Diagnostic Utility of MOG Antibody Testing in Cerebrospinal Fluid.

OBJECTIVE: The aim of this study was to assess the diagnostic utility of cerebrospinal fluid (CSF) myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) testing. METHODS: We retrospectively identified patients for CSF MOG-IgG testing from January 1, 1996, to May 1, 2023, at Mayo Clinic and other medical centers that sent CSF MOG-IgG for testing including: controls, 282; serum MOG-IgG positive MOG antibody-associated disease (MOGAD), 74; serum MOG-IgG negative high-risk phenotypes, 73; serum false positive MOG-IgG with alternative diagnoses, 18. A live cell-based assay assessed CSF MOG-IgG positivity (IgG-binding-index [IBI], ≥2.5) using multiple anti-human secondary antibodies and end-titers were calculated if sufficient sample volume. Correlation of CSF MOG-IgG IBI and titer was assessed. RESULTS: The pan-IgG Fc-specific secondary was optimal, yielding CSF MOG-IgG sensitivity of 90% and specificity of 98% (Youden's index 0.88). CSF MOG-IgG was positive in: 4/282 (1.4%) controls; 66/74 (89%) serum MOG-IgG positive MOGAD patients; and 9/73 (12%) serum MOG-IgG negative patients with high-risk phenotypes. Serum negative but CSF positive MOG-IgG accounted for 9/83 (11%) MOGAD patients, and all fulfilled 2023 MOGAD diagnostic criteria. Subgroup analysis of serum MOG-IgG low-positives revealed CSF MOG-IgG positivity more in MOGAD (13/16[81%]) than other diseases with false positive serum MOG-IgG (3/15[20%]) (p = 0.01). CSF MOG-IgG IBI and CSF MOG-IgG titer (both available in 29 samples) were correlated (Spearman's r = 0.64, p < 0.001). INTERPRETATION: CSF MOG-IgG testing has diagnostic utility in patients with a suspicious phenotype but negative serum MOG-IgG, and those with low positive serum MOG-IgG results and diagnostic uncertainty. These findings support a role for CSF MOG-IgG testing in the appropriate clinical setting. ANN NEUROL 2024;96:34-45.

Cerebellar leptomeningeal enhancement: An imaging finding of rapidly progressive Purkinje cell cytoplasmic autoantibody type 1 paraneoplastic cerebellar syndrome.

Purkinje cell cytoplasmic autoantibody type 1 (PCA1), also known as anti-Yo, is a 'high-risk' paraneoplastic antibody, associated with rapidly progressive cerebellar syndrome. In patients with this syndrome, various MRI abnormalities have been documented, including atrophy in the cerebellum and brainstem, T2 hyperintensity in the brainstem and spinal cord, and cranial nerve enhancement. This report introduces an imaging finding, cerebellar leptomeningeal enhancement, which was observed in all three cases at early stages. Despite neurological deterioration, all patients underwent immunotherapy, and subsequent follow-up MRI revealed resolution of the leptomeningeal enhancement, suggesting that this feature is distinct from meningeal carcinomatosis.

Multiple sclerosis and seizures: A retrospective observational study in a multiple sclerosis autoimmunity center of excellence.

