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IntroductionLimited 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).MethodsIn 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.ResultsEnhancement 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.ConclusionsEnhancement 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.

BackgroundRituximab (RTX) efficacy in patients with myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorders (MOGADs) is still poorly understood, though it appears to be lower than in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders (AQP4-IgG+NMOSDs). The aim of this systematic review and meta-analysis is to assess the efficacy and safety profile of RTX in patients with MOGAD and to compare RTX efficacy between MOGAD and AQP4-IgG+NMOSD.MethodsWe searched original English-language articles published between 2012 and 2021 in MEDLINE, Cochrane, Central Register of Controlled Trials and clinicaltrials.gov, reporting data on RTX efficacy in patients with MOGAD. The main outcome measures were annualised relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score mean differences (MDs) after RTX. The meta-analysis was performed with a random effects model. Covariates associated with the outcome measures were analysed with a linear meta-regression.ResultsThe systematic review included 315 patients (138 women, mean onset age 26.8 years) from 32 studies. Nineteen studies (282 patients) were included in the meta-analysis. After RTX, a significant decrease of ARR was found (MD: −0.92, 95% CI –1.24 to –0.60, p<0.001), markedly different from the AQP4-IgG+NMOSD (MD: −1.73 vs MOGAD −0.92, subgroup difference testing: Q=9.09, p=0.002). However, when controlling for the mean ARR pre-RTX, this difference was not significant. After RTX, the EDSS score decreased significantly (MD: −0.84, 95% CI −1.41 to –0.26, p=0.004). The frequency of RTX-related adverse events was 18.8% (36/192) and overall RTX-related mortality 0.5% (1/192).ConclusionsRTX showed effective in MOGAD, although to a lesser extent than in AQP4-IgG+NMOSD, while the safety profile warrants some caution in its prescription. Randomised-controlled trials are needed to confirm these findings and provide robust evidence to improve treatment strategies in patients with MOGAD.PROSPERO registration numberCRD42020175439.

ObjectiveTo compare acute treatment responses and long-term outcome in leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis.MethodsRetrospective case series of 118 patients with LGI1 antibody encephalitis evaluated at Mayo Clinic across all US sites from 1 May 2008 to 31 March 2019. Patient clinical data were identified and analysed through the neuroimmunology laboratory and electronic medical record. LGI1 antibody detection was by cell-based indirect immunofluorescence assay of serum, cerebrospinal fluid or both. Clinical outcomes were faciobrachial dystonic seizure (FBDS) resolution, modified Rankin Scale (mRS) score, Kokmen Short Test of Mental Status (STMS) score (0–38 point scale) and neuropsychometric testing results.ResultsCompared with intravenous immunoglobulin (IVIg) (n=21), patients treated with single-agent acute corticosteroids (intravenous, oral or both) (n=49) were more likely to experience resolution of FBDS (61% vs 7%, p=0.002) and improvements in mRS score (ΔmRS score 2 vs 0, p=0.008) and median Kokmen STMS scores (ΔKokmen STMS score 5 points vs 0 points, p=0.01). In 54 patients with long-term follow-up (≥2 years), the median mRS score was 1 (range 0–6) and the median Kokmen STMS score was 36 (range 24–38) after all combinations of immunotherapy. Neuropsychometric testing in 32 patients with long-term follow-up (≥2 years) demonstrated short-term memory impairments in 37%.ConclusionsCorticosteroids appeared more effective acutely than IVIg in improving LGI1 antibody encephalitis in this retrospective comparison of immunotherapies. While improvement with immunotherapy is typical and long-term outcome is favourable, short-term memory deficits are noted in approximately a third of the patients.

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•The Italian Island of Sardinia is recognized for the high risk of MS, but the epidemiology of other demyelinating diseases of the central nervous system is unknown.•We determined the incidence and prevalence of aquaporin-4-IgG-positive (AQP4-IgG+) NMOSD in Sardinia.•The crude incidence (January 2013 – December 2022) and prevalence (December 31, 2022) of AQP4-IgG+NMOSD in Sardinia were 1.9 (95 % CI, 1.3–2.7)/million and 2.6 (95 % CI, 1.9–3.5)/100,000, respectively.•Disease prevalence increased from 2013 (1.1/100,000) to 2022 (2.6/100,000); p= 0.002.•Age-standardized incidence and prevalence (95 % CI) to the European population were 1.7 (1.1–2.4)/million and 2.3 (1.6–3.0)/100,000; while age-standardized estimates to the world population were 1.3 (0.8–1.9)/million and 1.8 (1.2–2.5)/100,000.

