Search

Purpose of Review: To provide an overview of mimickers of large vessel vasculitis (LVV), by the main presenting manifestation, i.e., systemic, vascular, and cranial manifestations. Recent Findings: The main differential diagnoses in patients with giant cell arteritis (GCA) and Takayasu arteritis (TAK) presenting with systemic manifestations (i.e., fever, anorexia, weight loss, night sweats, arthralgia/myalgia, and/or increased inflammatory indexes) are neoplastic, infectious, or other inflammatory conditions. In patients with vascular manifestations (such as peripheral ischemia, vascular stenoses, or aneurysms), atherosclerosis and non-inflammatory vascular diseases should be excluded. In those presenting with predominant cranial symptoms (i.e., temporal headache, jaw claudication, scalp tenderness, transient or permanent vision loss), other causes of headache, cerebrovascular accidents, optic neuropathy, and neuromuscular syndromes need to be considered. Summary: The diagnosis of LVV maybe challenging, especially when patients present with atypical or incomplete clinical forms. In these cases, a multidisciplinary approach is strongly recommended. [ABSTRACT FROM AUTHOR]

• We assessed the frequency of LETM from a population-based MS cohort. • We found no cases of LETM among 92 MS myelitis attacks from 67 patients. • In two patients (2%) the coalescence of multiple short lesions mimicked LETM. Determining the frequency of longitudinally-extensive transverse myelitis (LETM: T2-lesion ≥3 vertebral segments) in multiple sclerosis (MS) is essential to assess its utility in differentiating from aquaporin-4-IgG (AQP4-IgG) positive neuromyelitis optica spectrum disorder (NMOSD) and myelin-oligodendrocyte-glycoprotein-IgG (MOG-IgG) myelitis. We sought to determine the frequency of LETM in MS during a myelitis attack. We identified Olmsted County (MN, USA) residents on 12/31/2011 with inflammatory demyelinating disease. Inclusion criteria were: 1) Clinical myelitis episode accompanied by a new spinal magnetic resonance imaging (MRI) lesion (≤6 weeks from onset); 2) MS diagnosis by 2010 McDonald criteria; 3) Seronegative for AQP4-IgG and MOG-IgG. MRI characteristics were determined. Sixty-seven patients (median age at myelitis: 41 years [range, 16–65]; 76% females) with 92 myelitis attacks accompanied by a new MRI spinal cord lesion were identified. The frequency of LETM was 0%. The median T2-hyperintense lesion length in vertebral segments was 1.0 (range, 0.5–2.5) and 82/92 (89%) were peripheral in location on axial sequences; 58% had associated gadolinium enhancement. Two patients (2% of attacks) had multiple short lesions resembling LETM on sagittal images but axial sequences confirmed multiple non-contiguous short lesions. LETM is rare in adult MS myelitis and its presence should prompt evaluation for AQP4-IgG, MOG-IgG or other etiologies. Careful scrutiny of axial images is important as coalescence of multiple short lesions may lead to the artifactual appearance of an LETM. [ABSTRACT FROM AUTHOR]

Purpose of review: To describe the clinical, laboratory, and MRI features that characterize cognitive decline in the setting of central nervous system (CNS) autoimmunity, and provide an overview of current treatment modalities. Recent findings: The field of autoimmune neurology is rapidly expanding due to the increasing number of newly discovered autoantibodies directed against specific CNS targets. The clinical syndromes associated with these autoantibodies are heterogeneous but frequently share common, recognizable clinical, and MRI characteristics. While the detection of certain autoantibodies strongly suggest the presence of an underlying malignancy (onconeural autoantibodies), a large proportion of cases remain idiopathic. Cognitive decline and encephalopathy are common manifestations of CNS autoimmunity, and can mimic neurodegenerative disorders. Recent findings suggest that the frequency of autoimmune encephalitis in the population is higher than previously thought, and potentially rivals that of infectious encephalitis. Moreover, emerging clinical scenarios that may predispose to CNS autoimmunity are increasingly been recognized. These include autoimmune dementia/encephalitis post-herpes simplex virus encephalitis, post-transplant and in association with immune checkpoint inhibitor treatment of cancer. Early recognition of autoimmune cognitive impairment is important given the potential for reversibility and disability prevention with appropriate treatment. Summary: Autoimmune cognitive impairment is treatable and may arise in a number of different clinical settings, with important treatment implications. Several clinical and para-clinical clues may help to differentiate these disorders from dementia of other etiologies. [ABSTRACT FROM AUTHOR]

Myasthenia gravis is an antibody-mediated autoimmune neurological disorder characterized by impaired neuromuscular junction transmission, resulting in muscle weakness. Recently, the involvement of Human Endogenous Retroviruses (HERVs) in the pathophysiology of different immune-mediated and neurodegenerative diseases, such as multiple sclerosis, has been demonstrated. We aimed to investigate potential immune system involvement related to humoral responses targeting specific epitopes of HERV-K and HERV-W envelope proteins in myasthenia gravis. Myasthenia gravis patients were recruited in the Neurology Unit, while healthy controls were selected from the Blood Transfusion Center, both affiliated with AOU Sassari. Highly immunogenic antigens of HERV-K and HERV-W envelope proteins were identified using the Immune Epitope Database (IEDB) online tool. These epitopes were utilized in enzyme-linked immunosorbent assays (ELISA) to detect autoantibodies in serum directed against these sequences. The study involved 39 Healthy Donors and 47 MG patients, further categorized into subgroups based on the presence of autoantibodies: MG-AchR Ab+ (n = 17), MG-MuSK Ab+ (n = 7), double seronegative patients (MG-DSN, n = 18), MG-LRP4 Ab + (n = 4), and one patient with no antibodies data (n = 1). Our findings revealed high levels of autoantibodies in myasthenia gravis patients directed against the HERV-K-env-su(19–37), HERV-K-env-su(109–126), HERV-K-env-su(164–186), HERV-W-env(93–108), HERV-W-env(129–14), and HERV-W-env(248–262) epitopes. Notably, these results remained highly significant even when patients were subdivided into MG-AchR Ab+ and MG-DSN subgroups. Correlation analysis further revealed significant positive associations between the antibody levels against HERV-K and HERV-W families in patients, suggesting a synergistic action of the two HERVs in the pathology context since this correlation is absent in the control group. This study marks the first identification of a specific humoral response directed against defined epitopes of HERV-K and HERV-W envelope proteins in myasthenia gravis patients. These findings lay the foundation for future investigations aimed at elucidating the molecular mechanisms driving this immune response. The detection of these autoantibodies suggests the potential for novel biomarkers, especially within the MG-DSN patient subgroup, addressing the need for new biomarkers in this population. [ABSTRACT FROM AUTHOR]

