Publications by authors named "Eoin P Flanagan"

160 Publications

Myelin oligodendrocyte glycoprotein (MOG) antibodies in a patient with glioblastoma: Red flags for false positivity.

J Neuroimmunol 2021 Oct 8;361:577743. Epub 2021 Oct 8.

Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

We present a patient with positive medium titer MOG-IgG and progressive neurological decline whose clinical and radiological phenotype were not consistent with a MOG-IgG associated disorder and ultimately received a diagnosis of glioblastoma after brain biopsy and died 4 weeks later. This represents an important topic with a high frequency of MOG-IgG testing in clinical practice. Due to this there are increasing reports of MOG-IgG positivity in atypical clinical phenotypes, raising the possibility of false positives, which can have important implications. It is important to highlight that judicious clinical evaluation is needed when interpreting MOG-IgG results in atypical settings.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577743DOI Listing
October 2021

Meta-analysis of effectiveness of steroid-sparing attack prevention in MOG-IgG-associated disorder.

Mult Scler Relat Disord 2021 Oct 4;56:103310. Epub 2021 Oct 4.

Department of Neurology, Texas Tech University Health Sciences Center, Lubbock TX, United States. Electronic address:

Objective: To estimate the efficacy of the commonly used long-term immunotherapies in myelin oligodendrocyte glycoprotein IgG associated disorder (MOGAD) METHOD: A comprehensive search of the databases including PubMed/MEDLINE, EMBASE, and Cochrane database was performed for all studies that assessed the efficacy of azathioprine (AZA), mycophenolate mofetil (MMF), rituximab (RTX), and maintenance intravenous immunoglobulin (mIVIG) in MOGAD. The random-effect model is used to estimate the standard mean difference (SMD) of annualized relapse rate (ARR) and expanded disability status scale (EDSS), mean ARR, probabilities of relapse and worsening EDSS during treatment.

Results: The initial search identified 714 articles, and 21 satisfied eligibility criteria. All immunotherapies significantly reduced ARR in both pediatric and adult populations. Relapse probabilities and pooled mean ARR (SE: standard error) during therapies were as follow: AZA 53.1% [95%CI 37.4% to 68.2%; ARR 0.291 (0.134)], MMF 38.5% [95%CI 19.4% to 62.0%; ARR 0.836 (0.176)], RTX 48.9% [95%CI 37.8% to 60.2%; ARR 0.629(0.162)], and mIVIG 25.3% [95%CI 14.0% to 41.3%; ARR 0.081 (0.058)]. Only RTX significantly improved EDSS, SMD -0.499 (95%CI -0.996 to -0.003). The proportion of worsening EDSS with immunotherapies were 20.7% (95%CI 8.8% to 41.6%), 8.1% (95%CI 1.1% to 41.2%), and 10.8% (95%CI 3.8% to 26.8%) for AZA, MMF, and RTX, respectively.

Conclusion: These commonly used immunotherapies significantly reduced ARR in MOGAD. Only RTX had a significant benefit in EDSS improvement. However, a substantial portion of patients continued to relapse with treatment. Randomized controlled studies are needed to verify these findings and perform head-to-head comparisons among these treatment options.
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http://dx.doi.org/10.1016/j.msard.2021.103310DOI Listing
October 2021

Evaluation and Management of Acute Myelopathy.

Semin Neurol 2021 Oct 7;41(5):511-529. Epub 2021 Oct 7.

Department of Neurology, Mayo Clinic, Rochester, Minnesota.

Acute myelopathies are spinal cord disorders characterized by a rapidly progressive course reaching nadir within hours to a few weeks that may result in severe disability. The multitude of underlying etiologies, complexities in confirming the diagnosis, and often unforgiving nature of spinal cord damage have always represented a challenge. Moreover, certain slowly progressive myelopathies may present acutely or show abrupt worsening in specific settings and thus further complicate the diagnostic workup. Awareness of the clinical and magnetic resonance imaging characteristics of different myelopathies and the specific settings where they occur is fundamental for a correct diagnosis. Neuroimaging helps distinguish compressive etiologies that may require urgent surgery from intrinsic etiologies that generally require medical treatment. Differentiation between various myelopathies is essential to establish timely and appropriate treatment and avoid harm from unnecessary procedures. This article reviews the contemporary spectrum of acute myelopathy etiologies and provides guidance for diagnosis and management.
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http://dx.doi.org/10.1055/s-0041-1733792DOI Listing
October 2021

CNS Demyelinating Attacks Requiring Ventilatory Support With Myelin Oligodendrocyte Glycoprotein or Aquaporin-4 Antibodies.

Neurology 2021 09 13;97(13):e1351-e1358. Epub 2021 Aug 13.

From the Department of Neurology (H.H.Z.-F., C.V.S., E.S., J.I., E.F.W., S.J.P., J.J.C., B.G.W., D.D., J.-M.T., M.T., E.P.F.), Department of Laboratory Medicine and Pathology (S.J.P., D.D., E.P.F.), Department of Ophthalmology (J.J.C.), and Division of Pulmonary and Critical Care Medicine (H.Y.), Mayo Clinic, Rochester, MN; Department of Neurology (D.M.W.), Mayo Clinic, Scottsdale, AZ; and Department of Neurology (S.L.-C.), Mayo Clinic, Jacksonville, FL.

Background And Objective: Severe attacks of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (MOGAD) and aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) may require ventilatory support, but data on episodes are limited, particularly for MOGAD. We sought to compare the frequency, characteristics, and outcomes of MOGAD and AQP4-NMOSD attacks requiring ventilatory support.

Methods: This retrospective descriptive study identified Mayo Clinic patients (January 1, 1996-December 1, 2020) with MOGAD or AQP4-NMOSD and an attack requiring noninvasive or invasive ventilation at Mayo Clinic or an outside facility by searching for relevant terms in their electronic medical record. Inclusion criteria were (1) attack-related requirement for noninvasive (bilevel positive airway pressure or continuous positive airway pressure) or invasive respiratory support (mechanical ventilation); (2) MOG or AQP4 antibody positivity with fulfillment of MOGAD and AQP4-NMOSD clinical diagnostic criteria, respectively; and (3) sufficient clinical details. We collected data on demographics, comorbid conditions, indication for and duration of respiratory support, MRI findings, treatments, and outcomes. The races of those with attacks requiring respiratory support were compared to those without such attacks in MOGAD and AQP4-NMOSD.

