Pittock, S J

Objective Myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) can be monophasic or relapsing, with early relapse being a feature. However, the relevance of early relapse on longer‐term relapse risk is unknown. Here, we investigate whether early relapses increase longer‐term relapse risk in patients with MOGAD. Methods A retrospective analysis of 289 adult‐ and pediatric‐onset patients with MOGAD followed for at least 2 years in 6 specialized referral centers. “Early relapses” were defined as attacks within the first 12 months from onset, with “very early relapses” defined within 30 to 90 days from onset and “delayed early relapses” defined within 90 to 365 days. “Long‐term relapses” were defined as relapses beyond 12 months. Cox regression modeling and Kaplan–Meier survival analysis were used to estimate the long‐term relapse risk and rate. Results Sixty‐seven patients (23.2%) had early relapses with a median number of 1 event. Univariate analysis revealed an elevated risk for long‐term relapses if any “early relapses” were present (hazard ratio [HR] = 2.11, p < 0.001), whether occurring during the first 3 months (HR = 2.70, p < 0.001) or the remaining 9 months (HR = 1.88, p = 0.001), with similar results yielded in the multivariate analysis. In children with onset below aged 12 years, only delayed early relapses were associated with an increased risk of long‐term relapses (HR = 2.64, p = 0.026). Interpretation The presence of very early relapses and delayed early relapses within 12 months of onset in patients with MOGAD increases the risk of long‐term relapsing disease, whereas a relapse within 90 days appears not to indicate a chronic inflammatory process in young pediatric‐onset disease. ANN NEUROL 2023;94:508–517

Autoimmune movement disorders are increasingly recognized, but isolated tremor is extremely rare. We describe a 70‐year‐old male with rapidly progressive, severe postural and intention tremor and weight loss. His cerebrospinal fluid was inflammatory and harbored a neural tissue‐restricted antibody. The autoantigen was identified by immunoprecipitation and mass spectrometry and confirmed by antigen‐specific assays to be specific for tenascin‐R. He was investigated for cancer and diagnosed with follicular lymphoma that expressed tenascin‐R suggesting a paraneoplastic origin; cancer treatment and immunotherapy led to complete recovery. With this individualized patient approach and antibody discovery, we expand the spectrum of antibodies accompanying autoimmune hyperkinetic movement disorders. ANN NEUROL 2023;94:502–507

AbstractObjectiveSeizures 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.MethodsPatients 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.ResultsSixty 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.SignificanceSeizures 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.

Objective This study was undertaken to investigate factors associated with aquaporin‐4 (AQP4)‐IgG serostatus change using a large serological database. Methods This retrospective study utilizes Mayo Clinic Neuroimmunology Laboratory data from 2007 to 2021. We included all patients with ≥2 AQP4‐IgG tests (by cell‐based assay). The frequency and clinical factors associated with serostatus change were evaluated. Multivariable logistic regression analysis examined whether age, sex, or initial titer was associated with serostatus change. Results There were 933 patients who had ≥2 AQP4‐IgG tests with an initial positive result. Of those, 830 (89%) remained seropositive and 103 (11%) seroreverted to negative. Median interval to seroreversion was 1.2 years (interquartile range [IQR] = 0.4–3.5). Of those with sustained seropositivity, titers were stable in 92%. Seroreversion was associated with age ≤ 20 years (odds ratio [OR] = 2.25; 95% confidence interval [CI] = 1.09–4.63; p = 0.028) and low initial titer of ≤1:100 (OR = 11.44, 95% CI = 3.17–41.26, p < 0.001), and 5 had clinical attacks despite seroreversion. Among 62 retested after seroreversion, 50% returned to seropositive (median = 224 days, IQR = 160–371). An initial negative AQP4‐IgG test occurred in 9,308 patients. Of those, 99% remained seronegative and 53 (0.3%) seroconverted at a median interval of 0.76 years (IQR = 0.37–1.68). Interpretation AQP4‐IgG seropositivity usually persists over time with little change in titer. Seroreversion to negative is uncommon (11%) and associated with lower titers and younger age. Seroreversion was often transient, and attacks occasionally occurred despite prior seroreversion, suggesting it may not reliably reflect disease activity. Seroconversion to positive is rare (<1%), limiting the utility of repeat testing in seronegative patients unless clinical suspicion is high. ANN NEUROL 2023;94:727–735