Background: Differentiating neuromyelitis optica spectrum disorder (NMOSD) from its mimics is crucial to avoid misdiagnosis, especially in the absence of aquaporin‐4‐IgG. While multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein‐IgG associated disease (MOGAD) represent major and well‐defined differential diagnoses, non‐demyelinating NMOSD mimics remain poorly characterized. Methods: We conducted a systematic review on PubMed/MEDLINE to identify reports of patients with non‐demyelinating disorders that mimicked or were misdiagnosed as NMOSD. Three novel cases seen at the authors' institutions were also included. The characteristics of NMOSD mimics were analyzed and red flags associated with misdiagnosis identified. Results: A total of 68 patients were included; 35 (52%) were female. Median age at symptoms onset was 44 (range, 1–78) years. Fifty‐six (82%) patients did not fulfil the 2015 NMOSD diagnostic criteria. The clinical syndromes misinterpreted for NMOSD were myelopathy (41%), myelopathy + optic neuropathy (41%), optic neuropathy (6%), or other (12%). Alternative etiologies included genetic/metabolic disorders, neoplasms, infections, vascular disorders, spondylosis, and other immune‐mediated disorders. Common red flags associated with misdiagnosis were lack of cerebrospinal fluid (CSF) pleocytosis (57%), lack of response to immunotherapy (55%), progressive disease course (54%), and lack of magnetic resonance imaging gadolinium enhancement (31%). Aquaporin‐4‐IgG positivity was detected in five patients by enzyme‐linked immunosorbent assay (n = 2), cell‐based assay (n = 2: serum, 1; CSF, 1), and non‐specified assay (n = 1). Conclusions: The spectrum of NMOSD mimics is broad. Misdiagnosis frequently results from incorrect application of diagnostic criteria, in patients with multiple identifiable red flags. False aquaporin‐4‐IgG positivity, generally from nonspecific testing assays, may rarely contribute to misdiagnosis. [ABSTRACT FROM AUTHOR]

Background: Magnetic resonance imaging (MRI) T2-lesions resolve more often in myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) than aquaporin-4 IgG-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and multiple sclerosis (MS) in adults but few studies analyzed children. Objective: The main objective of this study is to investigate MRI T2-lesion evolution in pediatric MOGAD, AQP4 + NMOSD, and MS. Methods: Inclusion criteria were as follows: (1) first clinical attack; (2) abnormal MRI (⩽6 weeks); (3) follow-up MRI beyond 6 months without relapses in that region; and (4) age < 18 years. An index T2-lesion (symptomatic/largest) was identified, and T2-lesion resolution or persistence on follow-up MRI was determined. Results: We included 56 patients (MOGAD, 21; AQP4 + NMOSD, 8; MS, 27) with 69 attacks. Index T2-lesion resolution was more frequent in MOGAD (brain 9 of 15 [60%]; spine 8 of 12 [67%]) than AQP4 + NMOSD (brain 1 of 4 [25%]; spine 0 of 7 [0%]) and MS (brain 0 of 18 [0%]; spine 1 of 13 [8%]), p < 0.01. Resolution of all T2-lesions occurred more often in MOGAD (brain 6 of 15 [40%]; spine 7 of 12 [58%]) than AQP4 + NMOSD (brain 1 of 4 [25%]; spine 0 of 7 [0%]), and MS (brain 0 of 18 [0%]; spine 1 of 13 [8%]), p < 0.01. Reductions in median index T2-lesion area were greater in MOGAD (brain, 305 mm; spine, 23 mm) than MS (brain, 42 mm [ p <0.001]; spine, 10 mm [ p <0.001]) without differing from AQP4 + NMOSD (brain, 133 mm [ p =0.42]; spine, 19.5 mm [ p =0.69]). Conclusion: In children, MRI T2-lesions resolved more often in MOGAD than AQP4 + NMOSD and MS which is similar to adults suggesting these differences are related to pathogenesis rather than age. [ABSTRACT FROM AUTHOR]

In recent years, the use of magnetic resonance imaging (MRI) for the diagnostic work-up of multiple sclerosis (MS) has evolved considerably. The 2017 McDonald criteria show high sensitivity and accuracy in predicting a second clinical attack in patients with a typical clinically isolated syndrome and allow an earlier diagnosis of MS. They have been validated, are evidence-based, simplify the clinical use of MRI criteria and improve MS patients' management. However, to limit the risk of misdiagnosis, they should be applied by expert clinicians only after the careful exclusion of alternative diagnoses. Recently, new MRI markers have been proposed to improve diagnostic specificity for MS and reduce the risk of misdiagnosis. The central vein sign and chronic active lesions (i.e., paramagnetic rim lesions) may increase the specificity of MS diagnostic criteria, but further effort is necessary to validate and standardize their assessment before implementing them in the clinical setting. The feasibility of subpial demyelination assessment and the clinical relevance of leptomeningeal enhancement evaluation in the diagnostic work-up of MS appear more limited. Artificial intelligence tools may capture MRI attributes that are beyond the human perception, and, in the future, artificial intelligence may complement human assessment to further ameliorate the diagnostic work-up and patients' classification. However, guidelines that ensure reliability, interpretability, and validity of findings obtained from artificial intelligence approaches are still needed to implement them in the clinical scenario. This review provides a summary of the most recent updates regarding the application of MRI for the diagnosis of MS. [ABSTRACT FROM AUTHOR]

Rapidly reversible weakness with neck flexion (McArdle sign) is common in patients with multiple sclerosis (MS). The pathophysiology is unknown.To evaluate changes in central motor conduction time (CMCT) in patients with and without McArdle sign.We measured McArdle sign with a torque cell and CMCT with neck flexed and extended in patients with MS, other causes of myelopathy, and healthy controls.CMCT was prolonged with neck flexion disproportionately in those with MS-associated myelopathy (MSAM) with prominent McArdle sign compared to MS patients with lesser degrees of McArdle sign, and to controls.McArdle sign may result from stretch-induced slowing of conduction due to demyelination. [ABSTRACT FROM AUTHOR]

Circulating and cerebrospinal fluid (CSF) neurofilament light chain (NfL) levels represent a reliable indicator of disease activity and axonal damage in different neuroinflammatory conditions. Recently, high CSF NfL levels have been detected in active autoimmune encephalitis, as opposed to significant lower levels after clinical improvement. The aim of the present study was to evaluate serum and CSF NfL concentration in patients with autoimmune encephalitis and to analyse the association between NfL levels and clinical, MRI, and CSF data. We retrospectively included 25 patients with neurological syndromes associated with autoantibodies to neuronal cell surface antigens and we collected clinical, MRI, CSF, and follow-up data. Using an ultrasensitive method (Simoa, Quanterix), we measured NfL levels in serum and CSF samples of all patients and in 25 sera of healthy controls. Serum NfL levels were higher in all cases, including 20 patients with inflammatory MRI/CSF features and 5 non-inflammatory cases (median 16.9 pg/ml, range 4.5–90) than in controls (median 6.9 pg/ml, range 2.7–12.8; p < 0.001). A correlation between serum and CSF NfL levels was found (r = 0.461, p = 0.023), whereas no significant association was observed between NfL levels and clinical, MRI/CSF inflammatory burden, and antibody type. In the 13 available follow-up samples, correlation between disease activity and NfL values was also observed. In conclusion, NfL levels are significantly increased in the serum of patients with antibody-mediated encephalitis, independently of the MRI/CSF inflammatory profile. These findings support the presence of ongoing axonal damage and suggest the co-occurrence of different mechanisms for neuronal/axonal involvement in antibody-associated CNS syndromes. [ABSTRACT FROM AUTHOR]

