a final, disease-associated TM diagnosis. The median mRS score at symptom onset was 3 (interquartile range 2–4), which remained unchanged at follow-up, although less than half (43.2%) of the patients received corticosteroids, IVIg, or plasma exchange. Approximately one-quarter of patients (24.3%) had longitudinal extensive TM, which was associated with poorer outcomes (p = 0.002). A total of 108 patients (10.8%) died during our review (94.4% males, median age 66.5%, and 70.4% Caucasian). Mortality was associated with a higher mRS score at follow-up (OR 1.94, 95% CI, 1.57–2.40) and tobacco use (OR 1.87, 95% CI, 1.17–2.99).
DISCUSSION: This national TM review highlights the relatively high prevalence of TM in a modern cohort. It also underscores the importance of a precise and thorough workup in this disabling disorder to ensure diagnostic precision and ensure optimal management for patients with TM in the future.
Aquaporin-4 Autoantibody Detection by ELISA: A Retrospective Characterization of a Commonly Used Assay
Abstract
OBJECTIVE: Aquaporin-4 (AQP4) serum autoantibodies are detected by a variety of methods. The highest sensitivity is achieved with cell-based assays, but the enzyme-linked immunosorbent assay (ELISA) is still commonly utilized by clinicians worldwide.
METHODS: We performed a retrospective review to identify all patients at the University of Utah who had AQP4 ELISA testing at ARUP Laboratories from 2010 to 2017. We then reviewed their diagnostic evaluation and final diagnosis based on the ELISA titer result.
RESULTS: A total of 750 tests for the AQP4 ELISA were analyzed, and 47 unique patients with positive titers were identified. Less than half of these patients (49%) met the clinical criteria for neuromyelitis optica spectrum disorder (NMOSD). In cases of low positive titers (3.0–7.9 U/mL, n = 19), the most common final diagnosis was multiple sclerosis (52.6%). In the moderate positive cohort (8.0–79.9 U/mL, n = 14), only a little more than half the cohort (64.3%) had NMOSD. In cases with high positives (80–160 U/mL, n = 14), 100% of patients met clinical criteria for NMOSD.
CONCLUSIONS: Our data illustrates diagnostic uncertainty associated with the AQP4 ELISA, an assay that is still commonly ordered by clinicians despite the availability of more sensitive and specific tests to detect AQP4 autoantibodies in patients suspected of having NMOSD. In particular, low positive titer AQP4 ELISA results are particularly nonspecific for the diagnosis of NMOSD. The importance of accessibility to both sensitive and specific AQP4 testing cannot be overemphasized in clinical practice.
Antibody Testing for Neurological Autoimmune Disorders: Evaluation of Best Practices at a Tertiary Referral Center
Abstract
BACKGROUND: Autoimmune neurology is a rapidly evolving field of study, where best practices for neurological antibody testing have yet to be determined. The growing number of options for antibody panel testing can create confusion amongst ordering clinicians and lead to ordering several concurrent panels (i.e., overlapping evaluations) or repeat panel evaluations. This study determined the frequency of these evaluations for autoimmune and paraneoplastic disorders and investigated how these practices informed clinical decision making and management.
METHODS: This was a retrospective observational study of adult patients presenting to University of Texas Southwestern (UTSW) in 2017 with requests for antibody panels for autoimmune encephalitis and paraneoplastic disorders. Individuals with more than one panel requested were defined as either an overlapping evaluation (more than one panel requested within 14 days) or repeat evaluation (more than one panel requested 14 or more days apart). For those individuals with repeat panel testing, the proportion of panels with a change in antibody status or subsequent changes in clinical diagnosis and decision making were recorded.
RESULTS: There was a total of 813 panels sent on 626 individuals. Twenty percent (126 individuals) had more than one panel requested. Only 10% of individuals had a matched serum and CSF evaluation. Forty-seven overlapping evaluations were performed in 46 (7.3%) of the individuals studied. Fifty-four (8.6%) individuals underwent 70 repeat evaluations encompassing 79 panels (9.7% of total panels ordered). Ten repeat evaluations showed a change in antibody status, of which only two were clinically significant. There was a single case where clinical management was affected by repeat autoantibody evaluation.
CONCLUSIONS: Ordering practices for suspected autoimmune encephalitis and paraneoplastic disorders are suboptimal with frequent overlapping antibody panel evaluations and non-paired serum/CSF samples at our center. Repeat autoantibody testing is a commonplace practice yet yielded novel information in only a minority of cases. These new results were, as a rule, clinically irrelevant and changed clinical decision making in <1% of cases. There is limited utility in these practice patterns. Future efforts should be directed at the development and standardization of neurological autoimmune and paraneoplastic autoantibody testing practice standards. Fredrich SE, Vernino S, Blackburn KM. Antibody testing for neurological autoimmune disorders: Evaluation of best practices at a tertiary referral center. Front Neurol. 2021; 12: 690415. Published online 2021 Jun 30. doi: 10.3389/fneur.2021.690415
2020
Acute flaccid myelitis: cause, diagnosis, and management
Abstract
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.
Neuronal Uptake, Antibody Binding, and Injury by Anti-Ma2 Antibodies in Organotypic Rat Brain Cultures: A Possible Direct Role for Paraneoplastic Autoantibody in Disease Pathogenesis
Galli JR (1, 2) , Carlson NG (1,2), Greenlee JE (1,2)
1. VA SLC HCS, Salt Lake City, UT
2. University of Utah School of Medicine, Salt Lake City, UT
Abstract presented virtually at the 2020 145th Annual Meeting of the American Neurological Association
Neurosarcoidosis: Longitudinal experience in a single-center, academic healthcare system
Abstract
OBJECTIVE: To characterize patients with neurosarcoidosis within the University of Utah healthcare system, including demographics, clinical characteristics, treatment, and long-term outcomes.
METHODS: We describe the clinical features and outcomes of patients with neurosarcoidosis within the University of Utah healthcare system (a large referral center for 10% of the continental United States by land mass). Patients were selected who met the following criteria: (1) at least one International Classification of Diseases Clinical Modification, 9th revision code 135 or International Classification of Diseases Clinical Modification, 10th revision code D86* (sarcoidosis) and (2) at least one outpatient visit with a University of Utah clinician in the Neurology Department within the University of Utah electronic health record.
RESULTS: We identified 56 patients meeting the study criteria. Thirty-five patients (63%) were women, and most patients (84%) were white. Twelve patients (22%) met the criteria for definite neurosarcoidosis, 36 patients (64%) were diagnosed with probable neurosarcoidosis, and 8 patients (14%) were diagnosed with possible neurosarcoidosis. A total of 8 medications were used for the treatment of neurosarcoidosis. Prednisone was the first-line treatment in 51 patients (91%). Infliximab was the most effective therapy, with 87% of patients remaining stable or improving on infliximab. Treatment response for methotrexate and azathioprine was mixed, and mycophenolate mofetil and rituximab were the least effective treatments in this cohort.
CONCLUSIONS: This is a comprehensive characterization of neurosarcoidosis within a single healthcare system at the University of Utah that reports long-term response to treatment and outcomes of patients with neurosarcoidosis. Our results suggest the use of infliximab as a first-line therapy for neurosarcoidosis.
Clinical and MRI phenotypes of sarcoidosis-associated myelopathy
Abstract
OBJECTIVE: To determine the characteristic clinical and spinal MRI phenotypes of sarcoidosis-associated myelopathy (SAM), we analyzed a large cohort of patients with this disorder.
METHODS: Patients diagnosed with SAM at a single center between 2000 and 2018 who met the established criteria for definite and probable neurosarcoidosis were included in a retrospective analysis to identify clinical profiles, CSF characteristics, and MRI lesion morphology.
RESULTS: Of 62 included patients, 33 (53%) were male, and 30 (48%) were African American. SAM was the first clinical presentation of sarcoidosis in 49 patients (79%). Temporal profile of symptom evolution was chronic in 81%, with sensory symptoms most frequently reported (87%). CSF studies showed pleocytosis in 79% and CSF-restricted oligoclonal bands in 23% of samples tested. Four discrete patterns of lesion morphology were identified on spine MRI: longitudinally extensive myelitis (n = 28, 45%), short tumefactive myelitis (n = 14, 23%), spinal meningitis/meningoradiculitis (n = 14, 23%), and anterior myelitis associated with areas of disc degeneration (n = 6, 10%). Postgadolinium enhancement was seen in all but 1 patient during the acute phase. The most frequent enhancement pattern was dorsal subpial enhancement (n = 40), followed by meningeal/radicular enhancement (n = 23) and ventral subpial enhancement (n = 12). In 26 cases (42%), enhancement occurred at locations with coexisting structural changes (e.g., spondylosis).
CONCLUSIONS: Recognition of the clinical features (chronically evolving myelopathy) and distinct MRI phenotypes (with enhancement in a subpial and/or meningeal pattern) seen in SAM can aid diagnosis of this disorder. Enhancement patterns suggest that SAM may have a predilection for areas of the spinal cord susceptible to mechanical stress.
Acute Flaccid Myelitis: A Clinical Review
Abstract
Acute flaccid myelitis (AFM) is an emerging disorder primarily affecting children that is characterized by acute flaccid paralysis accompanied by abnormalities of the spinal cord gray matter on magnetic resonance imaging. In most cases, prodromal fever or respiratory symptoms occur, followed by acute-onset flaccid limb weakness. Respiratory, axial, bulbar, facial, and extraocular muscles may also be affected. The clinical manifestations have been described as “polio-like,” due to striking similarities to cases of poliomyelitis. The primary site of injury in AFM is the anterior horn cells of the spinal cord, resulting in a motor neuronopathy. Seasonal peaks of cases have occurred in the United States every 2 years since 2012. However, AFM remains a rare disease, which can make it challenging for physicians to recognize and differentiate from other causes of acute flaccid paralysis such as Guillain-Barre syndrome, spinal cord stroke, and transverse myelitis. Epidemiological evidence suggests that AFM is linked to a viral etiology, with nonpolio enteroviruses (in particular enterovirus D68) demonstrating a plausible association. The epidemiology, possible etiological factors, clinical features, differential diagnosis, treatment, and outcomes of AFM are discussed in this review.
2019
Two Cases of aquaporin-4 Positive neuromyelitis optica associated with T-cell lymphoma
Abstract
Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory condition associated with antibodies against aquaporin-4 (AQP4). To date, 4 cases of B-cell lymphomas have been reported in patients with NMOSD. Here we describe two individuals with AQP4+ NMOSD and T-cell lymphomas (TCL).
Conclusion: Possible mechanisms that may explain co-existence of NMOSD with TCL include a paraneoplastic syndrome leading to AQP4 antibody production, or a generalized dysfunction of the adaptive immune system. Both patients were diagnosed with NMOSD and initiated on anti-CD20 agents prior to lymphoma diagnosis, though the short duration of exposure argues against a direct role. Further research is needed to examine the rate of lymphoproliferative disorders in NMOSD.
Blackburn K, Wang C, Greenberg B. Two cases of aquaporin-4 positive Neuromyelitis optica associated with T-cell lymphoma. Neuroimmunology. 2019; 338:577092.