PURPOSE: The prevalence of epilepsy in patients with multiple sclerosis (MS) is three to six times the prevalence in the general population. Mechanisms resulting in increased seizure risk are not fully understood. Our objective is to characterize patients with MS and epilepsy regarding timing of diagnoses, MS and seizure (SZ) type, EEG findings suggesting cortical dysfunction, frequency of status epilepticus (SE), and seizure freedom. METHODS: This was a single center retrospective study. Cases were obtained via DataDirect via the University of Michigan electronic medical record from January 1, 2006 through October, 12, 2016. The University of Michigan Health System is a large academic institute with a tertiary referral center and an Autoimmunity Center of Excellence. Patients were included if chart listed one or more of the top 62 epilepsy, and one or more of the top 2 MS, most frequently entered ICD9 and ICD10 codes. Patients with alternative epilepsy etiology were excluded. 74 of 361 patients were included. We collected information regarding demographics, MS and SZ type, age at diagnosis, imaging, EEG, seizure freedom, medications, and SE. RESULTS: We found a high percentage of patients with SE. Most patients with imaging had multiple lesions at seizure onset. 27/54 of patients with EEG data showed electrographic evidence of cortical dysfunction. 6/8 of EEGs in PPMS showed features consistent with cortical dysfunction, followed by 9/17 in SPMS and 11/23 in RRMS. 7/8 of patients with PPMS showed EEG evidence of temporal lobe dysfunction. CONCLUSION: Time of seizure onset relative to MS diagnosis varied with MS type suggesting distinct pathophysiology. EEG results correspond with reports of increased cortical damage and temporal dysfunction in PPMS, but are unique as a functional modality (EEG) as indicator of gray matter dysfunction. EEG findings differed in RRMS and progressive MS suggesting possibility of supportive diagnostic marker. Our data suggests higher risk of SE in progressive MS and diminished rate of seizure freedom for MS patients with SE. We conclude that early treatment with antiseizure medication would be beneficial for MS patients with SE and with progressive MS forms and SZ, in agreement with previous studies.

Immunosenescence and multiple sclerosis: inflammaging for prognosis and therapeutic consideration.

Aging is associated with a progressive decline of innate and adaptive immune responses, called immunosenescence. This phenomenon links to different multiple sclerosis (MS) disease courses among different age groups. While clinical relapse and active demyelination are mainly related to the altered adaptive immunity, including invasion of T- and B-lymphocytes, impairment of innate immune cell (e.g., microglia, astrocyte) function is the main contributor to disability progression and neurodegeneration. Most patients with MS manifest the relapsing-remitting phenotype at a younger age, while progressive phenotypes are mainly seen in older patients. Current disease-modifying therapies (DMTs) primarily targeting adaptive immunity are less efficacious in older patients, suggesting that immunosenescence plays a role in treatment response. This review summarizes the recent immune mechanistic studies regarding immunosenescence in patients with MS and discusses the clinical implications of these findings.

CDR2 and CDR2L line blot performance in PCA-1/anti-Yo paraneoplastic autoimmunity.

Background: Purkinje cytoplasmic autoantibody type 1 (PCA-1)/anti-Yo autoimmunity is a common high-risk paraneoplastic neurological disorder, traditionally attributed antigenically to cerebellar degeneration-related protein 2 (CDR2), predominantly affecting women with gynecologic or breast adenocarcinoma. Single-modality CDR2 testing may produce false-positive results. We assessed the performance characteristics of the more recently purported major PCA-1/Yo antigen, CDR2-like (CDR2L), side by side with CDR2, in a line blot format. Methods: CDR2 and CDR2L were tested in six specimen groups (serum and cerebrospinal fluid (CSF)). Group 1, PCA-1/Yo mouse brain indirect immunofluorescence assay (IFA) positives; Group 2, PCA-1/Yo IFA mimics; Group 3, suspected CDR2 line blot false positives; Group 4, consecutive patient samples tested for neural antibodies over 1 year; Group 5, healthy subject serums; and Group 6, polyclonal (non-specific) immunoglobulin G (IgG)-positive serums. Results: Group 1: Of 64 samples tested, all but two were CDR2 positive (both CSF samples) and all were CDR2L positive. In individual patients, CDR2L values were always higher than CDR2. The two "CDR2L-only" positives were CSF samples with low titer PCA-1/Yo by IFA with serum negativity but with typical clinical phenotype. Group 2: All 51 PCA-1/Yo mimics were CDR2/CDR2L negative. Group 3: Nine samples [six of 1289 (0.47%) serums and three of 700 CSF samples (0.43%) were PCA-1/Yo IFA negative/CDR2 positive; two of the six available (serums from the same patient) were also CDR2L positive; the other four CDR2L negative had low CDR2 values (17-22). Group 4: Twenty-two patients had unexpected CDR2 or CDR2L positivity; none had tissue IFA positivity. Eleven of the 2,132 serum (0.5%) and three of the 677 CSF (0.4%) samples were CDR2 positive; median value was 19 (range, 11-48). Seven of the 2,132 serum (0.3%) and three of the 677 CSF (0.4%) samples were CDR2L positive; median value was 18 (range, 11-96). Group 5: All 151 healthy serum samples were negative. Group 6: One of the 46 polyclonal serum samples was CDR2L positive. Optimum overall performance was accomplished by requiring both CDR2 and CDR2L positivity in serum (sensitivity, 100%; and specificity, 99.9%) and positivity for CDR2L in CSF (sensitivity, 100%; and specificity, 99.6%). Conclusion: CDR2L provides additional PCA-1/anti-Yo sensitivity in CSF, and dual positivity with CDR2 provides additional specificity assurance in serum. Combining antigen-specific and tissue-based assays optimizes PCA-1/anti-Yo testing.