To assess marked central canal T2-hyperintensity in patients with myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) myelitis compared to myelitis patients with aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and multiple sclerosis (MS). Two blinded raters evaluated spinal cord magnetic resonance imaging (MRIs) of myelitis patients with MOGAD (n = 63), AQP4 + NMOSD (n = 37), and MS (n = 26), assessing for marked central canal T2-hyperintensity and its evolution. If there were conflicting results, a third neurologist assessed the MRI. Marked central canal T2-hyperintensity was more frequent in patients with MOGAD (18/63[29%]) than MS (1/26[4%]; p = 0.01) myelitis but did not differ from AQP4 + NMOSD (13/37[35%]; p = 0.49). Marked central canal T2-hyperintensity had completely resolved on follow-up axial MRI for most MOGAD (12/14[86%]) and AQP4 + NMOSD (10/10[100%]; p = 0.49) patients. Marked central canal T2-hyperintensity is a common transient radiologic accompaniment of MOGAD and AQP4 + NMOSD myelitis, but not MS myelitis. • Marked central canal T2-hyperintensity is common in MOGAD and AQP4 + NMOSD myelitis. • Marked central canal T2-hyperintensity is rare in MS myelitis. • Marked central canal T2-hyperintensity was transient in most patients. • This radiologic finding in myelitis should prompt AQP4-IgG and MOG-IgG testing. [ABSTRACT FROM AUTHOR]

The diagnosis of autoimmune encephalitis (AE) requires reasonable exclusion of other conditions. The aim of this study is to characterize mimickers and misdiagnoses of AE, thus we performed an independent PubMed search for mimickers of AEs or patients with alternative neurological disorders misdiagnosed as AE. Fifty-eight studies with 66 patients were included. Neoplastic (n = 17), infectious (n = 15), genetic (n = 13), neurodegenerative (n = 8), and other neurological (n = 8) or systemic autoimmune (n = 5) disorders were misdiagnosed as AE. The lack of fulfillment of diagnostic criteria for AE, atypical neuroimaging findings, non-inflammatory CSF findings, non-specific autoantibody specificities and partial response to immunotherapy were major confounding factors. • Autoimmune encephalitis (AE) is a diagnosis of exclusion. • The spectrum of misdiagnoses and mimics of AE includes different conditions. • Non-inflammatory CSF, atypical neuroimaging findings suggest alternative diagnoses. • Non-specific autoantibodies and response to immunotherapy are major confounders. • The application of AE diagnostic criteria is useful to avoid mimics/misdiagnoses. [ABSTRACT FROM AUTHOR]

Objective: This article reviews the clinical features, MRI characteristics, diagnosis, and treatment of aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The main differences between these disorders and multiple sclerosis (MS), the most common demyelinating disease of the central nervous system (CNS), are also highlighted., Latest Developments: The past 20 years have seen important advances in understanding rare demyelinating CNS disorders associated with AQP4 IgG and myelin oligodendrocyte glycoprotein (MOG) IgG. The rapidly expanding repertoire of immunosuppressive agents approved for the treatment of AQP4-NMOSD and emerging as potentially beneficial in MOGAD mandates prompt recognition of these diseases. Most of the recent literature has focused on the identification of clinical and MRI features that help distinguish these diseases from each other and MS, simultaneously highlighting major diagnostic pitfalls that may lead to misdiagnosis. An awareness of the limitations of currently available assays for AQP4 IgG and MOG IgG detection is fundamental for identifying rare false antibody positivity and avoiding inappropriate treatments. For this purpose, diagnostic criteria have been created to help the clinician interpret antibody testing results and recognize the clinical and MRI phenotypes associated with AQP4-NMOSD and MOGAD., Essential Points: An awareness of the specific clinical and MRI features associated with AQP4-NMOSD and MOGAD and the limitations of currently available antibody testing assays is crucial for a correct diagnosis and differentiation from MS. The growing availability of effective treatment options will lead to personalized therapies and improved outcomes., (Copyright © 2024 American Academy of Neurology.)

Background and Purpose: Progressive MS is typically heralded by a myelopathic pattern of asymmetric progressive motor weakness. Focal individual "critical" demyelinating spinal cord lesions anatomically associated with progressive motor impairment may be a compelling explanation for this clinical presentation as described in progressive solitary sclerosis (single CNS demyelinating lesion), progressive demyelination with highly restricted MR imaging lesion burden (2-5 total CNS demyelinating lesions; progressive paucisclerotic MS), and progressive, exclusively unilateral hemi- or monoparetic MS (>5 CNS demyelinating progressive unilateral hemi- or monoparetic MS [PUHMS] lesions). Critical demyelinating lesions appear strikingly similar across these cohorts, and we describe their specific spinal cord MR imaging characteristics., Materials and Methods: We performed a retrospective, observational MR imaging study comparing spinal cord critical demyelinating lesions anatomically associated with progressive motor impairment with any additional "noncritical" (not anatomically associated with progressive motor impairment) spinal cord demyelinating lesions. All spinal cord MR images (302 cervical and 91 thoracic) were reviewed by an experienced neuroradiologist with final radiologic assessment on the most recent MR imaging. Anatomic association with clinical progressive motor impairment was confirmed independently by MS subspecialists., Results: Ninety-one individuals (PUHMS, 37 [41%], progressive paucisclerosis 35 [38%], progressive solitary sclerosis 19 [21%]) with 91 critical and 98 noncritical spinal cord MR imaging demyelinating lesions were evaluated. MR imaging characteristics that favored critical spinal cord demyelinating lesions over noncritical lesions included moderate-to-severe, focal, lesion-associated spinal cord atrophy: 41/91 (45%) versus 0/98 (0%) (OR, 161.91; 9.43 to >999.9); lateral column axial location (OR, 10.43; 3.88-28.07); central region (OR, 3.23; 1.78-5.88); ventral column (OR, 2.98; 1.55-5.72); and larger lesion size of the axial width (OR, 2.01;1.49-2.72), transverse axial size (OR, 1.66; 1.36-2.01), or lesion area (OR, 1.14; 1.08-1.2). Multiple regression analysis revealed focal atrophy and lateral axial location as having the strongest association with critical demyelinating lesions., Conclusions: Focal, lesion-associated atrophy, lateral column axial location, and larger lesion size are spinal cord MR imaging characteristics of critical demyelinating lesions. The presence of critical demyelinating lesions should be sought as these features may be associated with the development of progressive motor impairment in MS., (© 2024 by American Journal of Neuroradiology.)