IMPORTANCE: Myelin oligodendrocyte glycoprotein-IgG1–associated disorder (MOGAD) is a distinct central nervous system–demyelinating disease. Positive results on MOG-IgG1 testing by live cell-based assays can confirm a MOGAD diagnosis, but false-positive results may occur. OBJECTIVE: To determine the positive predictive value (PPV) of MOG-IgG1 testing in a tertiary referral center. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study was conducted over 2 years, from January 1, 2018, through December 31, 2019. Patients in the Mayo Clinic who were consecutively tested for MOG-IgG1 by live cell-based flow cytometry during their diagnostic workup were included. Patients without research authorization were excluded. MAIN OUTCOMES AND MEASURES: Medical records of patients who were tested were initially reviewed by 2 investigators blinded to MOG-IgG1 serostatus, and pretest probability was classified as high or low (suggestive of MOGAD or not). Testing of MOG-IgG1 used a live-cell fluorescence-activated cell-sorting assay; an IgG binding index value of 2.5 or more with an end titer of 1:20 or more was considered positive. Cases positive for MOG-IgG1 were independently designated by 2 neurologists as true-positive or false-positive results at last follow-up, based on current international recommendations on diagnosis or identification of alternative diagnoses; consensus was reached for cases in which disagreement existed. RESULTS: A total of 1617 patients were tested, and 357 were excluded. Among 1260 included patients tested over 2 years, the median (range) age at testing was 46 (0-98) years, and 792 patients were female (62.9%). A total of 92 of 1260 (7.3%) were positive for MOG-IgG1. Twenty-six results (28%) were designated as false positive by the 2 raters, with an overall agreement on 91 of 92 cases (99%) for true and false positivity. Alternative diagnoses included multiple sclerosis (n = 11), infarction (n = 3), B12 deficiency (n = 2), neoplasia (n = 2), genetically confirmed adrenomyeloneuropathy (n = 1), and other conditions (n = 7). The overall PPV (number of true-positive results/total positive results) was 72% (95% CI, 62%-80%) and titer dependent (PPVs: 1:1000, 100%; 1:100, 82%; 1:20-40, 51%). The median titer was higher with true-positive results (1:100 [range, 1:20-1:10000]) than false-positive results (1:40 [range, 1:20-1:100]; P &lt; .001). The PPV was higher for children (94% [95% CI, 72%-99%]) vs adults (67% [95% CI, 56%-77%]) and patients with high pretest probability (85% [95% CI, 76%-92%]) vs low pretest probability (12% [95% CI, 3%-34%]). The specificity of MOG-IgG1 testing was 97.8%. CONCLUSIONS AND RELEVANCE: This study confirms MOG-IgG1 as a highly specific biomarker for MOGAD, but when using a cutoff of 1:20, it has a low PPV of 72%. Caution is advised in the interpretation of low titers among patients with atypical phenotypes, because ordering MOG-IgG1 in low pretest probability situations will increase the proportion of false-positive results.

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.

ObjectiveTo determine the frequency and characteristics of brainstem or cerebellar involvement in myelin-oligodendrocyte-glycoprotein-antibody-associated-disorder (MOGAD) versus aquaporin-4-IgG-seropositive-neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD) and multiple sclerosis (MS).MethodsIn this observational study, we retrospectively identified 185 Mayo Clinic MOGAD patients with: (1) characteristic MOGAD phenotype, (2) MOG-IgG seropositivity by live cell-based assay and (3) MRI lesion(s) of brainstem, cerebellum or both. We compared the symptomatic attacks to AQP4-IgG-NMOSD (n=30) and MS (n=30).ResultsBrainstem or cerebellar involvement occurred in 62/185 (34%) MOGAD patients of which 39/62 (63%) were symptomatic. Ataxia (45%) and diplopia (26%) were common manifestations. The median age in years (range) in MOGAD of 24 (2–65) was younger than MS at 36 (16–65; p=0.046) and AQP4-IgG-NMOSD at 45 (6–72; p=0.006). Isolated attacks involving the brainstem, cerebellum or both were less frequent in MOGAD (9/39 (23%)) than MS (22/30 (73%); p<0.001) but not significantly different from AQP4-IgG-NMOSD (14/30 (47%); p=0.07). Diffuse middle cerebellar peduncle MRI-lesions favoured MOGAD (17/37 (46%)) over MS (3/30 (10%); p=0.001) and AQP4-IgG-NMOSD (3/30 (10%); p=0.001). Diffuse medulla, pons or midbrain MRI lesions occasionally occurred in MOGAD and AQP4-IgG-NMOSD but never in MS. Cerebrospinal fluid (CSF) oligoclonal bands were rare in MOGAD (5/30 (17%)) and AQP4-IgG-NMOSD (2/22 (9%); p=0.68) but common in MS (18/22 (82%); p<0.001). Disability at nadir or recovery did not differ between the groups.ConclusionInvolvement of the brainstem, cerebellum or both is common in MOGAD but usually occurs as a component of a multifocal central nervous system attack rather than in isolation. We identified clinical, CSF and MRI attributes that can help discriminate MOGAD from AQP4-IgG-NMOSD and MS.