Results: Attacks requiring ventilatory support were similarly rare in patients with MOGAD (8 of 279, 2.9%) and AQP4-NMOSD (11 of 503 [2.2%]) ( = 0.63). The age at attack (median years [range]) (MOGAD 31.5 [5-47] vs AQP4-NMOSD 43 [14-65]; = 0.01) and percentage of female sex (MOGAD 3 of 8 [38%] vs AQP4-NMOSD 10 of 11 [91%]; = 0.04) differed. The reasons for ventilation differed between MOGAD (inability to protect airway from seizure, encephalitis or encephalomyelitis with attacks of acute disseminated encephalomyelitis 5 [62.5%] or unilateral cortical encephalitis 3 [37.5%]) and AQP4-NMOSD (inability to protect airway from cervical myelitis 9 [82%], rhombencephalitis 1 [9%], or combinations of both 1 [9%]). Median ventilation duration for MOGAD was 2 days (range 1-7 days) vs 19 days (range 6-330 days) for AQP4-NMOSD ( = 0.01). All patients with MOGAD recovered, but 2 of 11 (18%) patients with AQP4-NMOSD died of the attack. For AQP4-NMOSD, Black race was overrepresented for attacks requiring ventilatory support vs those without these episodes (5 of 11 [45%] vs 88 of 457 [19%]; = 0.045).

Discussion: Ventilatory support is rarely required for MOGAD and AQP4-NMOSD attacks, and the indications differ. Compared to MOGAD, these attacks in AQP4-NMOSD may have higher morbidity and mortality, and those of Black race were more predisposed, which we suspect may relate to socially mediated health inequality.
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http://dx.doi.org/10.1212/WNL.0000000000012599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480400PMC
September 2021

Antibody-Mediated Autoimmune Diseases of the CNS: Challenges and Approaches to Diagnosis and Management.

Front Neurol 2021 7;12:673339. Epub 2021 Jul 7.

Department of Neurology, Mayo Clinic, Rochester, MN, United States.

Antibody-mediated disorders of the central nervous system (CNS) are increasingly recognized as neurologic disorders that can be severe and even life-threatening but with the potential for reversibility with appropriate treatment. The expanding spectrum of newly identified autoantibodies targeting glial or neuronal (neural) antigens and associated clinical syndromes (ranging from autoimmune encephalitis to CNS demyelination) has increased diagnostic precision, and allowed critical reinterpretation of non-specific neurological syndromes historically associated with systemic disorders (e.g., Hashimoto encephalopathy). The intracellular vs. cell-surface or synaptic location of the different neural autoantibody targets often helps to predict the clinical characteristics, potential cancer association, and treatment response of the associated syndromes. In particular, autoantibodies targeting intracellular antigens (traditionally termed onconeural autoantibodies) are often associated with cancers, rarely respond well to immunosuppression and have a poor outcome, although exceptions exist. Detection of neural autoantibodies with accurate laboratory assays in patients with compatible clinical-MRI phenotypes allows a definite diagnosis of antibody-mediated CNS disorders, with important therapeutic and prognostic implications. Antibody-mediated CNS disorders are rare, and reliable autoantibody identification is highly dependent on the technique used for detection and pre-test probability. As a consequence, indiscriminate neural autoantibody testing among patients with more common neurologic disorders (e.g., epilepsy, dementia) will necessarily increase the risk of false positivity, so that recognition of high-risk clinical-MRI phenotypes is crucial. A number of emerging clinical settings have recently been recognized to favor development of CNS autoimmunity. These include antibody-mediated CNS disorders following herpes simplex virus encephalitis or occurring in a post-transplant setting, and neurological autoimmunity triggered by TNFα inhibitors or immune checkpoint inhibitors for cancer treatment. Awareness of the range of clinical and radiological manifestations associated with different neural autoantibodies, and the specific settings where autoimmune CNS disorders may occur is crucial to allow rapid diagnosis and early initiation of treatment.
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http://dx.doi.org/10.3389/fneur.2021.673339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292678PMC
July 2021

Comparison of MRI Lesion Evolution in Different Central Nervous System Demyelinating Disorders.

Neurology 2021 09 14;97(11):e1097-e1109. Epub 2021 Jul 14.

From the Departments of Neurology (E.S., M.B., S.J.P., J.J.C., B.G.W., C.F.L., N.L.Z., J.M.T., A.K., S.B.S.-M., B.M.K., E.P.F.), Radiology (K.N.K., S.A.M., P.P.M.), Laboratory Medicine and Pathology (S.J.P., J.P.F., A.N., E.P.F.), and Ophthalmology (J.J.C., T.G.), Mayo Clinic, Rochester, MN; Department of Neurosciences, Biomedicine, and Movement Sciences (E.S., S.M.), University of Verona, Italy; and Department of Neurology (A.S.L.-C.), Mayo Clinic, Jacksonville, FL.

Background And Objective: There are few studies comparing lesion evolution across different CNS demyelinating diseases, yet knowledge of this may be important for diagnosis and understanding differences in disease pathogenesis. We sought to compare MRI T2 lesion evolution in myelin oligodendrocyte glycoprotein immunoglobulin G (IgG)-associated disorder (MOGAD), aquaporin 4 IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD), and multiple sclerosis (MS).

Methods: In this descriptive study, we retrospectively identified Mayo Clinic patients with MOGAD, AQP4-IgG-NMOSD, or MS and (1) brain or myelitis attack; (2) available attack MRI within 6 weeks; and (3) follow-up MRI beyond 6 months without interval relapses in that region. Two neurologists identified the symptomatic or largest T2 lesion for each patient (index lesion). MRIs were then independently reviewed by 2 neuroradiologists blinded to diagnosis to determine resolution of T2 lesions by consensus. The index T2 lesion area was manually outlined acutely and at follow-up to assess variation in size.

Results: We included 156 patients (MOGAD, 38; AQP4-IgG-NMOSD, 51; MS, 67) with 172 attacks (brain, 81; myelitis, 91). The age (median [range]) differed between MOGAD (25 [2-74]), AQP4-IgG-NMOSD (53 [10-78]), and MS (37 [16-61]) ( < 0.01) and female sex predominated in the AQP4-IgG-NMOSD (41/51 [80%]) and MS (51/67 [76%]) groups but not among those with MOGAD (17/38 [45%]). Complete resolution of the index T2 lesion was more frequent in MOGAD (brain, 13/18 [72%]; spine, 22/28 [79%]) than AQP4-IgG-NMOSD (brain, 3/21 [14%]; spine, 0/34 [0%]) and MS (brain, 7/42 [17%]; spine, 0/29 [0%]) ( < 0.001). Resolution of all T2 lesions occurred most often in MOGAD (brain, 7/18 [39%]; spine, 22/28 [79%]) than AQP4-IgG-NMOSD (brain, 2/21 [10%]; spine, 0/34 [0%]) and MS (brain, 2/42 [5%]; spine, 0/29 [0%]) ( < 0.01). There was a larger median (range) reduction in T2 lesion area in mm on follow-up axial brain MRI with MOGAD (213 [55-873]) than AQP4-IgG-NMOSD (104 [0.7-597]) ( = 0.02) and MS (36 [0-506]) ( < 0.001) and the reductions in size on sagittal spine MRI follow-up in MOGAD (262 [0-888]) and AQP4-IgG-NMOSD (309 [0-1885]) were similar ( = 0.4) and greater than in MS (23 [0-152]) ( < 0.001).