Purpose: The Italian Island of Sardinia (population, 1,578,146) is recognized for the high risk of multiple sclerosis (MS) but the epidemiological burden of other less common demyelinating diseases of the central nervous system (CNS), such as aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD), is unknown. In this study, we determined the incidence and prevalence of AQP4-IgG+NMOSD in Sardinia over a ten-year study period (2013-2022)., Methods: Patients with a diagnosis of AQP4-IgG+NMOSD (per 2015 IPND diagnostic criteria) were retrospectively identified using two sources: (1) Archives of the reference and only laboratory for AQP4-IgG testing in Sardinia; and (2) medical records of the four MS units in the island. Incidence (January 2013-December 2022) and prevalence (December 31, 2022) were calculated., Results: A total of 45 cases were included: incident, 31; prevalent, 41. The median age (range) at disease presentation was 51 (6-78) years; female/male ratio was 9:1. The crude (95 % CI) incidence and prevalence were 1.9 (1.3-2.7) per million and 2.6 (1.9-3.5) per 100,000, respectively. Prevalence increased from 2013 (1.1 per 100,000) to 2022 (2.6 per 100,000); p = 0.002. After age-standardization to the world, incidence and prevalence (95 % CI) decreased to 1.3 (0.7-2) per million and 1.8 (1.3-2.3) per 100,000, respectively. Coexisting immune-mediated disorders, mostly autoimmune thyroiditis, were reported in 50 % of patients., Conclusions: The epidemiology of AQP4-IgG+NMOSD in Sardinia is overall in line with other Caucasian populations. The high MS risk in the island seems disease-specific and not associated with an increased risk of other CNS demyelinating disorders, confirming different pathophysiology., Competing Interests: Declaration of competing interest Elia Sechi has received speaker honoraria and support for attending scientific meetings from Alexion. He serves as an editorial board member for BMC Neurology and Frontiers in Neurology. Dr. Sechi is a member of the medical advisory board of the MOG project. Stefania Leoni has received speaker honoraria and support for attending scientific meetings from Alexion, Sanofi and Merck. Giuseppe Fenu has received honoraria for consultancy or speaking from Novartis, Roche, Biogen, Merck, TEVA, and Bristol. Paolo Solla has received speaker honoraria from Bayer and Zambon. Eleonora Cocco has received honoraria for consultancy or speaking from Bayer Biogen, Novartis, Sanofi, Merck, TEVA, Roche, Bristol, Janssen, and Alexion. Jessica Frau serves on scientific advisory boards for Biogen and Genzyme, and has received honoraria as a speaker from Merck Serono, Genzyme, Biogen, Alexion, and Novartis. All other authors have no competing interests to declare that are relevant to the content of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction/aims: The global incidence and prevalence of myasthenia gravis (MG) range between 6-31/million and 10-37/100,000, respectively. Sardinia is a high-risk region for different immune-mediated disorders, but the epidemiology of MG remains unclear. We determined the epidemiology of MG with acetylcholine receptor (AChR)-immunoglobulin G (IgG) and muscle-specific tyrosine kinase (MuSK)-IgG in the district of Sassari (North-Western Sardinia; population, 325,288)., Methods: From the laboratory of the University Hospital of Sassari (reference for AChR/MuSK-IgG testing in Sardinia since 1998) and the main neurology units in Sardinia, we retrospectively identified MG patients with (1) AChR-IgG and/or MuSK-IgG positivity by radioimmunoprecipitation assay; and (2) residency in the district of Sassari. Incidence (January 2010-December 2019) and prevalence (December 31, 2019) were calculated., Results: A total of 202 patients were included (incident, 107; prevalent, 180). Antibody specificities were AChR (n = 187 [93%]) and MuSK (n = 15 [7%]). The crude MG incidence (95% confidence interval) was 32.6 (26.8-39.2)/million, while prevalence was 55.3 (47.7-63.9)/100,000. After age-standardization to the world population, incidence decreased to 18.4 (14.3-22.5)/million, while prevalence decreased to 31.6 (26.1-37.0)/100,000. Among incident cases, age strata (years) at MG onset were: <18 (2%), 18-49 (14%), 50-64 (21%), and ≥65 (63%)., Discussion: Sardinia is a high-risk region for MG, with a prevalence that exceeds the European threshold for rare disease. Identification of the environmental and genetic determinants of this risk may improve our understanding of disease pathophysiology., (© 2024 Wiley Periodicals LLC.)

Immune checkpoint inhibitors (ICIs) are cancer immunotherapies that enhance the body's own immune system to treat cancer. ICI treatment, however, can cause immune-related adverse events (irAEs) that can affect any organ, resulting in significant morbidity and mortality. Neurologic irAEs (nirAEs) are rare and can affect the peripheral nervous system more commonly than the central nervous system. Treatment is dependent on the severity of the neurologic manifestations and often includs discontinuation of the ICI and initiation of steroid therapy as the first line; other treatments have also been used. NirAEs and cardiac irAEs have higher fatality rates underlying the importance of early recognition and appropriate management. This chapter reviews the clinical manifestations of neurologic immune-related adverse events associated with ICI treatment as well as diagnostic and therapeutic modalities., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Among patients with paraneoplastic neurologic syndromes (PNS), emphasis has historically been placed on neural antibodies against intracellular proteins that have a strong association with malignancy. Because of the intracellular location of their antigenic targets, these antibodies are typically considered to be non-pathogenic surrogate markers of immune cell-mediated neural injury. Unfortunately, patients with these antibodies often have suboptimal response to immunotherapy and poor prognosis. Over the last two decades, however, dramatic advancements have been made in the discovery and clinical characterization of neural antibodies against extracellular targets. These antibodies are generally considered to be pathogenic, given their potential to directly alter antigen structure or function, and patients with these antibodies often respond favorably to prompt immunotherapy. These antibodies also associate with tumors and may thus occur as PNS, albeit more variably than neural antibodies against intracellular targets. The updated 2021 PNS diagnostic criteria, which classifies antibodies as high-risk, intermediate-risk, or lower-risk for an associated cancer, better clarifies how neural antibodies against extracellular targets relate to PNS. Using this recently created framework, the clinical presentations, ancillary test findings, oncologic associations, and treatment responses of syndromes associated with these antibodies are discussed., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Myasthenia gravis is an antibody-mediated autoimmune neurological disorder characterized by impaired neuromuscular junction transmission, resulting in muscle weakness. Recently, the involvement of Human Endogenous Retroviruses (HERVs) in the pathophysiology of different immune-mediated and neurodegenerative diseases, such as multiple sclerosis, has been demonstrated. We aimed to investigate potential immune system involvement related to humoral responses targeting specific epitopes of HERV-K and HERV-W envelope proteins in myasthenia gravis. Myasthenia gravis patients were recruited in the Neurology Unit, while healthy controls were selected from the Blood Transfusion Center, both affiliated with AOU Sassari. Highly immunogenic antigens of HERV-K and HERV-W envelope proteins were identified using the Immune Epitope Database (IEDB) online tool. These epitopes were utilized in enzyme-linked immunosorbent assays (ELISA) to detect autoantibodies in serum directed against these sequences. The study involved 39 Healthy Donors and 47 MG patients, further categorized into subgroups based on the presence of autoantibodies: MG-AchR Ab+ ( n = 17), MG-MuSK Ab+ ( n = 7), double seronegative patients (MG-DSN, n = 18), MG-LRP4 Ab + ( n = 4), and one patient with no antibodies data ( n = 1). Our findings revealed high levels of autoantibodies in myasthenia gravis patients directed against the HERV-K-env-su (19-37) , HERV-K-env-su (109-126) , HERV-K-env-su (164-186) , HERV-W-env (93-108) , HERV-W-env (129-14) , and HERV-W-env (248-262) epitopes. Notably, these results remained highly significant even when patients were subdivided into MG-AchR Ab+ and MG-DSN subgroups. Correlation analysis further revealed significant positive associations between the antibody levels against HERV-K and HERV-W families in patients, suggesting a synergistic action of the two HERVs in the pathology context since this correlation is absent in the control group. This study marks the first identification of a specific humoral response directed against defined epitopes of HERV-K and HERV-W envelope proteins in myasthenia gravis patients. These findings lay the foundation for future investigations aimed at elucidating the molecular mechanisms driving this immune response. The detection of these autoantibodies suggests the potential for novel biomarkers, especially within the MG-DSN patient subgroup, addressing the need for new biomarkers in this population.