Spinal Claudication Secondary to Anterior Disco-Osteo-Arterial Conflict and Mimicking Stiff Person Syndrome
Abstract
A 68-year-old man presented with a 2-year history of severe muscle spasms in the lower back and pelvis. His symptoms were always precipitated by a period of walking or sustained erect posture. The muscle spasms were described as a painful viselike grip and were relieved by dropping to the ground and flexing his trunk. The patient was ultimately referred to the clinic for evaluation of treatment-resistant stiff person syndrome, since baclofen and benzodiazepines had no clinical effect. Neurological examination results were remarkable only for depressed reflexes in the lower extremities, moderately reduced vibration in the toes, and slightly broad-based gait. He had no hyperlordosis or truncal rigidity. Nerve conduction studies, electromyography, and extensive laboratory testing results for autoimmune and rheumatological conditions were unremarkable. A magnetic resonance image of his lumbar spine showed mild lumbar spondylosis with multilevel facet arthropathy and notable anterior disc degeneration from the first to third lumbar vertebrae (L1 to L3) (Figure 1). In addition, a high T2 signal was seen in the gray matter of the conus medullaris. A spinal digital subtraction angiographic image suggested that a proximal nonostial stenosis of the left L2 intersegmental artery (ISA) from which the main anterior radiculomedullary artery (artery of Adamkiewicz) and a prominent posterior radiculomedullary artery both arose. A computed tomographic angiographic image visualized the bilateral ISAs at L2 to L3 coursing superiorly over an anterior disc osteophyte complex (Figure 2).
A Phase 1/2 Open-Label Study to Investigate the Safety of Transplantation (By Injection) of Human Glial Restricted Progenitor Cells into Subjects with Transverse Myelitis
Cameron Watts J, Bagley C, Garg S, Greenberg B
Poster presentation at the 2019 American Academy of Neurology Annual Meeting, Philadelphia, PA
Adult acute hemorrhagic leukoencephalitis: role of susceptibility-weighted imaging in diagnosis and importance of aggressive early immunotherapy
Sugar D (1,2), Galli JR (1) , Clardy SL (1,2), Greenlee JE (1,2)
1. University of Utah Department of Neurology
2. George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT
Poster presentation at the 2019 American Academy of Neurology Annual Meeting, Philadelphia, PA
Neurosarcoidosis: Longitudinal Experience in a Single-Center, Academic Health Care System
Lord J (1,3), Bacharach R (1), Galli J (1), Kresser K (2), Klein JM (1), DeWitt LD (1), Paz Soldan MM (1,3), Rose J (1), Greenlee J (1), Clardy SL (1,3)
1. Department of Neurology, University of Utah
2. Departments of Internal Medicine and Bioinformatics, University of Utah
3. George E. Wahlen Veterans Affairs Medical Center
Poster presentation at the 2019 American Academy of Neurology Annual Meeting, Philadelphia, PA
GAD65 and Glycine Receptor-Associated Neurologic Autoimmunity and Stiff-Person Syndrome within the University of Utah Health Care System
Galli JR (1), Piquet AL (1,2), Kresser J (3), Klein J (1), Warner J (1,4), Digre K (1,4), Peterson LK (5,6), Tebo AE (5,6), Haven TR (6), Soldan MMP (1,7), Rose J (1), Greenlee J (1), Clardy SL (1,7)
1. University of Utah, Department of Neurology, Salt Lake City, UT
2. University of Colorado, Department of Neurology, Aurora, CO
3. University of Utah, Departments of Internal Medicine and Bioinformatics, Salt Lake City, UT
4. University of Utah, Department of Ophthalmology, Salt Lake City, UT
5. University of Utah, Department of Pathology, Salt Lake City, UT
6. Associated Regional and University Pathologists, Inc. (ARUP Laboratories), Salt Lake City, UT
7. George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT
Poster presentation at the 2019 American Academy of Neurology Annual Meeting, Philadelphia, PA
Atypical Epilepsy in Common Variable Immunodeficiency: A Single Institution Case Series
Galli J (1), Crane P (2), Kresser J (3), Klein J (1), Gundlapalli A (4,5), Graff-Radford J (6), Greenlee JE (1), Clardy SL (1,5)
1. University of Utah, Department of Neurology, Salt Lake City, UT
2. University of Utah, School of Medicine, Salt Lake City, UT
3. University of Utah, Departments of Internal Medicine and Bioinformatics, Salt Lake City, UT
4. Department of Internal Medicine, University of Utah School of Medicine
5. George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT. 6Mayo Clinic, Department of Neurology, Rochester, MN
Poster presentation at the 2019 American Academy of Neurology Annual Meeting, Philadelphia, PA
MRI Analysis In 62 Cases Of Sarcoidosis-associated Myelitis Identifies Characteristic Imaging Features And Clues To Pathogenesis
Murphy OC (1), Jimenez JA (2,3), Barreras P (1), Diaz-Arias L (1), Garcia MA (1), Salazar-Camelo R (1), Reyes MI (1), Pardo CA (1)
1. Division of Neuroimmunology, Johns Hopkins Hospital, Baltimore, MD, USA
2. Department of Neurology, Universidad de Antioquia, Medellín, Colombia
3. Neuroclinica, Medellin, Colombia
Poster presentation at the 2019 American Academy of Neurology Annual Meeting, Philadelphia, PA
Spinal Claudication Due To Anterior Disco-osteo-arterial Conflict Mimicking Stiff Person Syndrome
Murphy O (1), Gailloud P (2), Newsome SD (1)
1. Division of Neuroimmunology, Johns Hopkins Hospital, MD, United States
2. Division of Interventional Neuroradiology, Johns Hopkins Hospital, MD, United States
Poster presentation at the 2019 American Academy of Neurology Annual Meeting, Philadelphia, PA
Unilateral Primary CNS Vasculitis in a Child Associated with Increased ICP and Treated with Maximal Medical Therapy and Decompressive Hemicraniectomy
Wang C (1,2), Miles D (2), Rajaram V (2), Whittemore B (2), Greenberg B (1,2)
1. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX
2. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
Poster presentation at the 2019 American Academy of Neurology Annual Meeting, Philadelphia, PA
Clinical Approach to Pediatric Transverse Myelitis, Neuromyelitis Optica Spectrum Disorder and Acute Flaccid Myelitis
Abstract
Pediatric transverse myelitis (TM) is an acquired, immune-mediated disorder that leads to injury of the spinal cord and often manifests as weakness, numbness, bowel dysfunction, and/or bladder dysfunction. Multiple etiologies for myelitis can result in a similar clinical presentation, including idiopathic transverse myelitis (TM), multiple sclerosis (MS), neuromyeltis optica spectrum disorder (NMOSD) associated with anti-aquaporin 4 antibodies, MOG antibody disease, and acute flaccid myelitis (AFM). Diagnosis relies on clinical recognition of the syndrome and confirming inflammation through imaging and/or laboratory studies. Acute treatment is targeted at decreasing immune-mediated injury, and chronic preventative therapy may be indicated if TM is determined to be a manifestation of a relapsing disorder (i.e., NMOSD). Timely recognition and treatment of acute transverse myelitis is essential, as it can be associated with significant morbidity and long-term disability.
New onset transverse myelitis diagnostic accuracy and patient experiences
Abstract
IMPORTANCE: Patients afflicted with rare diseases often have a delay in diagnosis and treatment. Understanding the prevalence and impact of delayed diagnosis in transverse myelitis could trigger directed educational initiatives to increase clinician awareness and improve care.
OBJECTIVE: To determine if symptoms at onset or care provider initially approached was associated with time to diagnosis, treatment or outcome in patients with transverse myelitis.
DESIGN: This was an online patient and caregiver standardized survey to collect data about the initial medical experience. Patients were recruited through social media to complete a survey about initial symptoms, care provider approached for diagnosis, first events (hospital admission, testing, sent home, etc.), first diagnosis, time to treatment and outcomes. The data was collected by an independent, non-profit patient advocacy organization (The Siegel Rare Neuroimmune Association) and provided to researchers for analysis.
SETTING: This was an online survey of a prevalent cohort of individuals diagnosis with transverse myelitis.
PARTICIPANTS: Patients with various autoimmune disorders responded to the survey. These included patients with multiple sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis and idiopathic transverse myelitis. Only data about patients, greater than a year of age, with a diagnosis of transverse myelitis were included in the study.
Greenberg B, Krishnan C, Harder L. New onset transverse myelitis diagnostic accuracy and patient experiences. Mult Scler Relat Disord. 2019;30:42-44
Two Patients with Aquaporin-4 Positive Neuromyelitis Optica and T-Cell Lymphoma
Blackburn K, Wang C, Greenberg B
Poster presentation at the 2019 ACTRIMS Forum, Dallas, TX
A Quality Improvement Project Studying the Integration of a Proposed Diagnostic Algorithm on Inpatient Encephalitis into the Electronic Medical Record and its Impact on Length of Hospital Stay
Kaplan T, Kresser J, Galli J, Cho T, Clardy S, Piquet A
Poster presentation at the 2019 American Academy of Neurology Annual Meeting. Philadelphia, PA
Neurosarcoidosis: Longitudinal Experience in a Single-Center, Academic Health Care System
Lord J, Bacharach R, Galli J, Kresser J, Klein J, Dewitt D, Paz Soldán MM, Rose J, Greenlee J, Clardy S
Poster presentation at the 2019 American Academy of Neurology Annual Meeting. Philadelphia, PA
Neurological Involvement in Seronegative Sjogren’s Syndrome with Positive Lip Biopsy: A Single Center Experience
Wong K-H, Galli J, Bacharach R, Klein J, Esquibel L, Pace L, Lebeidz-Odrobina D, Rose J, Trump B, Hull C, Greenlee J, Clardy S
Poster presentation at the 2019 American Academy of Neurology Annual Meeting. Philadelphia, PA
Adult acute hemorrhagic leukoencephalitis: role of susceptibility-weighted imaging in diagnosis and importance of aggressive early immunotherapy
Sugar D, Galli J, Clardy S, Greenlee J
Poster presentation at the 2019 American Academy of Neurology Annual Meeting. Philadelphia, PA
2018
Newly Diagnosed Anti-Myelin Oligodendrocyte Glycoprotein Syndromes in the Inpatient Setting: Six-month experience at a Tertiary Pediatric Center
Wang C (1,2), Greenberg B (1,2)
1. University of Texas Southwestern Medical Center, Department of Neurology and Neurotherapeutics, Dallas, TX
2. Children’s Medical Center Dallas, Dallas, TX
2. Children’s Medical Center Dallas, Dallas, TX
Poster presentation at the 2018 American Neurological Association Annual Meeting, Atlanta, GA
Acute Flaccid Myelitis: Treatment Outcomes From a Tertiary Referral Center
Plumb P (1), Wang C (1), Greenberg B (1)
1. University of Texas Southwestern Medical Center, Department of Neurology and Neurotherapeutics, Dallas, TX
Poster presentation at the 2018 American Academy of Neurology Annual Meeting, Los Angeles, CA
Case Series of Four High School Football Players with Multiple Sclerosis
Wang C (1,3), Harder L (1,2,3), Greenberg B (1,3)
1. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX
2. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX
2. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX
3. Children’s Medical Center Dallas, Dallas, TX
Poster presentation at the 2018 American Academy of Neurology Annual Meeting, Los Angeles, CA
Myelin oligodendrocyte glycoprotein positive cohort of 15 patients: Clinical, imaging, and optical coherence tomography characteristics
Wang C (1), Conger D (1), Greenberg B (1)
1. University of Texas Southwestern Medical Center, Department of Neurology and Neurotherapeutics, Dallas, TX
Poster presentation at the 2018 American Academy of Neurology Annual Meeting, Los Angeles, CA
Fulminant Acute Disseminated Encephalomyelitis Associated with Increased Intracranial Pressure and anti-MOG antibodies: Presentation of Four Cases
Wang C (1,2), Narayan R (3), Miles D (2), Greenberg B (1,2)
1. University of Texas Southwestern Medical Center, Department of Neurology and Neurotherapeutics, Dallas, TX
2. Children’s Medical Center Dallas, Dallas, TX
3. Barrow Neurological Institute, Phoenix, AZ
Poster presentation at the 2018 Child Neurology Society Annual Meeting, Chicago, IL
Unique characteristics of optical coherence tomography (OCT) results and visual acuity testing in myelin oligodendrocyte glycoprotein (MOG) antibody positive pediatric patients
Abstract
BACKGROUND: Optic nerve involvement in anti-myelin oligodendrocyte glycoprotein antibody associated syndrome (MOG ab syndrome) tends to have unique features. Few studies have reported optical coherence tomography (OCT) measures like retinal nerve fiber layer thickness findings in the setting of pediatric MOG ab syndrome.