ObjectiveTo determine clinical manifestations, immunotherapy responsiveness and outcomes of glutamic acid decarboxylase-65 (GAD65) neurological autoimmunity.MethodsWe identified 323 Mayo Clinic patients with high-titre (>20 nmol/L in serum) GAD65 antibodies out of 380 514 submitted anti-GAD65 samples (2003–2018). Patients classified as having GAD65 neurological autoimmunity after chart review were analysed to determine disease manifestations, immunotherapy responsiveness and predictors of poor outcome (modified Rankin score >2).ResultsOn review, 108 patients were classified as not having GAD65 neurological autoimmunity and 3 patients had no more likely alternative diagnoses but atypical presentations (hyperkinetic movement disorders). Of remaining 212 patients with GAD65 neurological autoimmunity, median age at symptom onset was 46 years (range: 5–83 years); 163/212 (77%) were female. Stiff-person spectrum disorders (SPSD) (N=71), cerebellar ataxia (N=55), epilepsy (N=35) and limbic encephalitis (N=7) could occur either in isolation or as part of an overlap syndrome (N=44), and were designated core manifestations. Cognitive impairment (N=38), myelopathy (N=23) and brainstem dysfunction (N=22) were only reported as co-occurring phenomena, and were designated secondary manifestations. Sustained response to immunotherapy ranged from 5/20 (25%) in epilepsy to 32/44 (73%) in SPSD (p=0.002). Complete immunotherapy response occurred in 2/142 (1%). Cerebellar ataxia and serum GAD65 antibody titre >500 nmol/L predicted poor outcome.InterpretationHigh-titre GAD65 antibodies were suggestive of, but not pathognomonic for GAD65 neurological autoimmunity, which has discrete core and secondary manifestations. SPSD was most likely to respond to immunotherapy, while epilepsy was least immunotherapy responsive. Complete immunotherapy response was rare. Serum GAD65 antibody titre >500 nmol/L and cerebellar ataxia predicted poor outcome.

IMPORTANCE: Recognizing the characteristics of myelin oligodendrocyte glycoprotein autoantibody (MOG-IgG) myelitis is essential for early accurate diagnosis and treatment. OBJECTIVE: To evaluate the clinical, radiologic, and prognostic features of MOG-IgG myelitis and compare with myelitis with aquaporin-4–IgG (AQP4-IgG) and multiple sclerosis (MS). DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified 199 MOG-IgG–positive Mayo Clinic patients from January 1, 2000, through December 31, 2017, through our neuroimmunology laboratory. Fifty-four patients met inclusion criteria of (1) clinical myelitis; (2) MOG-IgG positivity; and (3) medical records available. We excluded 145 patients without documented myelitis. Myelitis of AQP4-IgG (n = 46) and MS (n = 26) were used for comparison. MAIN OUTCOMES AND MEASURES: Outcome variables included modified Rankin score and need for gait aid. A neuroradiologist analyzed spine magnetic resonance imaging of patients with MOG-IgG and control patients blinded to diagnosis. RESULTS: Of 54 included patients with MOG-IgG myelitis, the median age was 25 years (range, 3-73 years) and 24 were women (44%). Isolated transverse myelitis was the initial manifestation in 29 patients (54%), and 10 (19%) were initially diagnosed as having viral/postviral acute flaccid myelitis. Cerebrospinal fluid–elevated oligoclonal bands occurred in 1 of 38 (3%). At final follow-up (median, 24 months; range, 2-120 months), 32 patients (59%) had developed 1 or more relapses of optic neuritis (n = 31); transverse myelitis (n = 7); or acute disseminated encephalomyelitis (n = 1). Clinical features favoring MOG-IgG myelitis vs AQP4-IgG or MS myelitis included prodromal symptoms and concurrent acute disseminated encephalomyelitis. Magnetic resonance imaging features favoring MOG-IgG over AQP4-IgG or MS myelitis were T2-signal abnormality confined to gray matter (sagittal line and axial H sign) and lack of enhancement. Longitudinally extensive T2 lesions were of similar frequency in MOG-IgG and AQP4-IgG myelitis (37 of 47 [79%] vs 28 of 34 [82%]; P = .52) but not found in MS. Multiple spinal cord lesions and conus involvement were more frequent with MOG-IgG than AQP4-IgG but not different from MS. Wheelchair dependence at myelitis nadir occurred in one-third of patients with MOG-IgG and AQP4-IgG but never with MS, although patients with MOG-IgG myelitis recovered better than those with AQP4-IgG. CONCLUSIONS AND RELEVANCE: Myelitis is an early manifestation of MOG-IgG–related disease and may have a clinical phenotype of acute flaccid myelitis. We identified a variety of clinical and magnetic resonance imaging features that may help clinicians identify those at risk in whom MOG-IgG should be tested.