Introduction: Limited data exist on brain MRI enhancement in myelin-oligodendrocyte-glycoprotein (MOG) antibody-associated disease (MOGAD) and differences from aquaporin-4-IgG-positive-neuromyelitis-optica-spectrum-disorder (AQP4+NMOSD), and multiple sclerosis (MS)., Methods: In this retrospective observational study, we identified 122 Mayo Clinic MOGAD patients (1 January 1996-1 July 2020) with cerebral attacks. We explored enhancement patterns using a discovery set (n=41). We assessed enhancement frequency and Expanded Disability Status Scale scores at nadir and follow-up in the remainder (n=81). Two raters assessed T1-weighted-postgadolinium MRIs (1.5T/3T) for enhancement patterns in MOGAD, AQP4+NMOSD (n=14) and MS (n=26). Inter-rater agreement was assessed. Leptomeningeal enhancement clinical correlates were analysed., Results: Enhancement occurred in 59/81 (73%) MOGAD cerebral attacks but did not influence outcome. Enhancement was often patchy/heterogeneous in MOGAD (33/59 (56%)), AQP4+NMOSD (9/14 (64%); p=0.57) and MS (16/26 (62%); p=0.63). Leptomeningeal enhancement favoured MOGAD (27/59 (46%)) over AQP4+NMOSD (1/14 (7%); p=0.01) and MS (1/26 (4%); p<0.001) with headache, fever and seizures frequent clinical correlates. Ring enhancement favoured MS (8/26 (31%); p=0.006) over MOGAD (4/59 (7%)). Linear ependymal enhancement was unique to AQP4+NMOSD (2/14 (14%)) and persistent enhancement (>3 months) was rare (0%-8%) across all groups. Inter-rater agreement for enhancement patterns was moderate., Conclusions: Enhancement is common with MOGAD cerebral attacks and often has a non-specific patchy appearance and rarely persists beyond 3 months. Leptomeningeal enhancement favours MOGAD over AQP4+NMOSD and MS., Competing Interests: Competing interests: PE has no conflicts of interests or financial disclosures to declare regarding this submission. LC received speaker and consultant honoraria from Biomedia, ACCMED, Roche, BMS Celgene and Sanofi. KNK and DG reports no disclosures. JJC has received consulting fees from Roche, UCB and Horizon. ASL-C has served on advisory boards for Genentech and Horizon Therapeutics. ES, VR and PPM reports no disclosures. JLC has received research support from Roche and Genentech for an MS clinical trial, and serves as chair of the DMSC for several migraine clinical trials. DMW has received consulting fees from Alexion, Roche, Genentech, Horizon Therapeutics, Imcyse, Bristol Myers Squibb and Reistone, serves on an attack adjudication committee for a MOGAD clinical trial funded by UCB Pharma and is co-editor in chief of the neurologist. J-MT is associate editor for Journal of Child Neurology. CV-S and ST no disclosures. SJP reports grants, personal fees and non-financial support from Alexion Pharmaceuticals; grants, personal fees, non-financial support and other support from MedImmune, Inc/Viela Bio.; personal fees for consulting from Genentech/Roche. He has a patent, Patent# 8889102 (application#12-678350, Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia)—issued; a patent, Patent# 9891219B2 (application#12-573942, Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive)—issued. EPF has served on advisory boards for Alexion, Genentech, Horizon Therapeutics and UCB. He has received research support from UCB. He has received speaker honoraria from Pharmacy Times. He received royalties from UpToDate. EPF was a site primary investigator in a randomised clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics. EPF has received funding from the NIH (R01NS113828). EPF is a member of the medical advisory board of the MOG project. EPF is an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1-IgG as a biomarker of paraneoplastic autoimmunity., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To determine the timing and predictors of T2-lesion resolution in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)., Methods: This retrospective observational study using standard-of-care data had inclusion criteria of MOGAD diagnosis, ≥2 MRIs 12 months apart, and ≥1 brain/spinal cord T2-lesion. The median (interquartile range [IQR]) number of MRIs (82% at disease onset) per-patient were: brain, 5 (2-8); spine, 4 (2-8). Predictors of T2-lesion resolution were assessed with age- and sex-adjusted generalized estimating equations and stratified by T2-lesion size (small <1 cm; large ≥1 cm)., Results: We studied 583 T2-lesions (brain, 512 [88%]; spinal cord, 71 [12%]) from 55 patients. At last MRI (median follow-up 54 months [IQR 7-74]) 455 T2-lesions (78%) resolved. The median (IQR) time to resolution was 3 months (1.4-7.0). Small T2-lesions resolved more frequently and faster than large T2-lesions. Acute T1-hypointensity decreased the likelihood (odds ratio [95% CI]) of T2-lesion resolution independent of size (small: 0.23 [0.09-0.60], p = 0.002; large: 0.30 [0.16-0.55], p < 0.001), whereas acute steroids favored resolution of large T2-lesions (1.75 [1.01-3.03], p = 0.046). Notably, 32/55 (58%) T2-lesions resolved without treatment., Discussion: The high frequency of spontaneous T2-lesion resolution suggests that this represents MOGAD's natural history. The speed of T2-lesion resolution and influence of size, corticosteroids, and T1-hypointensity on this phenomenon gives insight into MOGAD pathogenesis., (© 2023 American Academy of Neurology.)