OBJECTIVES: The aim of this study is to compare visual acuity between MOG ab positive and MOG ab negative pediatric cohorts and examine correlations with OCT findings.
METHODS: We included outpatients less than 18 years of age who had optic neuritis (ON) of at least one eye and who completed visual testing and OCT in the study. ON was defined based on clinical or OCT findings. Antibody testing was obtained using cell-based assay. The primary analyses of interest investigated differences in low-contrast visual acuity stratified by the defined RNFL ranges and by antibody positivity.
RESULTS: We analyzed 28 eyes from 14 anti-MOG ab patients (MOG-ON cohort), 18 eyes from 9 anti-AQP4 ab (AQP4-ON cohort) patients and 26 eyes from 13 patients who tested negative for both the antibodies (seronegative ON cohort). MOG-ON eyes with zero reported clinical events had lower RNFL thickness, than the minimum RNFL thickness of either the seronegative-ON or AQP4-ON eyes with zero clinical attacks in most retinal segments. Within the lowest range of the RNFL (RNFL <50 um) in most retinal segments, the MOG-ON cohort had a statistically significant greater visual acuity relative to the AQP4 cohort. CONCLUSIONS: Patients with anti-MOG antibody mediated CNS disorders can suffer from subclinical ON events with significant reductions in RNFL. Despite equally significant damage to the optic nerve, MOG-Ab positive patients have relatively preserved visual acuity. Narayan RN, McCreary M, Conger D, Wang C, Greenberg BM. Unique characteristics of optical coherence tomography (OCT) results and visual acuity testing in myelin oligodendrocyte glycoprotein (MOG) antibody positive pediatric patients. Mult Scler Relat Disord. 2018 Dec 15;28:86-90.
Acute Flaccid Myelitis—Keys to Diagnosis, Questions About Treatment, and Future Directions
Abstract
The increase in cases of acute flaccid myelitis (AFM) in 2018 in the United States, with 62 cases in 22 states confirmed by the US Centers for Disease Control and Prevention (CDC) as of October 16, 2018, follows the biennial pattern of late summer/early fall spikes in reported cases that was first widely recognized in 2014. Cases and clusters of AFM have been scattered throughout the country, and thus some clinicians have less experience with this emerging condition. Health care professionals and parents across the country are concerned for good reasons: the presentation may be subtle and easily missed, the differential diagnosis is complex, there are potential long-term complications, and no established effective treatments are available.
Hopkins SE, Elrick MJ, Messacar K. Acute Flaccid Myelitis-Keys to Diagnosis, Questions About Treatment, and Future Directions. JAMA Pediatr. 2018 Nov 30.
Investigational drugs in development to prevent neuromyelitis optica relapses
Abstract
In the short time since 2014, three pivotal, worldwide studies in neuromyelitis optica spectrum disorders have been launched: eculizumab, SA237 and inebelizumab, each based on a unique mechanism. Areas covered: In this review, we provide a discussion on the trial data available for each drug, a brief description of the trial design, and our expert opinion on the potential benefits and risks. Expert opinion: Eculizumab, a C5 complement inhibitor, may prove useful in the treatment of intractable cases of NMOSD, but physicians must be aware of the known risk of meningococcal infection. SA237, an interleukin-6 receptor blocker, may be effective at reducing relapse risk, and also has the potential to reduce neuropathic pain in NMOSD. Inebelizumab, a B cell depleting agent, has never been tested in NMOSD, but based on extensive evidence of efficacy with B cell depletion using rituximab, inebelizumab is expected to work at least as well.
Paul F, Murphy O, Pardo S, Levy M. Investigational drugs in development to prevent neuromyelitis optica relapses. Expert Opin Investig Drugs. 2018;27(3):265-271.
Atypical Anti-MOG syndrome with aseptic meningoencephalitis and pseudotumor cerebri-like presentations
Abstract
OBJECTIVE: To describe 2 atypical cases with Anti-MOG antibody related demyelinating syndrome.
METHODOLOGY: Case series.
RESULTS: We present two cases. Case 1 is an 18-year-old woman who presented with headache, blurred vision, and papilledema and was initially diagnosed with pseudotumor cerebri syndrome. CSF showed mildly elevated opening pressure and lymphocytic pleocytosis and a diagnosis of aseptic meningitis was considered. MRI brain and spinal cord revealed longitudinally extensive bilateral simultaneous optic neuritis and multiple spinal cord lesions. Case 2 is a 28-year old man who presented initially with unilateral optic neuritis followed by aseptic meningitis three weeks later and subsequently acute disseminated encephalomyelitis (ADEM). Serology was positive for Anti-MOG antibody on a cell-based assay in both these cases.
DISCUSSION: Although bilateral optic neuritis has been well described in MOG related disorders, aseptic meningitis and pseudotumor cerebri-like syndromes are notable alternate presentations. The presence of eosinophils in the CSF (in the first patient) is a unique finding in our case series.
CONCLUSION: In a patient with an aseptic meningitis like presentation, the presence of optic neuritis, brain and/or spinal cord lesions should raise suspicion for an MOG-Ab related syndrome.
Narayan RN, Wang C, Sguigna P, Husari K, Greenberg B. Atypical Anti-MOG syndrome with aseptic meningoencephalitis and pseudotumor cerebri-like presentations. Mult Scler Relat Disord. 2019 Jan;27:30-33. doi: 10.1016/j.msard.2018.10.003. Epub 2018 Oct 3.
Viral Encephalitis
Abstract
Viruses are a frequent cause of encephalitis. Common or important viruses causing encephalitis include herpesviruses, arboviruses, enteroviruses, parechoviruses, mumps, measles, rabies, Ebola, lymphocytic choriomeningitis virus, and henipaviruses. Other viruses may cause an encephalopathy. Host factors and clinical features of infection are important to consider in identifying the cause for encephalitis. Cerebrospinal fluid evaluation, serologic/polymerase chain reaction studies, and neuroimaging are cornerstones of diagnostic evaluation in encephalitis. Treatable forms of encephalitis are important to consider in all cases. Central nervous system inflammation may also occur because of postinfectious autoimmunity, such as acute disseminated encephalomyelitis or antibody-mediated encephalitis after herpes simplex virus encephalitis.
Venkatesan A, Murphy OC. Viral encephalitis. Neurol Clin. 2018.
Anti-Myelin Oligodendrocyte Glycoprotein Antibody Associated With Gray Matter Predominant Transverse Myelitis Mimicking Acute Flaccid Myelitis: A Presentation of Two Cases
Abstract
BACKGROUND:
Anti-myelin oligodendrocyte glycoprotein (MOG) antibody associated disorders frequently manifest as optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis. While their clinical phenotypes overlap with relapsing inflammatory Central nervous system (CNS) conditions such as multiple sclerosis and neuromyelitis optica spectrum disorder, MOG-related syndromes frequently occur in a younger age group. In children, longitudinally extensive transverse myelitis (LETM) is less specific for anti-aquaporin-4 associated neuromyelitis optica spectrum disorder, and has also been reported in pediatric multiple sclerosis, idiopathic transverse myelitis, and acute flaccid myelitis.
METHODS:
We summarize two patients with positive MOG antibodies and myelitis.
RESULTS:
We identified two individuals with anti-MOG associated LETM that demonstrate primarily gray matter involvement. Clinically these patients exhibited hyperreflexia and had rapid improvement with immunotherapies.
CONCLUSIONS:
Anti-MOG diseases can cause LETM with gray matter predominance mimicking acute flaccid myelitis, but clinically these patients can have retained reflexes and respond favorably to immunotherapies.
Wang C, Narayan R, Greenberg B. Anti-Myelin Oligodendrocyte Glycoprotein Antibody Associated With Gray Matter Predominant Transverse Myelitis Mimicking Acute Flaccid Myelitis: A Presentation of Two Cases. Pediatr Neurol. 2018 Sep;86:42-45. doi: 10.1016/j.pediatrneurol.2018.06.003. Epub 2018 Jul 10.
Comparative quantitative clinical, neuroimaging, and functional profiles in children with acute flaccid myelitis at acute and convalescent stages of disease
Abstract
AIM: To quantify characteristics in acute flaccid myelitis (AFM) at acute and convalescent stages.
METHOD: This was a retrospective case series of children with AFM evaluated at a single institution in the USA (2014-2017). Acute inflammatory/ischemic myelopathies were excluded. Neurological assessments and segmental quantitative analysis of signal abnormalities on magnetic resonance imaging (MRI) of the brain and spinal cord were performed.
RESULTS: Sixteen patients (11 males, five females) were evaluated. Median age at onset was 4 years (interquartile range [IQR] 3-6y). All had parainfectious acute-onset limb weakness, lower motor neuron examination, and spinal fluid pleocytosis. On acute spinal cord MRI, longitudinally extensive T2 hyperintensities were identified throughout the spinal cord mostly within grey matter; five out of 12 patients had dorsal brainstem T2 hyperintensities. At a median of 2 months follow-up (IQR 2-3mo), spinal cord MRI improved in seven out of nine patients although focal T2 hyperintensities persisted in cervical and lumbar grey matter. At a median follow-up of 4 months (IQR 2-6mo), Medical Research Council sum score rose from a median of 29 to 32; distal muscle groups improved more than proximal ones; four out of 16 patients were ventilator-dependent; and two out of 16 patients were quadriplegic.
INTERPRETATION: While patients may show marked improvement on neuroimaging from acute to convalescent stages, the majority of children with AFM have limited motor recovery and continued disability. Clinicians should consider the timing of clinical and neuroimaging exams when assessing diagnosis and prognosis.
WHAT THIS PAPER ADDS: During the 2014 to 2017 acute flaccid myelitis outbreak in the USA, clinical recovery was better in distal than proximal muscle groups. Lumbar spinal cord showed more residual abnormalities at convalescence.
Gordon-Lipkin E, Muñoz LS, Klein JL, Dean J, Izbudak I, Pardo CA. Comparative quantitative clinical, neuroimaging, and functional profiles in children with acute flaccid myelitis at acute and convalescent stages of disease. Dev Med Child Neurol. 2018 Sep 17.