Clinical presentations and treatment outcomes of Hashimoto encephalopathy at Siriraj Hospital - Thailand's largest national tertiary referral center.

BACKGROUND: Hashimoto encephalopathy has multiple clinical presentations, and other than the presence of thyroid antibody, laboratory and imaging investigations are all non-specific. Data specific to the clinical presentations and treatment outcomes of patients with Hashimoto encephalopathy in Thailand remain scarce. OBJECTIVES: To retrospectively investigate the clinical presentations and treatment outcomes of patients with Hashimoto encephalopathy at Siriraj Hospital. METHODS: Patients who presented with acute encephalopathy at our center during July 2012-March 2017 were evaluated for eligibility. The inclusion criteria were positive anti-thyroperoxidase (anti-TPO) or anti-thyroglobulin (anti-Tg) in serum with negative neuronal antibody in serum or cerebral spinal fluid (CSF). Clinical presentations, symptom duration, laboratory results of thyroid status and thyroid autoantibody, CSF study, and clinical outcomes were collected. RESULTS: Of the 204 patients who presented with encephalopathy, 31 (15.2%) were positive for the anti-TPO or anti-Tg antibody. Of those, 13 patients met the diagnostic criteria for Hashimoto encephalopathy. Clinical presentations included cognitive impairment (76.9%), clouding of consciousness (46.2%), and behavior change (30.8%). The neuropsychiatric presentations were visual hallucination (30.8%), auditory hallucination (15.4%), delusion (7.7%), and mood disturbance (23.1%). Other clinical presentations included seizure (38.5%), abnormal movement (23.1%), sleep disturbance (38.5%), ataxia (46.2%), stroke-like episode (15.4%), and fever (15.4%). Most patients (76.9%) had onset within < 3 months. Regarding outcomes, 1 patient who did not receive corticosteroid died from status epilepticus and septic shock. Among the 12 patients who received corticosteroid, 9 (75%) had marked improvement, 1 (8.3%) had slight improvement, and 2 (16.6%) had no clinical improvement. Seven patients (53.9%) had normal thyroid function, 4 patients (30.8%) had subclinical hypothyroidism, and 2 patients (15.4%) had subclinical hyperthyroidism. CONCLUSIONS: The results of this study revealed cognitive impairment, neuropsychiatric symptoms, seizure, ataxia, and sleep disturbance to be common manifestations of Hashimoto encephalopathy. This condition should always be considered in individuals with subacute onset of unexplained cognitive impairment or cerebellar ataxia. Laboratory and neuroimaging investigations were all found to be nonspecific in Hashimoto encephalopathy. Most patients responded well to treatment, so clinical suspicion and early diagnosis and treatment will lead to improved patient outcomes.

MOG-specific T cell response amplified in para- and post-SAR-CoV-2 infection in myelin oligodendrocyte glycoprotein antibody-associated disease.

We describe clinical characteristics and deep immunophenotypes in two patients with myelin-oligodendrocyte-glycoprotein (MOG)-antibody-associated-disease after COVID-19. The para-COVID case was a 74-year-old man who developed optic neuritis two days after COVID-19. Immunological assays revealed reduced absolute CD8+ T- and B-cell counts with increased frequency of NK cells. Post-COVID case was a 63-year-old man with optic neuritis six months after COVID-19, a frequency of CD8+ T-cells was elevated with a relatively low fraction of naïve and a high fraction of effector memory CD8+ T-cells. There was increased frequency of CD8+CD38+HLA-DR+ T-cells in the para-COVID case; interestingly, CD4+CD38+HLA-DR+ T cell frequency was increased in the post-COVID case. Both had increased SARS-CoV-2-specific and MOG-specific T-cell responses.