Discussion: The MRI T2 lesions in MOGAD resolve completely more often than in AQP4-IgG-NMOSD and MS. This has implications for diagnosis, monitoring disease activity, and clinical trial design, while also providing insight into pathogenesis of CNS demyelinating diseases.
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http://dx.doi.org/10.1212/WNL.0000000000012467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456356PMC
September 2021

Clinical Course and Features of Seizures Associated With LGI1-Antibody Encephalitis.

Neurology 2021 09 7;97(11):e1141-e1149. Epub 2021 Jul 7.

From the Department of Neurology (K.M.S., D.D., E.P.F., J.W.B.) and Department of Radiology (G.B.L.), Neuroradiology Division, Mayo Clinic, Rochester, MN.

Background And Objectives: To determine risk factors associated with clinical relapses and development of chronic epilepsy in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) immunoglobulin G encephalitis.

Methods: Patients with seizures related to LGI1-antibody encephalitis with ≥24 months of follow-up from disease onset were identified in the Mayo Clinic electronic medical record and neuroimmunology laboratory records. Charts were reviewed to determine clinical factors, seizure types, imaging, treatment, occurrence of relapse, and outcome. Binary logistic regression analysis was performed to identify predictors of the development of chronic epilepsy. Univariate Cox proportional hazards regression was used to examine the influence of baseline characteristics on relapse risk.

Results: Forty-nine patients with LGI1-antibody encephalitis and acute symptomatic seizures were identified. Almost all patients (n = 48, 98%) were treated with immunotherapy. Eight had definite and 2 had possible chronic epilepsy at the last follow-up (10 of 49, 20.4%). Female sex ( = 0.048) and younger age at disease onset ( = 0.02) were associated with development of chronic epilepsy. Relapses occurred in 20 (40.8%), with a median time to first relapse of 7.5 months (range 3-94 months). Initial treatment with long-term steroid-sparing immunotherapy was associated with reduced risk of relapse (hazard ratio 0.28, 95% confidence interval 0.11-0.73, = 0.009).

Discussion: Chronic epilepsy occurred in 20.4% of our patients with LGI1-antibody encephalitis despite aggressive immunotherapy. Risk factors for chronic epilepsy were female sex and earlier age at onset. Relapses occurred in 40.8% of patients with prolonged follow-up, and long-term steroid-sparing immunotherapy was associated with a lower relapse rate.
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http://dx.doi.org/10.1212/WNL.0000000000012465DOI Listing
September 2021

Brain dysfunction and thyroid antibodies: autoimmune diagnosis and misdiagnosis.

Brain Commun 2021 5;3(2):fcaa233. Epub 2021 Jan 5.

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

Hashimoto encephalopathy, also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis, has been defined by sub-acute onset encephalopathy, with elevated thyroid antibodies, and immunotherapy responsiveness, in the absence of specific neural autoantibodies. We aimed to retrospectively review 144 cases referred with suspected Hashimoto encephalopathy over a 13-year period, and to determine the clinical utility of thyroid antibodies in the course of evaluation of those patients. One hundred and forty-four patients (all thyroid antibody positive) were included; 72% were women. Median age of symptom onset was 44.5 years (range, 10-87). After evaluation of Mayo Clinic, 39 patients (27%) were diagnosed with an autoimmune CNS disorder [autoimmune encephalopathy (36), dementia (2) or epilepsy (1)]. Three of those 39 patients had neural-IgGs detected (high glutamic acid decarboxylase-65, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-receptor and neural-restricted unclassified antibody), and 36 were seronegative. Diagnoses among the remaining 105 patients (73%) were functional neurological disorder ( = 20), neurodegenerative disorder ( = 18), subjective cognitive complaints ( = 14), chronic pain syndrome ( = 12), primary psychiatric ( = 11), sleep disorder ( = 10), genetic/developmental ( = 8), non-autoimmune seizure disorders ( = 2) and other ( = 10). More patients with autoimmune CNS disorders presented with sub-acute symptom onset ( < 0.001), seizures ( = 0.008), stroke-like episodes ( = 0.007), aphasia ( = 0.04) and ataxia ( = 0.02), and had a prior autoimmune history ( = 0.04). Abnormal brain MRI ( = 0.003), abnormal EEG ( = 0.007) and CSF inflammatory findings ( = 0.002) were also more frequent in the autoimmune CNS patients. Patients with an alternative diagnosis had more depressive symptoms ( = 0.008), anxiety ( = 0.003) and chronic pain ( = 0.002). Thyoperoxidase antibody titre was not different between the groups (median, 312.7 versus 259.4 IU/ml;  = 0.44; normal range, <9 IU/ml). None of the non-autoimmune group and all but three of the CNS autoimmune group (two with insidious dementia presentation, one with seizures only) fulfilled the autoimmune encephalopathy criteria proposed by Graus (A clinical approach to diagnosis of autoimmune encephalitis. 2016; 15: 391-404.) (sensitivity, 92%; specificity, 100%). Among patients who received an immunotherapy trial at our institution and had objective post-treatment evaluations, the 16 responders with autoimmune CNS disorders more frequently had inflammatory CSF, compared to 12 non-responders, all eventually given an alternative diagnosis ( = 0.02). In total, 73% of the patients referred with suspected Hashimoto encephalopathy had an alternative non-immune-mediated diagnosis, and more than half had no evidence of a primary neurological disorder. Thyroid antibody prevalence is high in the general population, and does not support a diagnosis of autoimmune encephalopathy in the absence of objective neurological and CNS-specific immunological abnormalities. Thyroid antibody testing is of little value in the contemporary evaluation and diagnosis of autoimmune encephalopathies.
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http://dx.doi.org/10.1093/braincomms/fcaa233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152924PMC
January 2021

Clinical and Radiologic Features, Pathology, and Treatment of Baló Concentric Sclerosis.

Neurology 2021 07 19;97(4):e414-e422. Epub 2021 May 19.

From the Departments of Neurology (E.A.J., Y.G., E.P.F., C.F.L., W.O.T.) and Radiology (P.P.M.), Mayo Clinic, Rochester, MN; Department of Neurology (E.A.J.), Capital and Coast District Health Board, Wellington, New Zealand; Brain & Mind Centre (T.A.H.), University of Sydney; and Department of Neurology (T.A.H.), Concord Repatriation General Hospital, Sydney, NSW, Australia.

Objective: To describe clinical, radiologic, and pathologic features of Baló concentric sclerosis (BCS) and assess overlap between BCS and other CNS inflammatory demyelinating diseases.