Neuromyelitis Optica Spectrum Disorder in Active Duty Service Members
Williams JP (1,2,3), Galli J (1,2), Groshans KA (4), Horvat DE (4), Austin S (2), Pittock SJ (5), Rose JW (1,6), Carlson NG (1,6,7), Greenlee JE (1,2), Soldan MMP (1,2), Tagg NT (4,8), Clardy SL (1,2,6)
1. University of Utah, Department of Neurology, Salt Lake City, UT
2. George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT
3. US Air Force Institute of Technology
4. Walter Reed National Military Medical Center
5. Mayo Clinic Neuroimmunology Laboratory, Rochester, MN
6. University of Utah, School of Medicine, Salt Lake City, UT
7. University of Utah, Department of Neurobiology and Anatomy, Salt Lake City, UT
8. Uniformed Service University of Health Sciences
Poster presentation at the 2018 American Academy of Neurology Annual Meeting, Los Angeles, CA
Characterization and Alternative Diagnoses in Patients with False-Positive Aquaporin-4 Autoantibody Detection by Enzyme Linked Immunosorbent Assay (ELISA)
Williams JP (1,2,3), Street M (4), Badger JK (4), Peterson LK (4), Greenlee JE (1,2), Carlson NG (1,2,5), Rose JW (1,5), Soldan MMP (1,2), Clardy SL (1,2)
1. University of Utah, Department of Neurology, Salt Lake City, UT.
2. George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT.
3. US Air Force Institute of Technology.
4. ARUP Laboratories, Immunology, Salt Lake City, UT.
5. University of Utah, Department of Neurobiology and Anatomy, Salt Lake City, UT.Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD, USA.
Poster presentation at the 2018 American Academy of Neurology Annual Meeting, Los Angeles, CA
It’s Not All Transverse Myelitis: The Differential Diagnosis of Spinal Cord Myelopathy
Mealy M (1), Munoz L (1), Barreras P (1), Garcia M (1,2), Becker D (3), Newsome S (4), Gailloud P (5), Levy M (6), Pardo-Villamizar C (7)
1. Johns Hopkins University School of Medicine
2. Universidad De Los Andes
3. International Neurorehabilitation Institute, Johns Hopkins Hospital
4. Johns Hopkins Hospital
5. The Johns Hopkins Hospital
6. Johns Hopkins University
7. Johns Hopkins University, Med Dept of Neurology
Presentation at the 2018 American Academy of Neurology Annual Meeting, Los Angeles, CA
Abstract
Objective: To retrospectively investigate the spectrum of diagnoses in patients who presented with presumed transverse myelitis (TM) seen at a specialized center dedicated to TM care.
Background: TM is an inflammatory neurologic disorder that causes damage to motor and sensory tracts of the spinal cord. The cause of TM is variable and often never discovered. Patients may experience any combination of weakness, altered sensation, bowel and bladder dysfunction and dysautonomia. Non-immunologic myelopathies may cause a similar clinical presentation. As such, investigation is paramount to ensure appropriate treatment.
Design/Methods: We conducted a retrospective analysis of new patients referred to the Johns Hopkins TM Center (JHTMC) between 2010 and 2017. We reviewed the clinical/temporal profile, neuroimaging and laboratory assessment to establish a final diagnosis.
Results: One thousand patients were included in this analysis (66% White/Caucasian descent; 60% female), of which 62% were confirmed to have an inflammatory cause for their myelopathy, of which 35% was idiopathic. An additional 41% was attributable to an underlying disease such as multiple sclerosis or neuromyelitis optica spectrum disorder. However, 24% of patients who were initially diagnosed with TM were found to have non-inflammatory causes of myelopathy, including vascular abnormalities (38%) and compressive myelopathy (24%). Ten percent of cases had inadequate initial evaluations or follow-up, and a final diagnosis could not be established.
Conclusions: One quarter of patients initially referred to the JHTMC for the diagnosis of TM were found to have a non- myelopathic cause for their symptoms. Furthermore, of those with inflammatory TM, 41% had an underlying disease for which long-term immunotherapy was warranted. This analysis of a large cohort of patients suggests that a more detailed analysis at acute presentation is necessary to ensure patients receive adequate and timely treatment of the underlying cause of myelopathic symptoms towards the effort of improving patient outcomes.
Clinical characteristics of 100 patients with angiography-confirmed low-flow spinal arteriovenous fistulas
Murphy O (1), Pardo C (1), Gailloud P (2)
1. Department of Neurology, The Johns Hopkins Hospital, MD, United States
2. Division of Interventional Neuroradiology, The Johns Hopkins Hospital, MD, United States
Poster presentation at the 2018 American Academy of Neurology Annual Meeting, Los Angeles, CA
Abstract
Objective: To describe the clinical characteristics of a cohort of patients with symptomatic low-flow spinal arteriovenous fistulas (SAVF) and identify features that can orientate diagnosis.
Background: Low-flow SAVFs are the most common spinal vascular malformation. They result in severe disability typically including paraparesis, pain, bladder and sexual dysfunction. Once identified, most low-flow SAVFs are amenable to treatment using either endovascular or surgical means. However, these lesions are frequently misdiagnosed, resulting in prolonged delay before treatment (over a year on average) and jeopardized functional outcomes.
Methods: We reviewed 100 consecutive patients with low-flow SAVFS angiographically diagnosed at our institution between 2007 and 2017. Analyzed features included (but were not limited to) demographic information, associated conditions, clinical presentation (i.e., mode, timing, triggering factors, neurological examination), disability at presentation (Aminoff and Logue scale) and delay to diagnosis.
Results: The lesions included spinal dural arteriovenous fistulas (48 patients), spinal epidural arteriovenous fistulas (41 patients), and perimedullary arteriovenous fistulas (10 patients). One patient had both dural and epidural arteriovenous fistulas. The average age was 57.8 years, 79% of the patients were men. They initially consulted a range of specialists including neurologists, neurosurgeons and urologists. A history of intermittent claudication and risk factors for venous thrombosis, such as cancer or previous deep vein thrombosis, were identified in a significant proportion of this cohort. Initial diagnosis was frequently inaccurate and resulted in delayed SAVF recognition and treatment.
Conclusions: This is the largest cohort of patients with low-flow SAVF described to date. We highlight that diagnosis is frequently delayed in these patients and outline clinical features that may alert physicians to consider this diagnosis (e.g., older age, male gender, history of intermittent claudication, risk factor for venous thrombosis)
The spectrum of myelopathies in children: beyond idiopathic transverse myelitis
Munoz-Arcos L, Gordon-Lipkin E, Barreras P, Castañeda M, Mealy M, Piedra W, Murphy O, Newsome S, Becker D, Levy M, Pardo C
Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD, USA.
Poster presentation at the 2018 American Academy of Neurology Annual Meeting, Los Angeles, CA
Abstract
Objective: To investigate the differential diagnosis of pediatric myelopathy at a myelitis center.
Background: Transverse myelitis (TM) is clinically indistinguishable from other myelopathies. The differentiation between inflammatory or non-inflammatory myelopathies in children is important for treatment and prognosis.
Methods: Retrospective review of patients <21-years-of-age referred at the Johns Hopkins TM Center with a diagnosis of TM between 2010-2017. Temporal profile of symptoms, clinical presentation, cerebrospinal fluid (CSF) analysis and spinal cord (SC) magnetic resonance imaging (MRI) were reviewed. Results: Forty-three patients were included. Median age was 11 years [IQR 4-15] with a male/female ratio of 1. Clinical, laboratory and imaging findings were consistent with inflammatory myelopathy (IM) in 29 patients (infectious [n=10], idiopathic [n=5], neuromyelitis-optica [NMO] [n=1], NMO-spectrum-disorder [NMOSD] [n=1], clinical- isolated-syndrome [n=1], other-inflammatory [n=11]) and non-inflammatory myelopathy (NIM) in 11 patients (SC ischemia [n=9], metabolic [n=2]). In 3 patients, the etiology was unclear. Most patients achieved the neurological nadir in <6-hours (n=19), but this profile was less common in IM (n=11; 38%) than in NIM (n=8; 73%). Lumbar puncture was done in 42/43 patients; in 49% during the first 48 hours of presentation. In the IM group, CSF analysis demonstrated pleocytosis (>5cells/ul) in 24/29 (83%) patients and elevated protein (>45mg/dl) in 16/29 (55%) patients; in contrast to NIM, in which none had pleocytosis and 2/10 (20%) had elevated protein. Overall, SC-MRI lesions were predominantly monofocal (n=25/43, 58%) and longitudinally-extensive (n=37/43, 86%). The cervicothoracic-SC was mostly involved. Twelve (28%) cases had SC-enhancing lesions of which 9 presented with IM. 35/43 (81%) patients had received treatment with intravenous steroids. Patients were evaluated at a median of 11-months [IQR 5-36] after presentation. Twelve (28%) patients had complete recovery. NMO cases presented a relapsing disease.
Conclusion: A third of the cases referred with diagnosis of TM were NIM. A correct diagnosis of pediatric myelopathies allows proper treatment and better outcomes.
Clinical biomarkers differentiate myelitis from vascular and other causes of myelopathy
Abstract
OBJECTIVE: To assess the predictive value of the initial clinical and paraclinical features in the differentiation of inflammatory myelopathies from other causes of myelopathy in patients with initial diagnosis of transverse myelitis (TM).
METHODS: We analyzed the clinical presentation, spinal cord MRI, and CSF features in a cohort of 457 patients referred to a specialized myelopathy center with the presumptive diagnosis of TM. After evaluation, the myelopathies were classified as inflammatory, ischemic/stroke, arteriovenous malformations/fistulas, spondylotic, or other. A multivariable logistic regression model was used to determine characteristics associated with the final diagnosis and predictors that would improve classification accuracy.
RESULTS: Out of 457 patients referred as TM, only 247 (54%) were confirmed as inflammatory; the remaining 46% were diagnosed as vascular (20%), spondylotic (8%), or other myelopathy (18%). Our predictive model identified the temporal profile of symptom presentation (hyperacute <6 hours, acute 6-48 hours, subacute 48 hours-21 days, chronic >21 days), initial motor examination, and MRI lesion distribution as characteristics that improve the correct classification rate of myelopathies from 67% to 87% (multinomial area under the curve increased from 0.32 to 0.67), compared to only considering CSF pleocytosis and MRI gadolinium enhancement. Of all predictors, the temporal profile of symptoms contributed the most to the increased discriminatory power.
CONCLUSIONS: The temporal profile of symptoms serves as a clinical biomarker in the differential diagnosis of TM. The establishment of a definite diagnosis in TM requires a critical analysis of the MRI and CSF characteristics to rule out non-inflammatory causes of myelopathy.
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients presenting with myelopathy, temporal profile of symptoms, initial motor examination, and MRI lesion distribution distinguish those with inflammatory myelopathies from those with other causes of myelopathy.
Click here for the Full Open Access Paper
Barreras P, Fitzgerald KC, Mealy MA, Jimenez JA, Becker D, Newsome SD, Levy M, Gailloud P, Pardo CA. Clinical biomarkers differentiate myelitis from vascular and other causes of myelopathy. Neurology. 2018 Jan 2;90(1):e12-e21
Stiff person syndrome with Anti-GAD65 antibodies within the national veterans affairs health administration
Abstract
INTRODUCTION: Stiff person syndrome (SPS) is a neurological disorder characterized by muscle rigidity primarily in the truncal muscles, commonly associated with autoantibodies to the glutamic acid-decarboxylase 65 kD receptor (GAD65). There is limited epidemiological information on patients with SPS.