Seizure characteristics and outcomes in patients with neurological conditions related to high-risk paraneoplastic antibodies.

OBJECTIVE: Seizures are a common manifestation of paraneoplastic neurologic syndromes. The objective of this study was to describe the seizure characteristics and outcomes in patients with high-risk paraneoplastic autoantibodies (>70% cancer association) and to determine factors associated with ongoing seizures. METHODS: Patients from 2000 to 2020 with seizures and high-risk paraneoplastic autoantibodies were retrospectively identified. Factors associated with ongoing seizures at last follow-up were evaluated. RESULTS: Sixty patients were identified (34 males, median age at presentation = 52 years). ANNA1-IgG (Hu; n = 24, 39%), Ma2-IgG (n = 14, 23%), and CRMP5-IgG (CV2; n = 11, 18%) were the most common underlying antibodies. Seizures were the initial presenting symptom in 26 (43%), and malignancy was present in 38 (63%). Seizures persisted for >1 month in 83%, and 60% had ongoing seizures, with almost all patients (55/60, 92%) still being on antiseizure medications at last follow-up a median of 25 months after seizure onset. Ongoing seizures at last follow-up were associated with Ma2-IgG or ANNA1-IgG compared to other antibodies (p = .04), highest seizure frequency being at least daily (p = .0002), seizures on electroencephalogram (EEG; p = .03), and imaging evidence of limbic encephalitis (LE; p = .03). Death occurred in 48% throughout the course of follow-up, with a higher mortality in patients with LE than in those without LE (p = .04). Of 31 surviving patients at last follow-up, 55% continued to have intermittent seizures. SIGNIFICANCE: Seizures in the setting of high-risk paraneoplastic antibodies are frequently resistant to treatment. Ongoing seizures are associated with ANNA1-IgG and Ma2-IgG, high seizure frequency, and EEG and imaging abnormalities. Although a subset of patients may respond to immunotherapy and achieve seizure freedom, poor outcomes are frequently encountered. Death was more common among patients with LE.

Cerebral enhancement in MOG antibody-associated disease.

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.

Increased creativity associated with dopamine agonist therapy: A case report and short review of the literature.

Impulse control disorder (ICD) has been linked to dopamine agonist use in patients with Parkinson's disease. Increased creativity is another cognitive side effect of dopaminergic therapy. While ICD is well recognized in the literature, enhanced creativity as a positive phenomenon is underreported because it does not negatively affect the patients' quality of life. Herein, we report a case of a 49-year-old man with Parkinson's disease who developed enhanced creativity expressed by the acquisition of multiple, new artistic skills with ropinirole treatment. He spent a significant amount of time on painting, carving and axe restoration, selling these artistic products became a source of income. He also reports that these hobbies help him cope with physical limitations caused by Parkinson's disease.

Evaluation of Urea-Based Inhibitors of the Dopamine Transporter Using the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis.

The dopaminergic system is involved in the regulation of immune responses in various homeostatic and disease conditions. For conditions such as Parkinson's disease and multiple sclerosis (MS), pharmacological modulation of dopamine (DA) system activity is thought to have therapeutic relevance, providing the basis for using dopaminergic agents as a treatment of relevant states. In particular, it was proposed that restoration of DA levels may inhibit neuroinflammation. We have recently reported a new class of dopamine transporter (DAT) inhibitors with high selectivity to the DAT over other G-protein coupled receptors tested. Here, we continue their evaluation as monoamine transporter inhibitors. Furthermore, we show that the urea-like DAT inhibitor (compound 5) has statistically significant anti-inflammatory effects and attenuates motor deficits and pain behaviors in the experimental autoimmune encephalomyelitis model mimicking clinical signs of MS. To the best of our knowledge, this is the first study reporting the beneficial effects of DAT inhibitor-based treatment in animals with induced autoimmune encephalomyelitis, and the observed results provide additional support to the model of DA-related neuroinflammation.