Methods: Retrospective review of BCS cases from US and Australian tertiary care centers.

Results: We identified 40 BCS cases with 38 available MRIs. Solitary MRI lesions were present in 26% (10/38). We saw >1 active concurrent BCS lesion in 45% (17/38). A third (13/38) had multiple sclerosis-suggestive lesions on the index MRI, of which 10 fulfilled Barkhof criteria. In patients with serial MRI performed within 1 month of the index MRI, lesions expanded radially with sequentially increased numbers of T2 hyperintense rings 52% (14/27). Initially nonenhancing or centrally enhancing lesions subsequently developed single or multiple enhancing rings (41%; 9/22) and incomplete enhancing rings (14%; 3/22). Discordance between rings as they appear on apparent diffusion coefficient, diffusion-weighted imaging, and gadolinium-enhanced imaging was observed in 67% (22/33). Aquaporin-4 immunoglobulin G (n = 26) and myelin oligodendrocyte glycoprotein immunoglobulin G (n = 21) were negative in all patients with serum available. Clinical response to steroid treatment was seen in 46% (13/28). A monophasic clinical course was present in 56% (18/32) at last follow-up (median 27.5 months; range 3-100 months). The initial attack was fatal in 10% (4/40). Median time from symptom onset to death was 23 days (range 19-49 days). All 17 patients with pathology available demonstrated typical findings of multiple sclerosis. Patients with active demyelinating lesions all demonstrated oligodendrocytopathy (pattern III).

Conclusions: BCS may be a distinct subtype of multiple sclerosis characterized by pattern III immunopathology.
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http://dx.doi.org/10.1212/WNL.0000000000012230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362356PMC
July 2021

Paraneoplastic disorders of the nervous system.

Authors:
Eoin P Flanagan

J Neurol 2021 Apr 27. Epub 2021 Apr 27.

Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

This article on paraneoplastic neurologic disorders provides an update on the diagnostic approach, utility and pitfalls of autoantibody testing and emerging settings in which these disorders are encountered. Recognition of the clinical and neuroimaging features accompanying paraneoplastic neurologic disorders is crucial to select those at highest risk who need neural antibody testing and screening for cancer. Cursory knowledge of the antibody assay methodology being ordered is important as the false positive rate varies by the technique utilized for detection. Antibodies can generally be stratified by the location of the target antigen (intraceullar versus cell-surface/synaptic) which informs frequency of cancer association, treatment response and prognosis. The therapeutic approach generally involves detection of the underlying cancer and combinations of oncologic treatments and immunosuppressant medications. The occurrence of paraneoplastic autoimmune neurologic disorders in novel settings, such as with immune checkpoint inhibitor use, has improved understanding of their pathogenesis and increased the likelihood neurologists will encounter such patients in their practice.
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http://dx.doi.org/10.1007/s00415-021-10570-1DOI Listing
April 2021

Positive Predictive Value of Myelin Oligodendrocyte Glycoprotein Autoantibody Testing.

JAMA Neurol 2021 Jun;78(6):741-746

Department of Neurology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota.

Importance: Myelin oligodendrocyte glycoprotein-IgG1-associated disorder (MOGAD) is a distinct central nervous system-demyelinating disease. Positive results on MOG-IgG1 testing by live cell-based assays can confirm a MOGAD diagnosis, but false-positive results may occur.

Objective: To determine the positive predictive value (PPV) of MOG-IgG1 testing in a tertiary referral center.

Design, Setting, And Participants: This diagnostic study was conducted over 2 years, from January 1, 2018, through December 31, 2019. Patients in the Mayo Clinic who were consecutively tested for MOG-IgG1 by live cell-based flow cytometry during their diagnostic workup were included. Patients without research authorization were excluded.

Main Outcomes And Measures: Medical records of patients who were tested were initially reviewed by 2 investigators blinded to MOG-IgG1 serostatus, and pretest probability was classified as high or low (suggestive of MOGAD or not). Testing of MOG-IgG1 used a live-cell fluorescence-activated cell-sorting assay; an IgG binding index value of 2.5 or more with an end titer of 1:20 or more was considered positive. Cases positive for MOG-IgG1 were independently designated by 2 neurologists as true-positive or false-positive results at last follow-up, based on current international recommendations on diagnosis or identification of alternative diagnoses; consensus was reached for cases in which disagreement existed.

Results: A total of 1617 patients were tested, and 357 were excluded. Among 1260 included patients tested over 2 years, the median (range) age at testing was 46 (0-98) years, and 792 patients were female (62.9%). A total of 92 of 1260 (7.3%) were positive for MOG-IgG1. Twenty-six results (28%) were designated as false positive by the 2 raters, with an overall agreement on 91 of 92 cases (99%) for true and false positivity. Alternative diagnoses included multiple sclerosis (n = 11), infarction (n = 3), B12 deficiency (n = 2), neoplasia (n = 2), genetically confirmed adrenomyeloneuropathy (n = 1), and other conditions (n = 7). The overall PPV (number of true-positive results/total positive results) was 72% (95% CI, 62%-80%) and titer dependent (PPVs: 1:1000, 100%; 1:100, 82%; 1:20-40, 51%). The median titer was higher with true-positive results (1:100 [range, 1:20-1:10000]) than false-positive results (1:40 [range, 1:20-1:100]; P < .001). The PPV was higher for children (94% [95% CI, 72%-99%]) vs adults (67% [95% CI, 56%-77%]) and patients with high pretest probability (85% [95% CI, 76%-92%]) vs low pretest probability (12% [95% CI, 3%-34%]). The specificity of MOG-IgG1 testing was 97.8%.

Conclusions And Relevance: This study confirms MOG-IgG1 as a highly specific biomarker for MOGAD, but when using a cutoff of 1:20, it has a low PPV of 72%. Caution is advised in the interpretation of low titers among patients with atypical phenotypes, because ordering MOG-IgG1 in low pretest probability situations will increase the proportion of false-positive results.
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http://dx.doi.org/10.1001/jamaneurol.2021.0912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077043PMC
June 2021

Clinical Utility of Antiretinal Antibody Testing.

JAMA Ophthalmol 2021 Jun;139(6):658-662

Department of Neurology, Mayo Clinic, Rochester, Minnesota.

Importance: The clinical utility of most antiretinal antibodies (retina antibodies) currently available for testing remains unclear and unproven. Despite this, the presence of retinal antibodies is included in current diagnostic autoimmune retinopathy criteria.

Objective: To evaluate the clinical significance of comprehensive retinal antibody evaluations currently offered in North America.

Design, Setting, And Participants: In this cross-sectional study, 14 patients without autoimmune retinopathy were recruited into the Mayo Clinic Neuroimmunology Biorepository for this study between January 1, 2019, and October 1, 2019. These serum samples without autoimmune retinopathy were sent in masked fashion to a Clinical Laboratory Improvement Amendments-certified laboratory. Using similar methods, the Mayo Clinic Neuroimmunology Research Laboratory independently assessed the same sample to ascertain reproducibility of the findings.