METHODS: We performed a retrospective case review using the National United States Veterans Affairs Health Administration electronic medical record system. We analyzed prevalence, demographics, disease characteristics, and treatment outcomes in SPS patients who were anti-GAD65 antibody positive.
RESULTS: Fifteen patients met our criteria. Point prevalence was 2.06 per million, and period prevalence was 2.71 per million. Men to women ratio was 14:1. All patients benefitted from treatment with symptomatic antispasmodic agents. Ten of 15 patients received intravenous immunoglobulin, with a majority demonstrating stable or improved modified Rankin scores.
DISCUSSION: This investigation was a large North American epidemiological study of SPS with predominantly male patients. Symptomatic therapy was beneficial for most patients, with less clear sustained benefit of immunotherapy. Muscle Nerve 58:801-804, 2018.
Galli JR, Austin SD, Greenlee JE, Clardy SL. Stiff person syndrome with Anti-GAD65 antibodies within the national veterans affairs health administration. Muscle Nerve. 2018 Dec;58(6):801-804. doi: 10.1002/mus.26338. Epub 2018 Nov 20.
2017
Comparison of myelin oligodendrocyte glycoprotein (MOG) positive and negative pediatric patients at a tertiary center
Cynthia Wang, MD
Benjamin Greenberg, MD
Neurology, UT Southwestern Medical Center, Dallas, TX, USA.
Poster presentation at the 2017 American Neurological Association Annual Meeting, San Diego, CA
Familial Transverse Myelitis Associated with Mutation in VPS37A Gene
Michael Levy, MD, PhD
Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Oral presentation at the 2017 American Academy of Neurology Annual Meeting, Boston, MA
The yield of initial conventional MRI in 115 cases of angiographically confirmed spinal vascular malformations
Abstract
MRI is the primary screening tool for patients with myelopathy. The decision to obtain additional imaging, notably spinal angiography, is generally based on initial MRI findings. This study retrospectively analyzed the yield of initial MRI in a cohort of patients with angiographically confirmed vascular malformations. MRI obtained at symptom onset was available in 115 patients with either high-flow (29 cases) or low-flow (86 cases) vascular malformations. MRI was classified as “positive” when the report mentioned a vascular malformation or “negative” when considered normal or when another diagnosis was suggested. Initial MRI was positive in 61 patients (53.0%), correctly identifying 28 high-flow (96.6%) but only 33 low-flow (38.4%) lesions. Flow voids were noted in 96.6% of the high-flow lesions and 38.4% of the low-flow ones. T2-signal anomalies (77.4%) and parenchymal enhancement (54.5%) were also common in low-flow anomalies. Patients with negative MRI had an average delay of 111 days before angiography and 239 days before therapy; these intervals were 27 and 76 days for those with positive MRIs. In summary, MRI shows a high yield for high-flow vascular malformations, i.e., characterized by prominent flow voids on T2-weighted images, but misdiagnosed over 60% of low-flow lesions. The percentage of correctly identified anomalies matched the percentage of observed flow voids in both groups, indicating over-reliance on this sign for the diagnosis of slow-flow lesions. MRI findings in slow-flow vascular malformation overlap with other conditions, notably transverse myelitis, which was initially misattributed to 40% of the slow-flow lesions in our cohort.
El Mekabaty A, Pardo CA, Gailloud P. The yield of initial conventional MRI in 115 cases of angiographically confirmed spinal vascular malformations. J Neurol. 2017 Apr;264(4):733-739.
Analysis of 30 Spinal Angiograms Falsely Reported as Normal in 18 Patients with Subsequently Documented Spinal Vascular Malformations
Abstract
BACKGROUND AND PURPOSE: The early diagnosis of spinal vascular malformations suffers from the nonspecificity of their clinical and radiologic presentations. Spinal angiography requires a methodical approach to offer a high diagnostic yield. The prospect of false-negative studies is particularly distressing when addressing conditions with a narrow therapeutic window. The purpose of this study was to identify factors leading to missed findings or inadequate studies in patients with spinal vascular malformations.
MATERIALS AND METHODS: The clinical records, laboratory findings, and imaging features of 18 patients with spinal arteriovenous fistulas and at least 1 prior angiogram read as normal were reviewed. The clinical status was evaluated before and after treatment by using the Aminoff-Logue Disability Scale.
RESULTS: Eighteen patients with 19 lesions underwent a total of 30 negative spinal angiograms. The lesions included 9 epidural arteriovenous fistulas, 8 dural arteriovenous fistulas, and 2 perimedullary arteriovenous fistulas. Seventeen patients underwent endovascular (11) or surgical (6) treatment, with a delay ranging between 1 week and 32 months; the Aminoff-Logue score improved in 13 (76.5%). The following factors were identified as the causes of the inadequate results: 1) lesion angiographically documented but not identified (55.6%); 2) region of interest not documented (29.6%); or 3) level investigated but injection technically inadequate (14.8%).
CONCLUSIONS: All the angiograms falsely reported as normal were caused by correctible, operator-dependent factors. The nonrecognition of documented lesions was the most common cause of error. The potential for false-negative studies should be reduced by the adoption of rigorous technical and training standards and by second opinion reviews.
Barreras P, Heck D, Greenberg B, Wolinsky JP, Pardo CA, Gailloud P. Analysis of 30 Spinal Angiograms Falsely Reported as Normal in 18 Patients with Subsequently Documented Spinal Vascular Malformations. AJNR Am J Neuroradiol. 2017 Sep;38(9):1814-1819.
Immunosenescence: The Role of Aging in the Predisposition to Neuro-infectious Complications arising from the Treatment of Multiple Sclerosis
Abstract
PURPOSE OF REVIEW: This review highlights some of the important changes in the immune system that occur in the process of normal aging. Immunosenescence as a concept is directly relevant to the world of neuro-inflammation, as it may be a contributing factor to the risks associated with some of the current immunosuppressive and immunomodulatory therapies used in treating multiple sclerosis (MS) and other inflammatory disorders.
RECENT FINDINGS: Profound qualitative and quantitative changes occur in the adaptive and innate immunity compartments during aging. These changes may explain why patients of older age are at an increased risk of infections and infection-associated mortality. Immunosenescence-associated changes may be additive or synergistic with the effects produced by immunomodulatory and immunosuppressive medications. Clinicians should exercise a high level of vigilance in monitoring the risk of infections in older patients on these treatments.
Grebenciucova E, Berger JR. Immunosenescence: The Role of Aging in the Predisposition to Neuro-infectious Complications arising from the Treatment of Multiple Sclerosis. Curr Neurol Neurosci Rep. 2017 Aug;17(8):61.
2016
A longitudinally extensive myelopathy associated with multiple spinal arteriovenous fistulas in a patient with Cowden syndrome: a case report
Abstract
BACKGROUND CONTEXT: Cowden syndrome is an autosomal dominant syndrome characterized by multiple hamartomas and an increased cancer risk. It is associated with mutations in the phosphatase and tensin homologue (PTEN) gene that encodes a tumor suppressant phosphatase.
PURPOSE: The study aimed to report an unusual case of multiple spinal epidural arteriovenous fistulas in a patient diagnosed with Cowden syndrome.
STUDY DESIGN: This is a case report.
PATIENT SAMPLE: The patient is a 57-year-old woman.
METHODS: We report the case of a 57-year-old woman with a history of multiple cancers, with acute exacerbation of lower extremity weakness and numbness that had progressed over a month.
RESULTS: Magnetic resonance imaging showed abnormal signal in the thoracolumbar spinal cord, with enhancement after contrast administration. A spinal angiogram confirmed the presence of multiple spinal epidural arteriovenous fistulas. Genetic testing confirmed the diagnosis of Cowden syndrome with a mutation in intron 3 of the PTEN gene.
CONCLUSIONS: Spinal vascular malformations occur in patients with Cowden syndrome, and they can be multifocal and locally aggressive. It is important to raise the suspicion of Cowden syndrome in patients with spinal cord vascular anomalies and a history of multiple cancers, as the correct genetic diagnosis may have implications for management and cancer screening.
Barreras P, Gailloud P, Pardo CA. A longitudinally extensive myelopathy associated with multiple spinal arteriovenous fistulas in a patient with Cowden syndrome: a case report. Spine J. 2018 Jan;18(1):e1-e5.
2015
TNF-alpha inhibitor associated myelopathies: A neurological complication in patients with rheumatologic disorders
Abstract
OBJECTIVES: Tumor necrosis factor-alpha inhibitors (TNFα-I) are biological agents used in the treatment of rheumatologic disorders. TNFα-I have been associated with demyelinating disorders mimicking multiple sclerosis. The goal of this report is to illustrate cases of myelopathy which developed during the use of TNFα-I.
METHODS: We describe the clinical, neuroimaging and laboratory features of 4 cases of myelopathy associated with TNFα-I.
RESULTS: The mean period of TNFα-I exposure was 27 [12-36] months. Three of the four patients exhibited active inflammatory myelopathy as the spinal cord MRI lesions enhanced with gadolinium and CSF pleocytosis or oligoclonal bands were present. All patients had normal brain MRIs at the time of presentation.
CONCLUSIONS: TNFα-I may play a role in the development of myelopathies in absence of brain involvement or other features of demyelinating disease. TNFα-I associated myelopathy should be considered in patients with history of treatment with TNFα-I who exhibit symptoms of myelopathy.
Barreras P, Mealy MA, Pardo CA. TNF-alpha inhibitor associated myelopathies: A neurological complication in patients with rheumatologic disorders. J Neurol Sci. 2017 Feb 15;373:303-306.
Intravenous methylprednisolone versus therapeutic plasma exchange for treatment of anti-n-methyl-d-aspartate receptor antibody encephalitis: A retrospective review
Abstract
INTRODUCTION: Anti-N-methyl-d-aspartate (NMDA) receptor antibody encephalitis is an increasingly recognized form of autoimmune encephalitis. Conventional treatments include therapies such as corticosteroids, intravenous immunoglobulin (IVIg), and/or therapeutic plasma exchange (TPE). Although TPE is regularly used for treatment of anti-NMDA receptor antibody encephalitis, the American Society for Apheresis has given it a category III recommendation only. Earlier administered immunotherapies in tumor-negative patients may facilitate faster recoveries, but it remains unclear whether or not TPE is superior to steroids and/or IVIG.
METHODS: We retrospectively evaluated 10 of 14 patients that received steroids and TPE with modified Rankin scores and subjectively assessed the point of largest sustained improvement in all 14 patients.
RESULTS: In the patients that received both steroids and TPE at our institution during the same hospitalization (only 10 of 14 patients), 7/10 patients after TPE had improved with the modified Rankin score versus 3/10 patients after steroids. The average modified Rankin score improvement after steroids in this group was -0.1 as compared with 0.4 after TPE. Based on subjective chart review analysis during which all 14 patients were assessed, the largest sustained improvement occurred immediately following the third-fifth exchange in 9/14 patients, whereas only 2/14 patients appeared to have had significant benefit immediately following steroids.
CONCLUSIONS: This is compelling preliminary data that suggests that corticosteroids may not be as effective compared to steroids followed by TPE. Given the importance of time-sensitive treatment, more formal studies may illuminate the ideal first-line treatment for anti-NMDA receptor antibody encephalitis.