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

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.

Paraneoplastic neurological syndrome: an evolving story.

Paraneoplastic neurological syndrome (PNS) comprises a group of neurological disorders that result from a misguided immune response to the nervous system triggered by a distant tumor. These disorders frequently manifest before the diagnosis of the underlying neoplasm. Since the first reported case in 1888 by Oppenheim, the knowledge in this area has evolved rapidly. Several classic PNS have been described, such as limbic encephalitis, paraneoplastic cerebellar degeneration, encephalomyelitis, opsoclonus-myoclonus, sensory neuronopathy, Lambert-Eaton Myasthenic syndrome, and chronic gastrointestinal dysmotility. It is now recognized that PNS can have varied nonclassical manifestations that extend beyond the traditional syndromic descriptions. Multiple onconeural antibodies with high specificity for certain tumor types and neurological phenotypes have been discovered over the past 3 decades. Increasing use of immune checkpoint inhibitors (ICIs) has led to increased recognition of neurologic ICI-related adverse events. Some of these resemble PNS. In this article, we review the clinical, oncologic, and immunopathogenic associations of PNS.

Geographic heterogeneity in the association of varicella-zoster virus seropositivity and multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Although there has long been a suspected association between varicella-zoster virus (VZV) and multiple sclerosis (MS), the connection has remained unclear. In this study, we performed a meta-analysis in an attempt to assess the association between VZV IgG serostatus and MS. METHODS: A literature search was performed using three databases: MEDLINE, EMBASE, and Cochrane. Eligible results included observational studies investigating the seroprevalence of VZV immunoglobulin G (IgG) in adults with MS versus non-MS controls. Two authors performed a screen of the search results, evaluating them for quality and relevant outcomes. Using a random-effect model, we estimated pooled odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The literature search yielded 1,268 articles, 8 of which (2,266 MS patients and 1,818 controls) were eligible for inclusion in the meta-analysis. Evaluation of all included studies together showed no significant association between VZV IgG seropositivity and MS (OR 1.439; 95%CI, 0.503-4.118; p 0.497). However, when analyzed in subgroups based on geographical area, studies performed in Asian countries showed VZV IgG seropositivity was more common in MS patients than in controls (OR 4.470; 95%CI 1.959-10.203; p < 0.001). No significant association was found in European countries. CONCLUSIONS: This study found evidence of an association between VZV IgG seropositivity and MS in Asian countries. Additional studies are warranted to ascertain factors impacting this association.

The effect of tonsillectomy on John Cunningham virus serological status in multiple sclerosis patients: A retrospective case-control study.

Tonsils are believed to be the initial site of the John Cunningham virus (JCV) infection. The long-term effect of childhood tonsillectomy on JCV status in multiple sclerosis (MS) patients has not been investigated. In this retrospective case-control study, we analyzed data of 144 JCV seropositive cases and 82 JCV seronegative controls from three outpatient MS clinics in the United States. Early tonsillectomy (before the age of 8) was reported among 8 (5.56%) JCV seropositive subjects and 19 (23.17%) controls. Early tonsillectomy was associated with JCV negative status (adjusted odds ratio = 5.39, 95% confidence interval = 2.13-13.62, p < 0.001) independent of age and gender.

Adult Langerhans cell histiocytosis of the central nervous system.

Langerhans cell histiocytosis (LCH), a disorder characterized by aberrant function and proliferation of mononuclear phagocytic cells called Langerhans cells, usually occurs in those <15 years of age. Adult-onset LCH is extremely rare. We present a case of a 35-year-old woman who presented with multiple episodes of confusion, rapidly progressive cognitive decline, and multiple endocrinopathies, including diabetes insipidus. Brain imaging showed a hypothalamic lesion, and biopsy results confirmed the diagnosis of LCH. Given the wide variety of presentations and the multiple differential diagnoses of hypothalamic lesions, it is essential to be aware of this uncommon condition, especially in adults, where it may be underdiagnosed.