Main Outcomes And Measures: Results of the autoimmune retinopathy and cancer-associated retinopathy panels.

Results: Thirteen of 14 (93%; 95% CI, 66%-100%) serum samples tested positive for retinal antibodies, with a median of 5 retinal antibodies (range, 0-8) per patient at the Clinical Laboratory Improvement Amendments-certified laboratory, which provides a specificity of 7% (95% CI, 0%-34%). Confirmatory immunohistochemistry staining in human retina was present in 12 of 14 samples (86%). α-Enolase was found in 9 (64%). The only retinal antibody not present was recoverin. These nonspecific retinal antibody results were replicated at the Mayo Clinic Laboratory on Western blot using pig retina proteins as substrate.

Conclusions And Relevance: The presence of retinal antibodies in 93% of the patients without autoimmune retinopathy indicates a lack of specificity and that most detectable retinal antibodies have limited clinical relevance in the evaluation of patients for suspected autoimmune retinopathy. Current retinal antibody testing, other than recoverin, should be interpreted with caution, especially for cases of low clinical suspicion. The poor specificity is important to recognize to prevent the potentially unnecessary commencement of systemic immunosuppressants that may result in significant extraocular adverse effects. Identification of biomarkers that have a high predictive value for inflammatory or autoimmune retinal diseases is needed to move the field forward.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.0651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063133PMC
June 2021

Autoimmune encephalopathies presenting as dementia of subacute onset and rapid progression.

Ther Adv Neurol Disord 2021 19;14:1756286421998906. Epub 2021 Mar 19.

Departments of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.

The terms autoimmune dementia and autoimmune encephalopathy may be used interchangeably; autoimmune dementia is used here to emphasize its consideration in young-onset dementia, dementia with a subacute onset, and rapidly progressive dementia. Given their potential for reversibility, it is important to distinguish the rare autoimmune dementias from the much more common neurodegenerative dementias. The presence of certain clinical features [e.g. facio-brachial dystonic seizures that accompany anti-leucine-rich-glioma-inactivated-1 (LGI1) encephalitis that can mimic myoclonus] can be a major clue to the diagnosis. When possible, objective assessment of cognition with bedside testing or neuropsychological testing is useful to determine the degree of abnormality and serve as a baseline from which immunotherapy response can be judged. Magnetic resonance imaging (MRI) head and cerebrospinal fluid (CSF) analysis are useful to assess for inflammation that can support an autoimmune etiology. Assessing for neural autoantibody diagnostic biomarkers in serum and CSF in those with suggestive features can help confirm the diagnosis and guide cancer search in paraneoplastic autoimmune dementia. However, broad screening for neural antibodies in elderly patients with an insidious dementia is not recommended. Moreover, there are pitfalls to antibody testing that should be recognized and the high frequency of some antibodies in the general population limit their diagnostic utility [e.g., anti-thyroid peroxidase (TPO) antibodies]. Once the diagnosis is confirmed, both acute and maintenance immunotherapy can be utilized and treatment choice varies depending on the accompanying neural antibody present and the presence or absence of cancer. The target of the neural antibody biomarker may help predict treatment response and prognosis, with antibodies to cell-surface or synaptic antigens more responsive to immunotherapy and yielding a better overall prognosis than those with antibodies to intracellular targets. Neurologists should be aware that autoimmune dementias and encephalopathies are increasingly recognized in novel settings, including post herpes virus encephalitis and following immune-checkpoint inhibitor use.
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http://dx.doi.org/10.1177/1756286421998906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983436PMC
March 2021

Multiple Sclerosis Is Rare in Epstein-Barr Virus-Seronegative Children with Central Nervous System Inflammatory Demyelination.

Ann Neurol 2021 06 24;89(6):1234-1239. Epub 2021 Mar 24.

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

Although Epstein-Barr virus (EBV) is hypothesized to be a prerequisite for multiple sclerosis (MS), up to 15% of children with a diagnosis of MS were reported to be EBV-seronegative. When re-evaluating 25 EBV-seronegative children out of 189 pediatric patients with a diagnosis of clinically isolated syndrome/MS, we found anti-myelin oligodendrocyte glycoprotein (MOG) antibody in 11 of 25 (44%) EBV-seronegative but only 9 of 164 (5.5%, p < 0.001) EBV-seropositive patients. After critical review, MS remained a plausible diagnosis in only 4 of 14 EBV-seronegative/MOG antibody-negative patients. In children with an MS-like presentation, EBV seronegativity should alert clinicians to consider diagnoses other than MS, especially MOG-antibody disease. ANN NEUROL 2021;89:1234-1239.
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http://dx.doi.org/10.1002/ana.26062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244760PMC
June 2021

Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management.

J Neurol Neurosurg Psychiatry 2021 Jul 1;92(7):757-768. Epub 2021 Mar 1.

Neurology, Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.
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http://dx.doi.org/10.1136/jnnp-2020-325300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223680PMC
July 2021

Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management.

J Neurol Neurosurg Psychiatry 2021 Mar 1. Epub 2021 Mar 1.

Neurology, Erasmus Medical Center, Rotterdam, Zuid-Holland, Netherlands.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Most responders opted to cancer screening for 4 years in patients with neuronal surface antibodies (49%) or limbic encephalitis (46%) as opposed to non-limbic seronegative autoimmune encephalitis (36%). Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.
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http://dx.doi.org/10.1136/jnnp-2020-325302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292591PMC
March 2021

Clinical spectrum of high-titre GAD65 antibodies.

J Neurol Neurosurg Psychiatry 2021 Feb 9. Epub 2021 Feb 9.

Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA

Objective: To determine clinical manifestations, immunotherapy responsiveness and outcomes of glutamic acid decarboxylase-65 (GAD65) neurological autoimmunity.

Methods: We identified 323 Mayo Clinic patients with high-titre (>20 nmol/L in serum) GAD65 antibodies out of 380 514 submitted anti-GAD65 samples (2003-2018). Patients classified as having GAD65 neurological autoimmunity after chart review were analysed to determine disease manifestations, immunotherapy responsiveness and predictors of poor outcome (modified Rankin score >2).