DeSena AD, Noland DK, Matevosyan K, King K, Phillips L, Qureshi SS, Greenberg BM, Graves D. Intravenous methylprednisolone versus therapeutic plasma exchange for treatment of anti-n-methyl-d-aspartate receptor antibody encephalitis: A retrospective review. J Clin Apher. 2015 Aug;30(4):212-6.
2014
Three phenotypes of anti-N-methyl-D-aspartate receptor antibody encephalitis in children: prevalence of symptoms and prognosis
Abstract
BACKGROUND: Anti-N-methyl-d-aspartate (NMDA) receptor antibody encephalitis is becoming an increasingly recognized cause of encephalopathy in individuals previously presumed to have viral encephalitis. Various manifestations of this disease include altered mental status, behavioral changes, seizures, and movement disorders. We have noted three distinct subtypes of this disease which appear to have differential responses to immunotherapies and differences in prognosis.
METHODS AND PATIENTS: We report eight patients observed at our children’s hospital from 2009 through 2013 who appear to clearly fall into one of our three clinical categories. To find comparable articles reflecting this classification, we then performed a MEDLINE search of all articles involving the subject heading “anti-NMDA receptor encephalitis” or just the keyword phrase “NMDA encephalitis,” and we found 162 articles to review. Twenty-two articles were eliminated due to basic science, and we were able to review 105 of the remaining articles, most of which were case reports or case series, although a few were larger reviews. For the sake of our review, we defined type 1 or “classic” anti-NMDA receptor antibody encephalitis as having a duration of <60 days and being characterized predominantly by a catatonic or stuporous state, type 2 or psychiatric-predominant anti-NMDA receptor antibody encephalitis as having no noteworthy catatonic or stuporous state in addition to the presence of predominantly behavioral and psychiatric symptoms, and type 3 or catatonia-predominant anti-NMDA receptor antibody encephalitis as having a duration of ≥60 days in a predominantly catatonic or stuporous state. RESULTS: We note that the poorest responders, even to aggressive immunotherapies, are the patients with catatonia-persistent type anti-NMDA receptor antibody encephalitis, which has, as its hallmark, prolonged periods of severe encephalopathy. Patients with predominantly psychiatric symptoms, which we call the psychiatric-predominant anti-NMDA receptor antibody encephalitis, have had excellent responses to plasma exchange or other immunotherapies and appear to have the least residual deficits at follow-up. Patients with fairly equal representations of periods of altered mental status, behavioral problems, and movement disorders appear to have an intermediate prognosis and likely require early aggressive immunotherapy. CONCLUSIONS: In our series, we discuss representative examples of these clinical subtypes and their associated outcomes, and we suggest that tracking these subtypes in future cases of anti-NMDA receptor antibody encephalitis might lead to better understanding and better risk stratification with regard to immunotherapy decisions. DeSena AD, Greenberg BM, Graves D. Three phenotypes of anti-N-methyl-D-aspartate receptor antibody encephalitis in children: prevalence of symptoms and prognosis. Pediatr Neurol. 2014 Oct;51(4):542-9.
"Light switch" mental status changes and irritable insomnia are two particularly salient features of anti-NMDA receptor antibody encephalitis
Abstract
BACKGROUND: Anti-N-methyl-D-aspartate antibody encephalitis is becoming increasingly recognized as a cause of acute and subacute encephalopathy in both adults and children. The typical features of this disorder include some degree of encephalopathy, seizures, and often a movement disorder component. However, there is wide variability in its presentation, and diagnosis based on clinical features alone is often delayed.
PATIENTS: We report a series of four of 12 patients observed at our children’s hospital between 2011 and 2013 that we chose as particularly representative examples of two distinct clinical features.
RESULTS: In these individuals with anti-N-methyl-D-aspartate receptor antibody encephalitis, we note a very rapid on-off state between responsiveness and nonresponsiveness and/or insomnia accompanied by extreme irritability. We describe the abrupt mental status shift as “light switch” because the patients can awaken in seconds from a completely nonresponsive state. The insomnia noted in our patients was also impressive and often present early in the patients’ courses.
CONCLUSIONS: Light switch mental status changes and irritable insomnia are important early features of anti-N-methyl-D-aspartate receptor antibody encephalitis that can signal the presence of this disorder. The exact pathophysiology of these two symptoms has not been fully elucidated, and we feel that presence of one or both of these symptoms early in the disease course should prompt immediate concern for this disorder.
DeSena AD, Greenberg BM, Graves D. “Light switch” mental status changes and irritable insomnia are two particularly salient features of anti-NMDA receptor antibody encephalitis. Pediatr Neurol. 2014 Jul;51(1):151-3.
Transverse myelitis plus syndrome and acute disseminated encephalomyelitis plus syndrome: a case series of 5 children
Abstract
IMPORTANCE: Classically, transverse myelitis and acute disseminated encephalomyelitis are considered central nervous system demyelinating conditions. In both conditions, the spinal cord is involved to varying degrees, and there is a variety of presentations, usually involving some degree of progressive paralysis of the upper and/or lower extremities. Treatment usually consists of high-dose intravenous steroids in addition to plasma exchange and/or intravenous immunoglobulin. In some cases, immunosuppressive medications, such as intravenous cyclophosphamide, have been used with variable success. Cases with atypical features on examination, imaging, or with neurophysiological studies may be helpful in shedding light on the etiology and/or pathophysiology because many of these patients have permanent disabilities despite appropriate treatment.
OBSERVATIONS: This case series presents 5 pediatric cases observed from 2009-2012 at our medical center, Children’s Medical Center Dallas. These cases were notable because they provided evidence of autoimmune events affecting the central nervous system but with additional peripheral axonal pathology.
CONCLUSIONS AND RELEVANCE: We describe these cases with respect to findings that suggest a variant of these conditions that have concomitant nerve-root involvement. These patients had worse outcomes than typical patients with transverse myelitis/acute disseminated encephalomyelitis, and these observations build on previous work by other investigators that highlighted persistent flaccid paralysis and electrophysiological evidence of axonal loss portending a poorer prognosis. Furthermore, these cases suggest a potential role for approaching how we classify subtypes of transverse myelitis and acute disseminated encephalomyelitis.
DeSena A, Graves D, Morriss MC, Greenberg BM. Transverse myelitis plus syndrome and acute disseminated encephalomyelitis plus syndrome: a case series of 5 children. JAMA Neurol. 2014 May;71(5):624-9.
Herpes simplex encephalitis as a potential cause of anti-N-methyl-D-aspartate receptor antibody encephalitis: report of 2 cases
Abstract
IMPORTANCE: Encephalitis mediated by anti-N-methyl-D-aspartate (NMDA) receptor antibodies and herpes simplex (HS) encephalitis are seemingly separate causes of encephalopathy in adults and children. Herpes simplex encephalitis is infectious, and anti-NMDA receptor antibody encephalitis is autoimmune in origin. Both can cause seizures and encephalopathy, although the latter can also cause psychiatric symptoms and movement disorders. Owing to the rarity of these 2 diseases, patients with co-occurrence are important because they alert clinicians to possible links between 2 seemingly separate processes.
OBSERVATIONS: In a case series of 2 patients observed at our center, we describe an infant and an adult who had confirmed HS encephalitis and then developed confirmed anti-NMDA receptor antibody encephalitis. Polymerase chain reaction testing for HS virus was performed. Testing for NMDA receptor antibodies was performed by Associated Regional and University Pathologists Laboratory in Salt Lake City, Utah.
CONCLUSIONS AND RELEVANCE: We conclude that atypical cases of HS or other viral encephalitides should be investigated for concomitance of an autoimmune encephalitis. We suspect that the pathophysiologic mechanisms by which HS virus infects neurons produce a higher likelihood of contracting anti-NMDA receptor antibody encephalitis.
Desena A, Graves D, Warnack W, Greenberg BM. Herpes simplex encephalitis as a potential cause of anti-N-methyl-D-aspartate receptor antibody encephalitis: report of 2 cases. JAMA Neurol. 2014 Mar;71(3):344-6.
Differential Diagnosis of Transverse Myelitis
ABSTRACT
OBJECTIVE: To compile the spectrum of differential diagnoses in a patient cohort referred to a specialized center for evaluation of transverse myelitis (TM).
BACKGROUND: TM is an inflammatory spinal cord disorder that presents with a variable clinical profile. TM can present as a monophasic disorder or it may be a manifestation of autoimmune disorders including multiple sclerosis (MS), neuromyelitis optica (NMO) or rheumatologic diseases. However, other myelopathic disorders may mimic TM and are occasionally misdiagnosed as TM.
DESIGN/METHODS: We conducted a study of all new patients who presented to the Johns Hopkins Transverse Myelitis Center (JHTMC). We reviewed the clinical profile of patients evaluated for TM over a 36-month period. We confirmed the validity of the diagnosis of TM or established other diagnoses based on clinical, neuroimaging and laboratory criteria.
RESULTS: We evaluated 519 patients, of which 346 (67%) were confirmed to have inflammatory conditions consistent with TM. Idiopathic TM accounted for the majority of cases (26%), followed by NMO (16%), MS/CIS (11%); the remaining 14% were caused by other CNS inflammatory diseases. One hundred and eighteen patients who were initially diagnosed with TM were instead diagnosed with a non-inflammatory myelopathy (23%), including compressive myelopathy (7%) and vascular abnormalities (5%). Twenty-two of these (4%) involved progressive myelopathies ruled out for inflammatory, infectious, or compressive etiologies. Twenty-eight cases (5%) had an inadequate evaluation at the time of presentation and could not be characterized. The remaining 27 cases (5%) had symptoms not attributable to the spinal cord or no objective neurologic findings.
CONCLUSIONS: Although two-thirds of patients referred for TM were confirmed, 28% of patients initially diagnosed with TM were discovered to have another diagnosis and 5% presented with myelopathy that could not be characterized. Findings suggest that a subset of patients diagnosed with TM may have non-inflammatory causes of myelopathies that warrant a more detailed evaluation.
2013
Differentiating Vascular Myelopathy from Transverse Myelitis
Mealy MA, Jimenez JA, Gailloud P, Becker D, Newsome SD, Levy M, Pardo-Villamizar CA
Johns Hopkins University, Baltimore, MD
Poster presentation at the 2013 American Academy of Neurology Annual Meeting, San Diego, CA
Clinical and Neuroimaging Features of Sarcoid Associated Myelopathy
Jimenez JA, Reyes-Mantilla MI, Tapias DL, Pardo CA
Johns Hopkins University, Baltimore, MD
Universidad de Antioquia, Medellín, Colombia
Poster presentation at the 2013 American Academy of Neurology Annual Meeting, San Diego, CA
2009
Distinct subtypes of myelitis in systemic lupus erythematosus
Abstract
OBJECTIVE: Myelitis causes pain, weakness, and sphincteric deficits, and is 1,000-fold more prevalent in patients with systemic lupus erythematosus (SLE) than in the general population. For the last century, descriptions of SLE myelitis have been primarily limited to case reports. In contrast, larger-scale cohort studies have revealed that myelitis occurring in the idiopathic demyelinating diseases (i.e., multiple sclerosis versus neuromyelitis optica) represents distinct syndromes. This study was undertaken to determine whether SLE myelitis similarly encapsulates distinct syndromes.