Background and Purpose: Outcome and rechallenge data on central nervous system (CNS) autoimmunity triggered by immune checkpoint inhibitors (ICIs) are limited. We aim to describe a large series of patients with ICI-triggered CNS autoimmunity, and to compare these patients with spontaneous paraneoplastic syndromes (PNS)., Methods: We retrospectively reviewed Mayo Clinic patients with ICI-triggered CNS autoimmunity (February 2015-June 2021). Clinical characteristics were compared to spontaneous PNS patients (with antineuronal nuclear antibody [ANNA]-1 or anti-Hu neurological autoimmunity, and/or neuroendocrine tumors [NET]) evaluated within the same period., Results: Thirty-one patients were included (55% female, median age = 63 years, range = 39-76). Median time from ICI initiation was 3.65 months (range = 0.8-44.5). The most common associated malignancies were melanoma and small cell lung cancer. CNS manifestations included encephalitis (n = 16), meningoencephalitis (n = 8), cerebellar ataxia (n = 4), demyelinating syndrome (n = 2), and myelopathy (n = 1). Magnetic resonance imaging was abnormal in 62%. Cerebrospinal fluid was inflammatory in 70%. Neural autoantibodies were identified in 47%, more frequently in patients with NET (p = 0.046). ICI was discontinued in 97%; 90% received immunosuppressive treatment. After median 6.8 months follow-up (range = 0.7-46), 39% had unfavorable outcomes (grade ≥ 3). This was associated with higher severity degree at onset, shorter period from ICI to neurological symptom onset, and encephalitis. Four patients were rechallenged with ICI, and one relapsed. Patients with NET and with ANNA-1 ICI-triggered CNS autoimmunity had associated peripheral nervous system manifestations more frequently than their spontaneous counterparts (p = 0.007 and p = 0.028, respectively)., Conclusions: One third of ICI-related CNS autoimmunity patients have unfavorable outcomes. Relapses may occur after ICI rechallenge. Neural autoantibodies are often present, more commonly in patients with NET., (© 2023 European Academy of Neurology.)

Background and Objectives: Studies on tumefactive brain lesions in myelin oligodendrocyte glycoprotein-immunoglobulin G (IgG)-associated disease (MOGAD) are lacking. We sought to characterize the frequency clinical, laboratory, and MRI features of these lesions in MOGAD and compare them with those in multiple sclerosis (MS) and aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD)., Methods: We retrospectively searched 194 patients with MOGAD and 359 patients with AQP4+NMOSD with clinical/MRI details available from the Mayo Clinic databases and included those with ≥1 tumefactive brain lesion (maximum transverse diameter ≥2 cm) on MRI. Patients with tumefactive MS were identified using the Mayo Clinic medical record linkage system. Binary multivariable stepwise logistic regression identified independent predictors of MOGAD diagnosis; Cox proportional regression models were used to assess the risk of relapsing disease and gait aid in patients with tumefactive MOGAD vs those with nontumefactive MOGAD., Results: We included 108 patients with tumefactive demyelination (MOGAD = 43; AQP4+NMOSD = 16; and MS = 49). Tumefactive lesions were more frequent among those with MOGAD (43/194 [22%]) than among those with AQP4+NMOSD (16/359 [5%], p < 0.001). Risk of relapse and need for gait aid were similar in tumefactive and nontumefactive MOGAD. Clinical features more frequent in MOGAD than in MS included headache (18/43 [42%] vs 10/49 [20%]; p = 0.03) and somnolence (12/43 [28%] vs 2/49 [4%]; p = 0.003), the latter also more frequent than in AQP4+NMOSD (0/16 [0%]; p = 0.02). The presence of peripheral T2-hypointense rim, T1-hypointensity, diffusion restriction (particularly an arc pattern), ring enhancement, and Baló-like or cystic appearance favored MS over MOGAD ( p ≤ 0.001). MRI features were broadly similar in MOGAD and AQP4+NMOSD, except for more frequent diffusion restriction in AQP4+NMOSD (10/15 [67%]) than in MOGAD (11/42 [26%], p = 0.005). CSF analysis revealed less frequent positive oligoclonal bands in MOGAD (2/37 [5%]) than in MS (30/43 [70%], p < 0.001) and higher median white cell count in MOGAD than in MS (33 vs 6 cells/μL, p < 0.001). At baseline, independent predictors of MOGAD diagnosis were the presence of somnolence/headache, absence of T2-hypointense rim, lack of T1-hypointensity, and no diffusion restriction (Nagelkerke R 2 = 0.67). Tumefactive lesion resolution was more common in MOGAD than in MS or AQP4+NMOSD and improved model performance., Discussion: Tumefactive lesions are frequent in MOGAD but not associated with a worse prognosis. The clinical, MRI, and CSF attributes of tumefactive MOGAD differ from those of tumefactive MS and are more similar to those of tumefactive AQP4+NMOSD with the exception of lesion resolution, which favors MOGAD., (© 2023 American Academy of Neurology.)

Background and Objectives: Although the diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is based on serum MOG antibodies (MOG-Abs) positivity, patients with coexisting or restricted MOG-Abs in the CSF have been reported. The aim of this study is to characterize the relevance of CSF MOG-Abs positivity in clinical practice., Methods: Eleven medical centers retrospectively collected clinical and laboratory data of adult and pediatric patients with suspected inflammatory CNS disease and MOG-Abs positivity in serum and/or CSF using live cell-based assays. Comparisons were performed using parametric or nonparametric tests, as appropriate. Potential factors of unfavorable outcomes were explored by Cox proportional hazard models and logistic regression., Results: The cohort included 255 patients: 139 (55%) women and 132 (52%) children (i.e., <18-year-old). Among them, 145 patients (56.8%) had MOG-Abs in both serum and CSF (MOG-Abs seropositive and CSF positive), 79 (31%) only in serum (MOG-Abs seropositive and CSF negative), and 31 (12%) only in CSF (MOG-Abs seronegative and CSF positive). MOG-Abs seronegative and CSF positive predominated in adults (22% vs 3% of children), presented more commonly with motor (n = 14, 45%) and sensory symptoms (n = 13, 42%), and all but 4 (2 multiple sclerosis, 1 polyradiculoneuritis, and 1 Susac syndrome) had a final diagnosis compatible with MOGAD. When comparing seropositive patients according to MOG-Abs CSF status, MOG-Abs seropositive and CSF positive patients had a higher Expanded Disability Status Scale (EDSS) at nadir during the index event (median 4.5, interquartile range [IQR] 3.0-7.5 vs 3.0, IQR 2.0-6.8, p = 0.007) and presented more commonly with sensory (45.5% vs 24%, p = 0.002), motor (33.6% vs 19%, p = 0.021), and sphincter symptoms (26.9% vs 7.8%, p = 0.001) than MOG-Abs seropositive and CSF negative. At the last follow-up, MOG-Abs seropositive and CSF positive cases had more often persistent sphincter dysfunction (17.3% vs 4.3%, p = 0.008) . Compared with seropositive patients, those MOG-Abs seronegative and CSF positive had higher disability at the last follow-up ( p ≤ 0.001), and MOG-Abs seronegative and CSF positive status were independently associated with an EDSS ≥3.0., Discussion: Paired serum and CSF MOG-Abs positivity are common in MOGAD and are associated with a more severe clinical presentation. CSF-only MOG-Abs positivity can occur in patients with a phenotype suggestive of MOGAD and is associated with a worse outcome. Taken together, these data suggest a clinical interest in assessing CSF MOG-Abs in patients with a phenotype suggestive of MOGAD, regardless of the MOG-Abs serostatus., (© 2022 American Academy of Neurology.)