Results: On review, 108 patients were classified as not having GAD65 neurological autoimmunity and 3 patients had no more likely alternative diagnoses but atypical presentations (hyperkinetic movement disorders). Of remaining 212 patients with GAD65 neurological autoimmunity, median age at symptom onset was 46 years (range: 5-83 years); 163/212 (77%) were female. Stiff-person spectrum disorders (SPSD) (N=71), cerebellar ataxia (N=55), epilepsy (N=35) and limbic encephalitis (N=7) could occur either in isolation or as part of an overlap syndrome (N=44), and were designated core manifestations. Cognitive impairment (N=38), myelopathy (N=23) and brainstem dysfunction (N=22) were only reported as co-occurring phenomena, and were designated secondary manifestations. Sustained response to immunotherapy ranged from 5/20 (25%) in epilepsy to 32/44 (73%) in SPSD (p=0.002). Complete immunotherapy response occurred in 2/142 (1%). Cerebellar ataxia and serum GAD65 antibody titre >500 nmol/L predicted poor outcome.

Interpretation: High-titre GAD65 antibodies were suggestive of, but not pathognomonic for GAD65 neurological autoimmunity, which has discrete core and secondary manifestations. SPSD was most likely to respond to immunotherapy, while epilepsy was least immunotherapy responsive. Complete immunotherapy response was rare. Serum GAD65 antibody titre >500 nmol/L and cerebellar ataxia predicted poor outcome.
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http://dx.doi.org/10.1136/jnnp-2020-325275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142435PMC
February 2021

Myelitis and Other Autoimmune Myelopathies.

Continuum (Minneap Minn) 2021 02;27(1):62-92

Purpose Of Review: This article provides an update on the clinical diagnosis and management of immune-mediated myelopathies, including the relevance of imaging, ancillary testing with an emphasis on autoantibody biomarkers, recognition of myelitis mimics, and therapeutic approach.

Recent Findings: The imaging characterization of immune-mediated myelopathies and the discovery of neural autoantibodies have been crucial in improving our ability to accurately diagnose myelitis. The identification of autoantibodies directed against specific central nervous system targets has led to major improvements in our understanding of the mechanisms underlying inflammation in myelitis. It has also allowed distinction of these myelopathy etiologies from noninflammatory etiologies of myelopathy and from multiple sclerosis and provided insight into their risk of recurrence, treatment response, and long-term clinical outcomes. Prompt recognition and appropriate testing in the setting of acute and subacute myelopathies is critical as timely administration of immunotherapy can help improve symptoms and prevent permanent neurologic disability. A patient should not be classified as having "idiopathic transverse myelitis" without a comprehensive evaluation for a more specific etiology. Achieving the correct diagnosis and learning to recognize noninflammatory myelitis mimics is crucial as they have therapeutic and prognostic implications.

Summary: Identifying the clinical and radiographic features of immune-mediated myelitis and recognizing mimics and pitfalls will help clinicians treat confirmed autoimmune myelitis appropriately.
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http://dx.doi.org/10.1212/CON.0000000000000900DOI Listing
February 2021

Spinal cord transient ischemic attack: Insights from a series of spontaneous spinal cord infarction.

Neurol Clin Pract 2020 Dec;10(6):480-483

Department of Neurology (SWE), Emory University, Atlanta, GA; and Department of Neurology (AAR, EPF, NLZ), Mayo Clinic, Rochester, MN.

Objective: To define the prevalence and characteristics of spinal cord transient ischemic attack (sTIA) in a large retrospective series of patients who met diagnostic criteria for spontaneous spinal cord infarction (SCI).

Methods: An institution-based search tool was used to identify patients evaluated at the Mayo Clinic in Rochester, MN, from 1997 to 2017 with spontaneous SCI (n = 133). Cases were subsequently reviewed for transient myelopathic symptoms preceding infarction that were suspected ischemic in nature. We performed a descriptive analysis of patients with sTIA before SCI.

Results: Of 133 patients with a diagnosis of spontaneous SCI, we identified 4 patients (3%) who experienced sTIA before SCI. The median age at presentation was 61.5 years (range 46-75 years), 2 (50%) were women, and 3 (75%) had traditional vascular risk factors. Localization was cervical cord in 2 cases (50%) and thoracic cord in 2 cases (50%); all patients developed SCI in the same distribution as their preceding sTIA symptoms. All patients experienced recurrent sTIA before SCI. Symptoms ranged from seconds to a few minutes before returning to baseline. No patients had pain as a feature of sTIA.

Conclusions: sTIAs are possible but rare in patients who subsequently have a SCI. Clinical features are similar to those of SCI, with rapid onset of severe myelopathic deficits, followed by prompt resolution. Vascular risk factors are common in these patients. Thus, recognition of a sTIA may represent a valuable opportunity for vascular risk factor modification and stroke prevention. However, given the rarity, physicians should explore other possible explanations when sTIA is considered.
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http://dx.doi.org/10.1212/CPJ.0000000000000778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837427PMC
December 2020

Serum Neurofilament to Magnetic Resonance Imaging Lesion Area Ratio Differentiates Spinal Cord Infarction From Acute Myelitis.

Stroke 2021 Jan 11;52(2):645-654. Epub 2021 Jan 11.

Departments of Neurology (E.S., A.M., S.J.P., E.P.F., A.A.R., D.M.N., N.L.Z.), Mayo Clinic, Rochester.

Background And Purpose: The diagnosis of spontaneous spinal cord infarction (SCI) is limited by the lack of diagnostic biomarkers and MRI features that often overlap with those of other myelopathies, especially acute myelitis. We investigated whether the ratio between serum neurofilament light chain levels and MRI T2-lesion area (neurofilament light chain/area ratio-NAR) differentiates SCI from acute myelitis of similar severity.

Methods: We retrospectively identified Mayo Clinic patients (January 1, 2000-December 31, 2019) with (1) SCI, (2) AQP4 (aquaporin 4)-IgG or MOG (myelin oligodendrocyte glycoprotein)-IgG-associated myelitis at disease clinical presentation, or (3) idiopathic transverse myelitis from a previously identified population-based cohort of patients seronegative for AQP4-IgG and MOG-IgG. Serum neurofilament light chain levels (pg/mL) were assessed at the Verona University (SIMOA, Quanterix) in a blinded fashion on available stored samples obtained ≤3 months from myelopathy presentation. For each patient, the largest spinal cord lesion area (mm) was manually outlined by 2 independent raters on sagittal T2-weighted MRI images, and the mean value was used to determine NAR (pg/[mL·mm]).

Results: Forty-eight patients were included SCI, 20 (definite, 11; probable, 6; possible, 3); acute myelitis, 28 (AQP4-IgG-associated, 17; MOG-IgG-associated, 5; idiopathic transverse myelitis, 6). The median expanded disability status scale score (range) at myelopathy nadir were 7.75 (2-8.5) and 5.5 (2-8), respectively. Serum neurofilament light chain levels (median [range] pg/mL) in patients with SCI (188 [14.3-2793.4]) were significantly higher compared with patients with AQP4-IgG-associated myelitis (37 [0.8-6942.9]), MOG-IgG-associated myelitis (45.8 [4-283.8]), and idiopathic transverse myelitis (15.6 [0.9-217.8]); =0.01. NAR showed the highest accuracy for identification of SCI versus acute myelitis with values ≥0.35 pg/(mL·mm) yielding 86% specificity and 95% sensitivity (area under the curve=0.93). The positive and negative likelihood ratios were 6.67 and 0.06, respectively. NAR remained independently associated with SCI after adjusting for age, gender, immunotherapy before sampling, and days from myelopathy symptoms onset to sampling (=0.0007).