Background: The N-MOmentum trial investigated safety and efficacy of inebilizumab in participants with neuromyelitis optica spectrum disorder (NMOSD). Objective: Evaluate the attack identification process and adjudication committee (AC) performance in N-MOmentum. Methods: Adults ( n = 230) with NMOSD and Expanded Disability Status Scale score ⩽8 were randomized (3:1) to inebilizumab 300 mg or placebo. The randomized controlled period was 28 weeks or until adjudicated attack. Attacks were adjudicated according to 18 predefined criteria. Magnetic resonance imaging (MRI) and biomarker (serum glial fibrillary acidic protein [sGFAP]) analyses were performed. Results: A total of 64 participant-reported neurological events occurred; 51 (80%) were investigator-determined to be attacks. The AC confirmed 43 of the investigator-determined attacks (84%). There was high inter- and intra-AC-member agreement. In 25/64 events (39%) and 14/43 AC-adjudicated attacks (33%), MRI was reviewed during adjudication. Retrospective analysis revealed new domain-specific T1 and T2 MRI lesions in 90% of adjudicated attacks. Increased mean sGFAP concentrations (>2-fold change) from baseline were observed in 56% of adjudicated attacks versus 14% of investigator-determined attacks rejected by the AC and 31% of participant-reported events determined not to be attacks. Conclusion: AC adjudication of NMOSD attacks according to predefined criteria appears robust. MRI lesion correlates and sGFAP elevations were found in most adjudicated attacks.

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.

AbstractBackgroundStiff person spectrum disorder (SPSD) is heterogeneous, and accurate diagnosis can be challenging.MethodsPatients referred for diagnosis/suspicion of SPSD at the Mayo Autoimmune Neurology Clinic from July 01, 2016, to June 30, 2021, were retrospectively identified. SPSD diagnosis was defined as clinical SPSD manifestations confirmed by an autoimmune neurologist and seropositivity for high‐titer GAD65‐IgG (>20.0 nmol/L), glycine‐receptor‐IgG or amphiphysin‐IgG, and/or confirmatory electrodiagnostic studies (essential if seronegative). Clinical presentation, examination, and ancillary testing were compared to differentiate SPSD from non‐SPSD.ResultsOf 173 cases, 48 (28%) were diagnosed with SPSD and 125 (72%) with non‐SPSD. Most SPSD were seropositive (41/48: GAD65‐IgG 28/41, glycine‐receptor‐IgG 12/41, amphiphysin‐IgG 2/41). Pain syndromes or functional neurologic disorder were the most common non‐SPSD diagnoses (81/125, 65%). SPSD patients more commonly reported exaggerated startle (81% vs. 56%, p = 0.02), unexplained falls (76% vs. 46%, p = 0.001), and other associated autoimmunity (50% vs. 27%, p = 0.005). SPSD more often had hypertonia (60% vs. 24%, p < 0.001), hyperreflexia (71% vs. 43%, p = 0.001), and lumbar hyperlordosis (67% vs. 9%, p < 0.001) and less likely functional neurologic signs (6% vs. 33%, p = 0.001). SPSD patients more frequently had electrodiagnostic abnormalities (74% vs. 17%, p < 0.001), and at least moderate symptomatic improvement with benzodiazepines (51% vs. 16%, p < 0.001) or immunotherapy (45% vs. 13% p < 0.001). Only 4/78 non‐SPSD patients who received immunotherapy had alternative neurologic autoimmunity.InterpretationMisdiagnosis was threefold more common than confirmed SPSD. Functional or non‐neurologic disorders accounted for most misdiagnoses. Clinical and ancillary testing factors can reduce misdiagnosis and exposure to unnecessary treatments. SPSD diagnostic criteria are suggested.

Abstract 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.