METHODS: We analyzed a cohort of 22 patients with SLE and myelitis. Patients were assessed for neurologic variables related to myelitis and for clinical and serologic features of SLE. Magnetic resonance images of the spine, cerebrospinal fluid profiles, and autoantibody profiles were obtained.
RESULTS: Eleven patients presented with signs of gray matter dysfunction (i.e., flaccidity and hyporeflexia), whereas 11 patients presented with signs of white matter dysfunction (i.e., spasticity and hyperreflexia). Patients with gray matter dysfunction were more likely to have irreversible paraplegia (P < 0.01), despite presenting with a monophasic versus polyphasic course (P = 0.01), higher levels of SLE activity (mean SLE Disease Activity Index 9.8 versus 2.0; P = 0.01), and a cerebrospinal fluid profile indistinguishable from bacterial meningitis. Prior to irreversible paraplegia, these patients presented with prodromes of fever and urinary retention, but were misdiagnosed by physicians of different specialties as having urinary tract infections. Patients with white matter dysfunction were more likely to meet criteria for neuromyelitis optica (P = 0.04) and were also more likely to have antiphospholipid antibodies (lupus anticoagulant) (P = 0.01). CONCLUSION: Our findings indicate that SLE myelitis encapsulates 2 distinct and previously unrecognized syndromes that can be distinguished clinically by gray matter versus white matter findings. Recognition of fever and urinary retention as prodromes of irreversible paraplegia may allow earlier diagnosis and treatment in SLE patients presenting with gray matter findings. Birnbaum J, Petri M, Thompson R, Izbudak I, Kerr D. Distinct subtypes of myelitis in systemic lupus erythematosus. Arthritis Rheum. 2009 Nov;60(11):3378-87.
Nineteen episodes of recurrent myelitis in a woman with neuromyelitis optica and systemic lupus erythematosus
Abstract
OBJECTIVES: To describe the case of a patient with systemic lupus erythematosus (SLE) and neuromyelitis optica (NMO) who experienced 19 recurrent attacks of myelitis.
DESIGN: Case report. SETTING: An outpatient neurorheumatology clinic at the Johns Hopkins Hospital devoted to care of patients with neurological manifestation of rheumatic diseases. Patient A woman with NMO and SLE. Intervention Rituximab therapy.
MAIN OUTCOME MEASURES: Clinical and neuroimaging features of relapsing disease. RESULTS: Recurrent and increasingly severe myelitis attacks still occurred after treatment with rituximab.
CONCLUSIONS: It may be progressively more difficult to prevent relapses and commensurate disability in patients with later stages of relapsing NMO. Recognition of NMO as a distinct diagnostic entity in patients with SLE and other rheumatic diseases is crucial, in that institution of earlier targeted immunosuppressant treatment may be more effective than later targeted immunosuppression. The cellular arm of the immune system may be recruited by pathogenic B cells and may explain why relapses may occur after treatment with B cell-depleting therapy.
Nasir S, Kerr DA, Birnbaum J. Nineteen episodes of recurrent myelitis in a woman with neuromyelitis optica and systemic lupus erythematosus. Arch Neurol. 2009 Sep;66(9):1160-3.
Priapism in infantile transverse myelitis
Abstract
BACKGROUND: Transverse myelitis is an autoimmune neurological disorder of the spinal cord that affects individuals of all age groups, including infants.
OBJECTIVE: To report priapism as a unique clinical manifestation of infantile transverse myelitis.
DESIGN: Case series.
SETTING: Transverse Myelitis Center at Johns Hopkins, Johns Hopkins Hospital, Baltimore, Maryland.
PATIENTS: Three infants younger than 12 months.
INTERVENTIONS: Intravenous corticosteroids, intravenous immunoglobulin, physical therapy, and rehabilitation.
MAIN OUTCOME MEASURE: Clinical outcomes in infants with priapism and transverse myelitis.
RESULTS: All 3 infants demonstrated rapidly progressive quadriplegia that resulted in substantial disability and proved fatal for 1 infant.
CONCLUSION: Priapism in infants with transverse myelitis may be an indication of severe inflammation and neural injury that necessitates immediate and aggressive treatment.
Hammond ER, Kerr DA. Priapism in infantile transverse myelitis. Arch Neurol. 2009 Jul;66(7):894-7.
Quality care in transverse myelitis: a responsive protocol
Abstract
This study was conducted to aid in the development of a multidisciplinary care center for patients with transverse myelitis. We surveyed the parents of 20 children diagnosed with transverse myelitis between the ages of 0.5 and 21 years to understand their experiences in navigating the health care system. We analyzed acute care events and long-term follow-up in relation to patient satisfaction. Results showed satisfactory ratings in the vicinity of 50% in key areas such as the articulation of a treatment plan. A significant disparity was found in the patients’ desire for specialty care and their ability to procure such care. In all, 90% of patients expressed a desire to consult with a psychiatrist, but only 25% were successful in making a visit, a 64% deficit; 70% of respondents also desired to see a gastroenterologist, with only 25% actually doing so, leaving a 43% gap. Recommendations and patient opinions regarding the creation of a collaborative care environment are noted. Research with a larger sample will further elucidate the needs in transverse myelitis patient care.
Trecker CC, Kozubal DE, Quigg M, Hammond E, Krishnan C, Sim PA, Kaplin AI. Quality care in transverse myelitis: a responsive protocol. J Child Neurol. 2009 May;24(5):577-83.
2008
Optic neuritis and recurrent myelitis in a woman with systemic lupus erythematosus
Abstract
Background: A 38-year-old woman with systemic lupus erythematosus presented with headaches and bilateral hearing loss. Brain MRI was initially suggestive of small-vessel disease developing in the context of neuropsychiatric systemic lupus erythematosus. Several months later, the patient developed optic neuritis, followed by recurrent attacks of myelitis.
Investigations: MRI of the spine revealed multifocal regions of myelitis affecting the cervical spine. Serological evaluation revealed the presence of neuromyelitis optica-IgG antibodies. MRI of the brain was nondiagnostic for multiple sclerosis.
Diagnosis: Recurrent myelitis and optic neuritis, occurring in the context of neuromyelitis optica (also known as Devic’s syndrome).
Management: The patient had recurrent attacks of myelitis despite treatment with pulse cyclophosphamide. After initiation of rituximab, the patient experienced symptomatic improvement and had no further attacks of opticospinal disease.
Birnbaum J, Kerr D. Optic neuritis and recurrent myelitis in a woman with systemic lupus erythematosus. Nat Clin Pract Rheumatol. 2008 Jul;4(7):381-6.
Interleukin-17 in transverse myelitis and multiple sclerosis
Abstract
CSF IL-6 is elevated in transverse myelitis (TM) and predicts disability. Since IL-17 regulates cytokines (TNFalpha, IL-1beta and IL-6) known to stimulate IL-6 production by astrocytes, we sought to determine whether IL-17 was increased in TM and MS compared to healthy controls (HC) and other neurologic diseases (OND). IL-17 and IL-6 levels were measured in stimulated peripheral blood mononuclear cell (PBMC) supernatants from HC, MS, TM and OND. IL-17 was increased in TM compared to HC, MS, and OND (mean pg/ml+/-standard error; HC: 36.1+/-11.7, MS: 89.4+/-23.3, TM: 302.6+/-152.5, OND: 41.2+/-13.0, p=0.01). IL-6 was increased in TM relative to MS and HC (HC: 2624 pg/ml+/-641, MS: 6129+/-982, TM: 12,536+/-2657, OND: 6920+/-1801, p<0.002). MS patients with early disease (<2 years) also had increased levels of IL-17 (p<0.04) and IL-6 (p<0.05). Cytokine neutralization experiments demonstrated that IL-6 was the main inducer of astrocyte IL-6 production. We conclude that IL-17 and IL-6 production from PBMC in TM and early MS are increased and induce astrocyte IL-6 production through IL-6. Graber JJ, Allie SR, Mullen KM, Jones MV, Wang T, Krishnan C, Kaplin AI, Nath A, Kerr DA, Calabresi PA. Interleukin-17 in transverse myelitis and multiple sclerosis. J Neuroimmunol. 2008 May 30;196(1-2):124-32.
2007
Idiopathic transverse myelitis: corticosteroids, plasma exchange, or cyclophosphamide
Abstract
Transverse myelitis is a focal disorder of the spinal cord in which an immune-mediated process results in neural injury. In this large retrospective study, we compare patients who received one of four treatments to identify the most effective therapies. We identified subsets of patients who received clinical benefit from plasma exchange or cyclophosphamide being included in their treatment regimen.
Greenberg BM, Thomas KP, Krishnan C, Kaplin AI, Calabresi PA, Kerr DA. Idiopathic transverse myelitis: corticosteroids, plasma exchange, or cyclophosphamide. Neurology. 2007 May 8;68(19):1614-7.
Acute transverse myelitis in childhood: center-based analysis of 47 cases
Abstract
OBJECTIVE: To relate clinical characteristics associated with acute transverse myelitis (ATM) in children with functional outcomes at follow-up.
METHODS: We identified 47 patients for whom ATM occurred under the age of 18 years. Chart analysis, clinical evaluation, and administration of functional measures were completed.
RESULTS: The age at onset clustered between ages 0 to 2 and 5 to 17. Febrile illness had occurred in 47% and vaccination in 28%. Major disability at the nadir of the clinical course was noted. Eighty-nine percent were unable to walk, required assisted ventilation, or both. At a median of 3.2 years after acute illness, 43% were unable to walk 30 ft and 21% required a walker or other support, 68% experienced urinary urgency, 50% required bladder catheterization, 54% were troubled by persistent dysesthesias, and 75% had numbness. Factors associated with a better functional outcome included older age at time of diagnosis, shorter time to diagnosis, lower sensory and anatomic levels of spinal injury, absence of T1 hypointensity on spinal MRI obtained during the acute period, lack of white blood cells in the CSF, and fewer affected spinal cord segments. Neither rapid progression to maximum impairment in less than 1 day nor any antecedent illness, immunization, or trauma was associated with a worse outcome.
CONCLUSION: Persisting disability was present in many children with acute transverse myelitis. Urinary problems and sensory symptoms were the most common issues. Age at onset below 3 years was associated with worse functional outcomes.
Pidcock FS, Krishnan C, Crawford TO, Salorio CF, Trovato M, Kerr DA. Acute transverse myelitis in childhood: center-based analysis of 47 cases. Neurology. 2007 May 1;68(18):1474-80.
2006
Demyelinating disorders: update on transverse myelitis
Abstract
Transverse myelitis (TM) is a focal inflammatory disorder of the spinal cord. Perivascular monocytic and lymphocytic infiltration, demyelination, and axonal injury are prominent histopathogic features of TM. The clinical manifestations of TM are consequent to dysfunction of motor, sensory, and autonomic pathways. At peak deficit, 50% of patients with TM are completely paraplegic (with no volitional movements of legs), virtually all have some degree of bladder dysfunction, and 80% to 94% have numbness, paresthesias, or band-like dysesthesias. Longitudinal case series of TM reveal that approximately one third of patients recover with little to no sequelae, one third are left with a moderate degree of permanent disability, and one third have severe disability. Recent studies have shown that the cytokine interleukin-6 may be a useful biomarker, as the levels of interleukin-6 in the cerebrospinal fluid of acute TM patients strongly correlate with and are highly predictive of disability. Clinical trials testing the efficacy of promising axonoprotective agents in combination with intravenous steroids in the treatment of TM are currently underway.