Conclusions: NAR is a novel and promising clinical biomarker for differentiation of SCI from acute myelitis.
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http://dx.doi.org/10.1161/STROKEAHA.120.031482DOI Listing
January 2021

Teaching Video NeuroImages: Paroxysmal Dysarthria-Ataxia in Multiple Sclerosis.

Neurology 2021 04 5;96(17):e2245-e2246. Epub 2021 Jan 5.

From the Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN.

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http://dx.doi.org/10.1212/WNL.0000000000011498DOI Listing
April 2021

Brainstem and cerebellar involvement in MOG-IgG-associated disorder versus aquaporin-4-IgG and MS.

J Neurol Neurosurg Psychiatry 2020 Dec 28. Epub 2020 Dec 28.

Neurology, Mayo Clinic, Rochester, Minnesota, USA

Objective: To determine the frequency and characteristics of brainstem or cerebellar involvement in myelin-oligodendrocyte-glycoprotein-antibody-associated-disorder (MOGAD) versus aquaporin-4-IgG-seropositive-neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD) and multiple sclerosis (MS).

Methods: In this observational study, we retrospectively identified 185 Mayo Clinic MOGAD patients with: (1) characteristic MOGAD phenotype, (2) MOG-IgG seropositivity by live cell-based assay and (3) MRI lesion(s) of brainstem, cerebellum or both. We compared the symptomatic attacks to AQP4-IgG-NMOSD (n=30) and MS (n=30).

Results: Brainstem or cerebellar involvement occurred in 62/185 (34%) MOGAD patients of which 39/62 (63%) were symptomatic. Ataxia (45%) and diplopia (26%) were common manifestations. The median age in years (range) in MOGAD of 24 (2-65) was younger than MS at 36 (16-65; p=0.046) and AQP4-IgG-NMOSD at 45 (6-72; p=0.006). Isolated attacks involving the brainstem, cerebellum or both were less frequent in MOGAD (9/39 (23%)) than MS (22/30 (73%); p<0.001) but not significantly different from AQP4-IgG-NMOSD (14/30 (47%); p=0.07). Diffuse middle cerebellar peduncle MRI-lesions favoured MOGAD (17/37 (46%)) over MS (3/30 (10%); p=0.001) and AQP4-IgG-NMOSD (3/30 (10%); p=0.001). Diffuse medulla, pons or midbrain MRI lesions occasionally occurred in MOGAD and AQP4-IgG-NMOSD but never in MS. Cerebrospinal fluid (CSF) oligoclonal bands were rare in MOGAD (5/30 (17%)) and AQP4-IgG-NMOSD (2/22 (9%); p=0.68) but common in MS (18/22 (82%); p<0.001). Disability at nadir or recovery did not differ between the groups.

Conclusion: Involvement of the brainstem, cerebellum or both is common in MOGAD but usually occurs as a component of a multifocal central nervous system attack rather than in isolation. We identified clinical, CSF and MRI attributes that can help discriminate MOGAD from AQP4-IgG-NMOSD and MS.
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http://dx.doi.org/10.1136/jnnp-2020-325121DOI Listing
December 2020

A multi-center case series of sarcoid optic neuropathy.

J Neurol Sci 2021 01 19;420:117282. Epub 2020 Dec 19.

Mayo Clinic, Department of Neurology, 200 1st St. SW, Rochester, MN, USA. Electronic address:

Objective: The diagnosis of sarcoid optic neuropathy is time-sensitive, as delayed treatment risks irreversible vision loss. We sought to analyze its characteristics and outcomes.

Methods: We performed a multi-center retrospective study of sarcoid optic neuropathy among 5 USA medical centers. Inclusion criteria were: 1) clinical optic neuropathy; 2) optic nerve/sheath enhancement on neuroimaging; 3) pathological confirmation of systemic or nervous system sarcoidosis.

Results: Fifty-one patients were included. The median onset age of sarcoid optic neuropathy was 50 years (range, 17-70 years) and 71% were female. The median visual acuity at nadir in the most affected eye was 20/80 (range, 20/20 to no-light-perception). Thirty-four of 50 (68%) patients had radiologic evidence of other nervous system involvement and 20 (39%) patients had symptoms/signs of other cranial nerve dysfunction. Cerebrospinal fluid analysis revealed an elevated white blood cell count in 22 of 31 (71%) patients (median: 14/μL; range: 1-643/μL). Pathologic confirmation of sarcoidosis was by biopsy of systemic/pulmonary site, 34 (67%); optic nerve/sheath, 9 (18%); or other nervous system region, 8 (16%). Forty patients improved with treatment (78%), 98% receiving corticosteroids and 65% receiving steroid-sparing immunosuppressants, yet 11/46 patients (24%) had a visual acuity of 20/200 or worse at last follow-up.

Conclusions: Sarcoid optic neuropathy frequently occurs with other clinical and radiologic abnormalities caused by neurosarcoidosis and diagnostic confirmation occasionally requires optic nerve/sheath biopsy. Improvement with treatment is common but most patients have some residual visual disability. Improved recognition and a more expeditious diagnosis and treatment may spare patients from permanent vision loss.
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http://dx.doi.org/10.1016/j.jns.2020.117282DOI Listing
January 2021

Variability of cerebrospinal fluid findings by attack phenotype in myelin oligodendrocyte glycoprotein-IgG-associated disorder.

Mult Scler Relat Disord 2021 Jan 23;47:102638. Epub 2020 Nov 23.

Department of Neurology and Ophthalmology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: The variability in cerebrospinal fluid (CSF) findings of myelin oligodendrocyte glycoprotein-IgG-associated disorder (MOGAD) is not fully elucidated.

Objective And Methods: We retrospectively analyzed 203 attack-associated CSFs from Mayo Clinic patients (2000-2019) with MOGAD.

Results: White-blood-cell (>5/mm) elevation was less with clinically isolated optic neuritis (23%), compared to myelitis, brain/brainstem attacks, or combinations thereof (>70%), p<0.0001. CSF pleocytosis in optic neuritis was more common in patients with coexisting asymptomatic brain and/or spine MRI T2-lesions (53%) than in those without (16%), p=0.005. Abnormal CSF oligoclonal bands ranged from 1% (optic neuritis) to 18% (brain/brainstem attacks). CSF pleocytosis was less common after immunotherapy.