Objective: To determine whether MRI gadolinium enhancement patterns in myelopathies with longitudinally extensive T2 lesions can be reliably distinguished and assist in diagnosis., Methods: We retrospectively identified 74 Mayo Clinic patients (January 1, 1996-December 31, 2019) fulfilling the following criteria: (1) clinical myelopathy; (2) MRI spine available; (3) longitudinally extensive T2 hyperintensity (≥3 vertebral segments); and (4) characteristic gadolinium enhancement pattern associated with a specific myelopathy etiology. Thirty-nine cases with alternative myelopathy etiologies, without previously described enhancement patterns, were included as controls. Two independent readers, educated on enhancement patterns, reviewed T2-weighted and postgadolinium T1-weighted images and selected the diagnosis based on this knowledge. These were compared with the true diagnoses, and agreement was measured with Kappa coefficient., Results: Among all cases and controls (n = 113), there was excellent agreement for diagnosis using postgadolinium images (kappa, 0.76) but poor agreement with T2-weighted characteristics alone (kappa, 0.25). A correct diagnosis was more likely when assessing postgadolinium image characteristics than with T2-weighted images alone (rater 1: 100/113 [88%] vs 61/113 [54%] correct, p < 0.0001; rater 2: 95/113 [84%] vs 68/113 [60%] correct, p < 0.0001). Of the 74 with characteristic enhancement patterns, 55 (74%) were assigned an alternative incorrect or nonspecific diagnosis when originally evaluated in clinical practice, 12 (16%) received immunotherapy for noninflammatory myelopathies, and 2 (3%) underwent unnecessary spinal cord biopsy., Conclusions: Misdiagnosis of myelopathies is common. The gadolinium enhancement patterns characteristic of specific diagnoses can be identified with excellent agreement between raters educated on this topic. This study highlights the potential diagnostic utility of enhancement patterns in myelopathies with longitudinally extensive T2 lesions., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Immune checkpoint inhibitors (ICIs) have transformed the prognosis of cancers previously considered lethal. The spectrum of therapeutic indications is rapidly expanding, including the vast majority of thoracic malignancies. By enhancing the immune responses against cancer, the ICI treatments lead to the development of immune-related adverse events (irAEs) that may affect any organ. Severity varies from mild to fatal clinical manifestations. Neurologic involvement is relatively rare and highly heterogeneous, including central and peripheral nervous system diseases associated with neural-specific autoantibodies or not, central nervous system vasculitis, and granulomatous and demyelinating disorders. Symptoms often manifest within the first four cycles of treatment and can develop regardless of the class of ICI used. An unfavorable outcome is found in up to one-third of patients and is generally associated with the patients' clinical characteristics (e.g., age, coexistence of systemic adverse events), cancer type (e.g., lung cancer versus other), and specific clinical setting (e.g., ICI treatment in patients with preexisting paraneoplastic neurologic autoimmunity, ICI rechallenge after a first neurologic irAE). Diagnosis should be suspected in patients with new-onset neurologic symptoms while on ICI treatment which are not explained by metastatic disease or other metabolic/infectious disorders. Recommended treatment is based on clinical severity and consists of ICI discontinuation with or without immunosuppressive/immunomodulatory therapy, although alternative approaches are reasonable depending on cancer status (e.g., aggressive immunosuppression without discontinuing ICI in patients with initial cancer response). Early recognition and appropriate treatment of these neurologic irAEs are crucial for improved patient outcomes and therapeutic planning., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

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 2 ) 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 2 ])., 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]); P =0.01. NAR showed the highest accuracy for identification of SCI versus acute myelitis with values ≥0.35 pg/(mL·mm 2 ) 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 ( P =0.0007)., Conclusions: NAR is a novel and promising clinical biomarker for differentiation of SCI from acute myelitis.

Objective: To describe neural autoantibody profiles and outcomes in patients with neurologic autoimmunity associated with immune checkpoint inhibitor (ICI) cancer immunotherapy., Methods: In this retrospective descriptive study, 63 patients with ICI-related neurologic autoimmunity were included: 39 seen at the Mayo Clinic Neurology Department (clinical cohort) and 24 whose serum/CSF was referred to the Mayo Clinic Neuroimmunology Laboratory for autoantibody testing. Serum/CSF samples were tested for neural-specific autoantibodies. Predictors of unfavorable outcome (residual adverse event severity grade ≥3) were explored (logistic regression)., Results: Median age at neurologic symptom onset was 65 years (range 31-86); 40% were female. Neurologic manifestations were CNS-restricted (n = 26), neuromuscular (n = 30), combined (n = 5), or isolated retinopathy (n = 2). Neural-specific autoantibodies were common in patients with CNS involvement (7/13 [54%] in the unbiased clinical cohort) and included known or unidentified neural-restricted specificities. Only 11/31 patients with CNS manifestations had neuroendocrine malignancies typically associated with paraneoplastic autoimmunity. Small-cell lung cancer (SCLC)-predictive antibodies were seen in 3 patients with non-neuroendocrine tumors (neuronal intermediate filament immunoglobulin G [IgG] and antineuronal nuclear antibody 1 with melanoma; amphiphysin IgG with non-SCLC). A median of 10 months from onset (range, 0.5-46), 14/39 in the clinical cohort (36%) had unfavorable outcomes; their characteristics were age ≥70 years, female, CNS involvement, lung cancer, higher initial severity grade, and lack of systemic autoimmunity. By multivariate analysis, only age remained independently associated with poor outcome ( p = 0.01). Four of 5 patients with preexistent neurologic autoimmunity experienced irreversible worsening after ICI., Conclusions: Neural-specific autoantibodies are not uncommon in patients with ICI-related CNS neurologic autoimmunity. Outcomes mostly depend on the pre-ICI treatment characteristics and clinical phenotype., (© 2020 American Academy of Neurology.)