We appreciate the comments on our case.1Although we agree that a bilateral hemifacial spasm is typically characterized by asynchronous muscle contractions on the left and right sides, contractions are also often asymmetric in severity, as observed in our case. The cheek movements on the right side of the face were likely the consequence of a stronger contraction of the palpebral part of the orbicularis oculi muscle, rather than the result of cheek muscle contractions as the orbicularis oris did not move during spasms. While a central origin cannot entirely be ruled out, the exclusive involvement of the upper facial muscles in our patient seems more consistent with a peripheral irritation of the superior branch of the facial nerves.

An 80-year-old man developed bitemporal headache and scalp tenderness. Both temporal arteries were prominent (Figure, A), with halo sign on ultrasonography.1Temporal arteritis was diagnosed and oral prednisone (50 mg/d) initiated. Three days later, he developed spasms of the orbicularis oculi and frontalis muscles with eyebrow elevation and eye twitching (other Babinski sign),2consistent with bilateral hemifacial spasm (Video 1). Brain MRI and time-of-flight angiography revealed exclusively supratentorial acute infarcts (Figure, B and C) without intracranial neurovascular conflicts. Intravenous methylprednisolone (1 g/d for 5 days) was started with resolution of spasms within 24 hours and clinical stabilization. Temporal artery inflammation may cause facial nerve irritation and hemifacial spasm (Figure, D).

A paradoxical effectof antiepileptic drugs was defined as an increased seizure frequency or severity occurring shortly after introducing a drug considered effective for that kind of epilepsy. In addition, this effect should occur at nontoxic drug serum levels. So far, pathophysiological mechanisms underlying this phenomenon have not been clarified. Recent evidence suggests that the variability of drug effects may depend on precise intrinsic properties of dynamic networks involving the drug and its binding site. Although several reports of paradoxical seizure exacerbation have been reported for levetiracetam (LEV), a possible association with focal cortical dysplasia has never been described nor investigated. In this report, we document a paradoxical effect induced by LEV monotherapy in a patient with type II focal cortical dysplasia at LEV serum levels within the therapeutic range. A hint of pathophysiological hypothesis underlying this potential relationship will be also suggested.

Objectives: In this retrospective multicenter study, we evaluated the safety of SARS-CoV-2 vaccination in patients harboring autoantibodies targeting neuronal surface and/or synaptic antigens.

•We studied 56 patients with AQP4-IgG+NMOSD (n = 26) or MOGAD (n = 30) who received at least one dose of SARS-CoV-2 vaccination (mRNA-based).•Disease relapses within 1 month of vaccination occurred in only one patient with AQP4-IgG+NMOSD (4%).•The frequency of disease relapses was higher in patients who contracted SARS-CoV-2 infection before the vaccine (20%; 1/5).•In patients with AQP4-IgG+NMOSD or MOGAD the benefits of SARS-CoV-2 vaccination outweigh the risk of potential disease reactivation.

•The frequency of cerebrospinal fluid (CSF) abnormalities in myelin oligodendrocyte glycoprotein-IgG-associated disorder (MOGAD) depends on the clinical and radiologic extent of central nervous system (CNS) involvement•CSF reveals pleocytosis (>5 white blood cells [WBC]/mm3) and absence of oligoclonal bands in ≥70% of patients with myelitis, brain/brainstem dysfunction, or multifocal CNS MOGAD syndromes; while marked pleocytosis (>50 WBC/mm3) occurs in approximately 50%.•A non-inflammatory CSF is typical with clinically and radiologically isolated optic neuritis (84% of cases), but coexisting asymptomatic MRI lesions in the brain, spinal cord, or both increase the likelihood of pleocytosis to >50%.•Immunosuppressive treatment (typically corticosteroids) before CSF sampling may reduce the probability of detecting abnormal CSF findings.

•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.

A 21-year-old woman presented with coma after 5 days of fever, gait ataxia, and somnolence. Brain MRI showed lesions in medial thalami, caudate heads, and periaqueductal region (figure). Hyperlactatemia was present; serum thiamine levels were normal.