Conclusions: CSF findings in MOGAD vary by attack phenotype and preceding treatment.
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http://dx.doi.org/10.1016/j.msard.2020.102638DOI Listing
January 2021

Paraneoplastic Disorders of the Nervous System.

Authors:
Eoin P Flanagan

Continuum (Minneap Minn) 2020 12;26(6):1602-1628

Purpose Of Review: This article reviews paraneoplastic neurologic disorders and includes an overview of the diagnostic approach, the role of autoantibody testing, the pathophysiology of these disorders, and treatment approaches. This article also provides an overview of the emerging clinical scenarios in which paraneoplastic and autoimmune neurologic disorders may occur.

Recent Findings: The number of autoantibodies associated with paraneoplastic neurologic disorders has rapidly expanded over the past 2 decades. These discoveries have improved our ability to diagnose patients with these disorders and have provided insight into their pathogenesis. It is now recognized that these antibodies can be broadly divided into two major categories based on the location of the target antigen: intracellular and cell surface/synaptic. Antibodies to intracellular antigens are almost always accompanied by cancer, respond less well to immunotherapy, and have an unfavorable outcome. In contrast, antibodies to cell surface or synaptic targets are less often accompanied by cancer, generally respond well to immunotherapy, and have a good prognosis. Paraneoplastic and autoimmune neurologic disorders are now being recognized in novel settings, including their occurrence as an immune-related adverse effect of immune checkpoint inhibitor treatment for cancer.

Summary: This article discusses when to suspect a paraneoplastic neurologic syndrome, the diagnostic utility and pitfalls of neural autoantibody testing, how to best detect the underlying tumor, and the treatment approach that involves combinations of antineoplastic treatments, immunosuppressants, and supportive/symptomatic treatments.
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http://dx.doi.org/10.1212/CON.0000000000000941DOI Listing
December 2020

Neural Antibody Testing in Patients with Suspected Autoimmune Encephalitis.

Clin Chem 2020 Dec;66(12):1496-1509

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Background: Autoimmunity is an increasingly recognized cause of encephalitis with a similar prevalence to that of infectious etiologies. Over the past decade there has been a rapidly expanding list of antibody biomarker discoveries that have aided in the identification and characterization of autoimmune encephalitis. As the number of antibody biomarkers transitioning from the research setting into clinical laboratories has accelerated, so has the demand and complexity of panel-based testing. Clinical laboratories are increasingly involved in discussions related to test utilization and providing guidance on which testing methodologies provide the best clinical performance.

Content: To ensure optimal clinical sensitivity and specificity, comprehensive panel-based reflexive testing based on the predominant neurological phenotypic presentation (e.g., encephalopathy) is ideal in the workup of cases of suspected autoimmune neurological disease. Predictive scores based on the clinical workup can aid in deciding when to order a test. Testing of both CSF and serum is recommended with few exceptions. Appropriate test ordering and interpretation requires an understanding of both testing methodologies and performance of antibody testing in different specimen types.

Summary: This review discusses important considerations in the design and selection of neural antibody testing methodologies and panels. Increased collaboration between pathologists, laboratorians, and neurologists will lead to improved utilization of complex autoimmune neurology antibody testing panels.
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http://dx.doi.org/10.1093/clinchem/hvaa254DOI Listing
December 2020

Holmes Tremor With Perirolandic Demyelinating Lesions: A Distinct Clinicoradiographic Syndrome.

Neurology 2021 02 20;96(5):231-232. Epub 2020 Nov 20.

From the Departments of Neurology (A.B., H.D.S., J.H.B., A.H., B.L.C., E.P.F.) and Laboratory Medicine and Pathology (E.P.F.), Mayo Clinic, Rochester, MN; and Department of Clinical Neurological Sciences (A.B.), London Health Sciences Centre, Western University, Canada.

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http://dx.doi.org/10.1212/WNL.0000000000011235DOI Listing
February 2021

Paraneoplastic Myeloneuropathies: Clinical, Oncologic, and Serologic Accompaniments.

Neurology 2021 01 18;96(4):e632-e639. Epub 2020 Nov 18.

From the Departments of Neurology (S.S., R.V.D.C., N.K., A.M., E.P.F., C.K., S.J.P., D.D.) and Laboratory Medicine and Pathology (A.M., E.P.F., C.K., S.J.P., D.D.), Mayo Clinic College of Medicine, Rochester, MN.

Objective: To test the hypothesis that myeloneuropathy is a presenting phenotype of paraneoplastic neurologic syndromes we retrospectively reviewed clinical, radiologic, and serologic features of 32 patients with concomitant paraneoplastic spinal cord and peripheral nervous system involvement.

Methods: Observational study investigating patients with myeloneuropathy and underlying cancer or onconeural antibody seropositivity.

Results: Among 32 patients with paraneoplastic myeloneuropathy, 20 (63%) were women with median age 61 years (range 27-84 years). Twenty-six patients (81%) had classified onconeural antibodies (amphiphysin, n = 8; antineuronal nuclear antibody [ANNA] type 1 [anti-Hu], n = 5; collapsin response mediator protein 5 [CRMP5] [anti-CV2], n = 6; Purkinje cell cytoplasmic antibody type 1 [PCA1] [anti-Yo], n = 1; Purkinje cell cytoplasmic antibody type 2 [PCA2], n = 2; kelch-like protein 11 [KLHL11], n = 1; and combinations thereof: ANNA1/CRMP5, n = 1; ANNA1/amphiphysin, n = 1; ANNA3/CRMP5, n = 1). Cancer was confirmed in 25 cases (onconeural antibodies, n = 19; unclassified antibodies, n = 3; no antibodies, n = 3). Paraneoplastic myeloneuropathies had asymmetric paresthesias (84%), neuropathic pain (78%), subacute onset (72%), sensory ataxia (69%), bladder dysfunction (69%), and unintentional weight loss >15 pounds (63%). Neurologic examination demonstrated concomitant distal or asymmetric hyporeflexia and hyperreflexia (81%), impaired vibration and proprioception (69%), Babinski response (68%), and asymmetric weakness (66%). MRI showed longitudinally extensive (45%), tract-specific spinal cord T2 hyperintensities (39%) and lumbar nerve root enhancement (38%). Ten of 28 (36%) were unable to ambulate independently at last follow-up (median 24 months, range 5-133 months). Combined oncologic and immunologic therapy had more favorable modified Rankin Scale scores at post-treatment follow-up compared to those receiving either oncologic or immunologic therapy alone (2 [range 1-4] vs 4 [range 2-6], < 0.001).

Conclusions: Paraneoplastic etiologies should be considered in the evaluation of subacute myeloneuropathies. Recognition of key characteristics of paraneoplastic myeloneuropathy may facilitate early tumor diagnosis and initiation of immunosuppressive treatment.
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http://dx.doi.org/10.1212/WNL.0000000000011218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905784PMC
January 2021
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