Objective: Progressive motor impairment anatomically attributable to a single critical demyelinating lesion on eloquent corticospinal tract locations occurs in progressive solitary sclerosis and in some patients with multiple sclerosis (MS) with highly restricted CNS lesion burden (2-5 lesions). We determined whether a similar critical lesion is found in patients with MS with unilateral motor progression and unlimited lesion burden., Methods: In this observational study, we retrospectively identified Mayo Clinic patients (January 1, 1996-December 31, 2017) with an MS diagnosis (2017 McDonald criteria), ≥1 year of exclusively unilateral motor progression, and >5 demyelinating lesions on MRI. A blinded neuroradiologist identified a single critical lesion (last available MRI) based on prominent size, atrophy, and eloquent corticospinal tract location (spinal cord lateral columns, medullary pyramids, cerebral peduncles, internal capsules). We then determined whether the motor impairment was anatomically attributable to the identified lesion., Results: Thirty-eight patients with MS were included: 20 (53%) with primary progressive MS and 18 (47%) with secondary progressive MS. Median age at progression onset was 54 (range 39-73) years. Median Expanded Disability Status Scale score was 5 (range 2.5-7.5) at the last follow-up (median 132.5 months from symptom onset, range 23-390 months). A single critical lesion was identified in 25 of 38 cases (66%): 19 in the cervical cord and 6 in the thoracic cord. In the remaining patients, >1 potential critical lesions were present. The overall probability to detect demyelinating lesions was higher along the corticospinal tract where the motor deficit localized (38 of 38 [100%]) than on the contralateral side (15 of 38 [39%]) ( p < 0.0001)., Conclusions: In patients with MS with unilateral motor progression, the motor deficit may be attributable to a single critical corticospinal tract lesion., (© 2019 American Academy of Neurology.)

Objective: Diagnostic criteria from 2002 classify transverse myelitis (TM) as idiopathic or disease associated but predate the discovery of aquaporin-4 (AQP4)-immunoglobulin G (IgG) and myelin oligodendrocyte glycoprotein (MOG)-IgG, which associate with TM. Prior incidence estimates of idiopathic TM (ITM) range from 1 to 6.2 per 1 million. We sought to determine whether the population-based incidence and prevalence of ITM were reduced by testing patients with ITM for AQP4/MOG-IgG and reclassifying seropositive cases as having disease-associated TM., Methods: For this observational study, we retrospectively identified all cases of incident (January 1, 2003-December 31, 2016) and prevalent (December 31, 2016) ITM in Olmsted County (85% white) by using the Rochester Epidemiology Project medical records linkage system. ITM was defined by the 2002 Transverse MyelitisConsortium Working Group diagnostic criteria. Available sera were tested for AQP4-IgG and MOG-IgG., Results: Twenty-four patients (incident 22, prevalent 17) initially met 2002 ITM criteria (longitudinally extensive TM [LETM] 6). Sera were tested for AQP4-IgG in 22 of 24 (92%) and MOG-IgG in 21 of 24 (88%). Three seropositive cases (AQP4-IgG 2, MOG-IgG 1) were identified and reclassified as having disease-associated TM, accounting for 14% of total incident and 12% of total prevalent cases. AQP4-IgG and MOG-IgG seropositive cases represented 50% (3 of 6) of idiopathic LETM. After reclassification of seropositive patients, the final ITM incidence was 8.6 per 1,000,000 and prevalence was 7.9 per 100,000. Three cases of ITM (14%) subsequently fulfilled multiple sclerosis criteria within the study period., Conclusions: The availability of AQP4-IgG and MOG-IgG modestly reduced ITM incidence and prevalence, which remained higher than previously reported in this predominantly white population. Incorporation of these biomarkers into future revisions of TM diagnostic criteria should be considered., (© 2019 American Academy of Neurology.)

Anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) recently emerged as a potential biomarker in patients with inflammatory demyelinating diseases of the central nervous system. We here compare the clinical and laboratory findings observed in a cohort of MOG-Ab seropositive and seronegative cases and describe IgG subclass analysis results. Consecutive serum samples referred to Verona University Neuropathology Laboratory for aquaporin-4 (AQP4)-Ab and/or MOG-Ab testing were analysed between March 2014 and May 2017. The presence of AQP4-Ab was determined using a cell-based assay. A live cell immunofluorescence assay was used for the detection of MOG-IgG and IgG subclass analysis. Among 454 analysed samples, 29 were excluded due to AQP4-Ab positivity or to the final demonstration of a disorder not compatible with MOG-Ab. We obtained clinical data in 154 out of 425 cases. Of these, 22 subjects resulted MOG-Ab positive. MOG-Ab positive patients were mainly characterised by the involvement of the optic nerve and/or spinal cord. Half of the cases presented relapses and the recovery was usually partial. Brain MRI was heterogeneous while short lesions were the prevalent observation on spinal cord MRI. MOG-Ab titre usually decreased in non-relapsing cases. In all MOG-IgG positive cases, we observed IgG1 antibodies, which were predominant in most subjects. IgG2 (5/22), IgG3 (9/22) and IgG4 (3/22) antibodies were also detectable. We confirm that MOG-Ab-related syndromes have distinct features in the spectrum of demyelinating conditions, and we describe the possible role of the different IgG subclasses in this condition.

In 2010, we reported the successful clinical outcome related to a 20-month course of intravenous, cyclical ceftriaxone, in a patient with adult-onset Alexander's disease. We now provide evidence that the progression of the patient's signs/symptoms was halted and reversed with a 4-year-long extension of the trial.The patient's clinical signs/symptoms were evaluated before the start and every 6 months for 6 years. For the early 2 years, without therapy, and for the following 4 years, after intravenous ceftriaxone 2 g daily, for 3 weeks monthly during the initial 4 months, then for 15 days monthly.Gait ataxia and dysarthria were assessed clinically on a 0 to 4 scale. Palatal myoclonus and nystagmus/oscillopsia were monitored by videotape and a self-evaluation scale. The degree of disability, measured by a modified Rankin scale, and the brain MRI were periodically evaluated.Before ceftriaxone therapy, in a 2-year period, gait ataxia and dysarthria worsened from mild to marked, palatal myoclonus spread from the soft palate to lower facial muscles, and the patient complained of oscillopsia. After 4 years of ceftriaxone therapy, gait ataxia and dysarthria improved, from marked to mild at clinical rating scales. The palatal myoclonus was undetectable; the patient did not complained of oscillopsia and declared a progressively better quality of life. Ceftriaxone was safe.This case report provides Class IV evidence that intravenous cycles of ceftriaxone may halt and/or reverse the progression of neurodegeneration in patients with adult-onset Alexander's disease and may significantly improve their quality of life.