Krishnan C, Kaplin AI, Pardo CA, Kerr DA, Keswani SC. Demyelinating disorders: update on transverse myelitis. Curr Neurol Neurosci Rep. 2006 May;6(3):236-43.
2005
IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis
Abstract
Transverse myelitis (TM) is an immune-mediated spinal cord disorder associated with inflammation, demyelination, and axonal damage. We investigated the soluble immune derangements present in TM patients and found that IL-6 levels were selectively and dramatically elevated in the cerebrospinal fluid and directly correlated with markers of tissue injury and sustained clinical disability. IL-6 was necessary and sufficient to mediate cellular injury in spinal cord organotypic tissue culture sections through activation of the JAK/STAT pathway, resulting in increased activity of iNOS and poly(ADP-ribose) polymerase (PARP). Rats intrathecally infused with IL-6 developed progressive weakness and spinal cord inflammation, demyelination, and axonal damage, which were blocked by PARP inhibition. Addition of IL-6 to brain organotypic cultures or into the cerebral ventricles of adult rats did not activate the JAK/STAT pathway, which is potentially due to increased expression of soluble IL-6 receptor in the brain relative to the spinal cord that may antagonize IL-6 signaling in this context. The spatially distinct responses to IL-6 may underlie regional vulnerability of different parts of the CNS to inflammatory injury. The elucidation of this pathway identifies specific therapeutic targets in the management of CNS autoimmune conditions.
Click here for the Full Open Access Paper
Kaplin AI, Deshpande DM, Scott E, Krishnan C, Carmen JS, Shats I, Martinez T, Drummond J, Dike S, Pletnikov M, Keswani SC, Moran TH, Pardo CA, Calabresi PA, Kerr DA. IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis. J Clin Invest. 2005 Oct;115(10):2731-41.
Recurrent transverse myelitis following neurobrucellosis: immunologic features and beneficial response to immunosuppression
Abstract
The authors report the clinical course and immune system response of a patient with disease-associated recurrent transverse myelitis (TM) following cerebral infection with Brucellosis melitensis. The patient suffered four recurrences of his TM (each at a distinct spinal cord level) over the course of 2 years following his initial presentation, which ultimately progressed to quadriplegia. He had progressively declining cerebrospinal fluid (CSF) brucella antibody titers, suggesting a postinfectious, rather than an infectious, etiology. The authors simultaneously examined the expression of multiple cytokines in the CSF of this patient using cytokine antibody arrays and found a marked elevation of interleukin (IL)-6, IL-8, and macrophage chemoattractant protein (MCP)-1 levels relative to controls. Quantitative enzyme-linked immunosorbent assay (ELISA) analysis of the CSF confirmed a 1700-fold elevation of IL-6 and more modest elevations of IL-8 and MCP-1. IL-6 levels returned to baseline following treatment of the patient with intravenous cyclophosphamide and plasma exchange and the patient experienced a significant and sustained recovery of function.
Krishnan C, Kaplin AI, Graber JS, Darman JS, Kerr DA. Recurrent transverse myelitis following neurobrucellosis: immunologic features and beneficial response to immunosuppression. J Neurovirol. 2005 Apr;11(2):225-31.
Transverse myelitis after lumbar steroid injection in a patient with Behcet’s disease
Abstract
STUDY DESIGN: Case report.
OBJECTIVE: We describe a patient who developed transverse myelitis (TM) following a nerve root injection of steroids and anesthetic at L2 for radicular pain.
SETTING: Baltimore, MD, USA.
CLINICAL PRESENTATION: A 42-year-old woman developed progressive lower extremity weakness and paresthesias, a T12 sensory level and urinary urgency 8 h following the injection of Marcaine and Celestone into the left L2 nerve root. Magnetic resonance imaging showed T2 signal abnormality with gadolinium enhancement from T12 to the conus medullaris and there was no evidence of traumatic injury to the spinal cord. The patient had undiagnosed Behcet’s disease (BD) and had experienced multiple episodes of pathergy: hyper-responsiveness of the skin to local trauma, resulting in inflammation and edema. Intravenous steroids were initiated and the patient experienced a near total clinical resolution and a complete radiologic resolution.
CONCLUSION: Since the spinal cord inflammation developed after and immediately adjacent to local spinal trauma, we suggest that the TM in this patient was related to BD and was a pathergy response in the spinal cord.
Deshpande DM, Krishnan C, Kerr DA. Transverse myelitis after lumbar steroid injection in a patient with Behcet’s disease. Spinal Cord. 2005 Dec;43(12):735-7.
Idiopathic transverse myelitis
Reports in the medical literature of “acute myelitis” date back to 1882 and are credited to H. C. Bastain, MD Lond, FRS, a consulting physician to what was then called University College Hospital and the National Hospital for the Paralysed and Epileptic (London, England).1 He described several cases of acute myelitis resulting in “softening of the spinal cord.”2(p1531) He presented the pathologic findings of several autopsies from patients who died of the myelitis and divided the cases into those that he thought were due to “blood changes and toxins, often associated with feeble cardiac action, which may well act as causes of thrombosis in vessels of the spinal cord”2(p1532) and those that were due to acute inflammation. The “inflammatory” cases were postulated to be due to an infectious or an allergic mechanism.
Krishnan C, Kerr DA. Idiopathic transverse myelitis. Arch Neurol. 2005 Jun;62(6):1011-3.
Diagnosis and management of acute myelopathies
Abstract
BACKGROUND: Acute myelopathies represent a heterogeneous group of disorders with distinct etiologies, clinical and radiologic features, and prognoses. Transverse myelitis (TM) is a prototype member of this group in which an immune-mediated process causes neural injury to the spinal cord, resulting in varying degrees of weakness, sensory alterations, and autonomic dysfunction. TM may exist as part of a multifocal CNS disease (eg, MS), multisystemic disease (eg, systemic lupus erythematosus), or as an isolated, idiopathic entity.
REVIEW SUMMARY: In this article, we summarize recent classification and diagnostic schemes, which provide a framework for the diagnosis and management of patients with acute myelopathy. Additionally, we review the state of current knowledge about the epidemiology, natural history, immunopathogenesis, and treatment strategies for patients with TM.
CONCLUSIONS: Our understanding of the classification, diagnosis, pathogenesis, and treatment of TM has recently begun to expand dramatically. With more rigorous criteria applied to distinguish acute myelopathies and with an emerging understanding of immunopathogenic events that underlie TM, it may now be possible to effectively initiate treatments in many of these disorders. Through the investigation of TM, we are also gaining a broader appreciation of the mechanisms that lead to autoimmune neurologic diseases in general.
Kaplin AI, Krishnan C, Deshpande DM, Pardo CA, Kerr DA. Diagnosis and management of acute myelopathies. Neurologist. 2005 Jan;11(1):2-18.
2004
Venous hypertensive myelopathy as a potential mimic of transverse myelitis
Abstract
STUDY DESIGN: Case report.
OBJECTIVE: We describe a patient who developed a myelopathy associated with a noncompressive herniated cervical intervertebral disc at the same level. We provide clinical and radiological evidence that reveals that even though the disc herniation did not compress the spinal cord, it diminished venous blood flow out of the spinal cord, possibly resulting in a venous hypertensive myelopathy (VHM).
SETTING: Baltimore, MD, USA.
CLINICAL PRESENTATION: A 29-year-old woman developed a cervical radiculopathy, followed by a slowly progressive cervical myelopathy associated with a herniated C5-C6 disc. Magnetic resonance imaging showed a noncompressive disc herniation, a swollen spinal cord with increased T2 signal most prominent at the site of the herniated disc, extending several levels above and below the disc. The patient was diagnosed with acute transverse myelitis (ATM) and was started on IV steroids. However, unlike most cases of transverse myelitis, spinal fluid analysis was noninflammatory. In contrast, several features suggested that the patient instead had VHM. We suggest that the disc herniation resulted in impaired drainage of blood from the spinal cord through compression of the venous plexus near the intervertebral foramen.
INTERVENTION: Although the patient did not recover function following high-dose steroid administration, she recovered completely following C5-C6 discectomy and fusion.
CONCLUSION: To our knowledge, this is the first report of likely VHM in the absence of a spinal arteriovenous malformation. We suggest that some patients diagnosed with ATM in the setting of extrinsic spinal column abnormalities may actually have a noninflammatory myelopathy associated with impaired spinal venous drainage.
Krishnan C, Malik JM, Kerr DA. Venous hypertensive myelopathy as a potential mimic of transverse myelitis. Spinal Cord. 2004 Apr;42(4):261-4.
Transverse Myelitis: pathogenesis, diagnosis and treatment
Abstract
Transverse Myelitis (TM) is a clinical syndrome in which an immune-mediated process causes neural injury to the spinal cord, resulting in varying degrees of weakness, sensory alterations and autonomic dysfunction. TM may exist as part of a multi-focal CNS disease (e.g. MS), multi-systemic disease (e.g. systemic lupus erythematosus), or as an isolated, idiopathic entity. In this article, we will summarize recent classification and diagnostic schemes (1), which provide a framework for the acute management of patients with TM. Additionally, we will review current concepts on the natural history, immunopathogenesis and treatment strategies for patients with TM.
Krishnan C, Kaplin AI, Deshpande DM, Pardo CA, Kerr DA. Transverse Myelitis: pathogenesis, diagnosis and treatment. Front Biosci. 2004 May 1;9:1483-99.
Recurrent transverse myelitis associates with anti-Ro (SSA) autoantibodies
Abstract
Transverse myelitis (TM) is an idiopathic inflammatory disorder of the spinal cord. The authors observed cases of recurrent TM in patients where anti-Ro (SSA) antibodies were present and therefore performed a case-control study to examine the frequency of anti-Ro autoantibodies in patients with recurrent TM and control subjects. Antibodies to 52-kd Ro were demonstrated in 77% of cases (10/13) compared with only 33% of control subjects (4/12).
Hummers LK, Krishnan C, Casciola-Rosen L, Rosen A, Morris S, Mahoney JA, Kerr DA, Wigley FM. Recurrent transverse myelitis associates with anti-Ro (SSA) autoantibodies. Neurology. 2004 Jan 13;62(1):147-9.
2002
Proposed diagnostic criteria and nosology of acute transverse myelitis
Abstract
Acute transverse myelitis (ATM) is a focal inflammatory disorder of the spinal cord, resulting in motor, sensory, and autonomic dysfunction. A set of uniform diagnostic criteria and nosology for ATM is proposed to avoid the confusion that inevitably results when investigators use differing criteria. This will ensure a common language of classification, reduce diagnostic confusion, and lay the groundwork necessary for multicenter clinical trials. In addition, a framework is suggested for evaluation of individuals presenting with signs and symptoms of ATM. Best treatment often depends on a timely and accurate diagnosis. Because acute transverse myelopathies are relatively rare, delayed and incomplete work-ups often occur. Rapid and precise diagnosis will ensure not only that compressive lesions are detected and treated but also that idiopathic ATM is distinguished from ATM secondary to a known underlying disease. Identification of etiologies may suggest medical treatment, whereas no clearly established medical treatment currently exists for idiopathic ATM. Establishment of a diagnostic algorithm will likely lead to improved care, although it is recognized that the entire evaluation may not be performed for each patient.
Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology. 2002 Aug 27;59(4):499-505.
