Citations

Abstract Digital pathology (DP) has transformative potential, especially for Alzheimer disease and related disorders. However, infrastructure barriers may limit adoption. To provide benchmarks and insights into implementation barriers, a survey was conducted in 2019 within National Institutes of Health’s Alzheimer’s Disease Centers (ADCs). Questions covered infrastructure, funding sources, and data management related to digital pathology. Of the 35 ADCs to which the survey was sent, 33 responded. Most respondents (81%) stated that their ADC had digital slide scanner access, with the most frequent brand being Aperio/Leica (62.9%). Approximately a third of respondents stated there were fees to utilize the scanner. For DP and machine learning (ML) resources, 41% of respondents stated none was supported by their ADC. For scanner purchasing and operations, 50% of respondents stated they received institutional support. Some were unsure of the file size of scanned digital images (37%) and total amount of storage space files occupied (50%). Most (76%) were aware of other departments at their institution working with ML; a similar (76%) percentage were unaware of multiuniversity or industry partnerships. These results demonstrate many ADCs have access to a digital slide scanner; additional investigations are needed to further understand hurdles to implement DP and ML workflows.

Background: Data on corpus callosum involvement in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited. Objective: The objective of the study was to compare callosal lesions in MOGAD, multiple sclerosis (MS), and aquaporin-4-IgG positive neuromyelitis optica spectrum disorder (AQP4+NMOSD). Results: Callosal lesion frequency was similar in MOGAD (38/171 (22%)), MS (24/72 (33%)), and AQP4+NMOSD (18/63 (29%)). Clinical phenotypes included encephalopathy (47%) and focal supratentorial (21%) or infratentorial (45%) deficits. None had callosal-disconnection syndromes. Maximal callosal-T2-lesion diameter (median (range)) in millimeter was similar in MOGAD (21 (4–77)) and AQP4+NMOSD (22 (5–49); p = 0.93) but greater than in MS (10.5 (2–64)). Extracallosal extension (21/38 (55%)) and T2-lesion resolution (19/34 (56%)) favored MOGAD. Conclusions: Despite similar frequency and imaging overlap, larger lesions, sagittal midline involvement, and lesion resolution favored MOGAD.

Respiratory tract resident memory T cells (T RM ), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory T RM . We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron–based nanoparticles. Here, we report how routes of immunization in mice, including contralateral versus ipsilateral intramuscular boosts, or intravenous and intranasal routes, influenced influenza-specific cell–mediated and humoral immunity. Parabiotic surgeries revealed that intramuscular immunization was sufficient to establish CD8 T RM in the lung and draining lymph nodes. Contralateral, compared with ipsilateral, intramuscular boosting broadened the distribution of lymph node T RM and T follicular helper cells but slightly diminished resulting levels of serum antibody. Intranasal mRNA delivery established modest circulating CD8 and CD4 T cell memory but augmented distribution to the respiratory mucosa. Combining intramuscular immunizations with an intranasal mRNA boost achieved high levels of both circulating T cell memory and lung T RM . Thus, routes of mRNA vaccination influence humoral and cell-mediated immunity, and intramuscular prime-boosting establishes lung T RM that can be further expanded by an additional intranasal immunization.

ImportanceAutoimmune encephalitis misdiagnosis can lead to harm.ObjectiveTo determine the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis.Design, Setting, and ParticipantsThis retrospective multicenter study took place from January 1, 2014, to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics including Mayo Clinic (n = 44), University of Oxford (n = 18), University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), Washington University in St Louis (n = 6), and University of Utah (n = 4). Inclusion criteria were adults (age ≥18 years) with a prior autoimmune encephalitis diagnosis at a participating center or other medical facility and a subsequent alternative diagnosis at a participating center. A total of 393 patients were referred with an autoimmune encephalitis diagnosis, and of those, 286 patients with true autoimmune encephalitis were excluded.Main Outcomes and MeasuresData were collected on clinical features, investigations, fulfillment of autoimmune encephalitis criteria, alternative diagnoses, potential contributors to misdiagnosis, and immunotherapy adverse reactions.ResultsA total of 107 patients were misdiagnosed with autoimmune encephalitis, and 77 (72%) did not fulfill diagnostic criteria for autoimmune encephalitis. The median (IQR) age was 48 (35.5-60.5) years and 65 (61%) were female. Correct diagnoses included functional neurologic disorder (27 [25%]), neurodegenerative disease (22 [20.5%]), primary psychiatric disease (19 [18%]), cognitive deficits from comorbidities (11 [10%]), cerebral neoplasm (10 [9.5%]), and other (18 [17%]). Onset was acute/subacute in 56 (52%) or insidious (>3 months) in 51 (48%). Magnetic resonance imaging of the brain was suggestive of encephalitis in 19 of 104 patients (18%) and cerebrospinal fluid (CSF) pleocytosis occurred in 16 of 84 patients (19%). Thyroid peroxidase antibodies were elevated in 24 of 62 patients (39%). Positive neural autoantibodies were more frequent in serum than CSF (48 of 105 [46%] vs 7 of 91 [8%]) and included 1 or more of GAD65 (n = 14), voltage-gated potassium channel complex (LGI1 and CASPR2 negative) (n = 10), N-methyl-d-aspartate receptor by cell-based assay only (n = 10; 6 negative in CSF), and other (n = 18). Adverse reactions from immunotherapies occurred in 17 of 84 patients (20%). Potential contributors to misdiagnosis included overinterpretation of positive serum antibodies (53 [50%]), misinterpretation of functional/psychiatric, or nonspecific cognitive dysfunction as encephalopathy (41 [38%]).Conclusions and RelevanceWhen evaluating for autoimmune encephalitis, a broad differential diagnosis should be considered and misdiagnosis occurs in many settings including at specialized centers. In this study, red flags suggesting alternative diagnoses included an insidious onset, positive nonspecific serum antibody, and failure to fulfill autoimmune encephalitis diagnostic criteria. Autoimmune encephalitis misdiagnosis leads to morbidity from unnecessary immunotherapies and delayed treatment of the correct diagnosis.

AbstractMisdiagnosis of myelopathies is common and can lead to irreversible disability when diagnosis- and disease-specific treatments are delayed. Therefore, quickly determining the etiology of myelopathy is crucial. Clinical evaluation and MRI spine are paramount in establishing the correct diagnosis and subsequently an appropriate treatment plan. Herein, we review an approach to myelopathy diagnosis focused on the time course of neurologic symptom progression and neuroimaging pearls, and apply them to a variety of inflammatory, structural, and vascular myelopathy cases.

Cerebral cortical encephalitis (CCE) is a recently described myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) phenotype. In this observational retrospective study, we characterized 19 CCE patients (6.7% of our MOGAD cohort). Headache (n = 15, 79%), seizures (n = 13, 68%), and encephalopathy (n = 12, 63%) were frequent. Magnetic resonance imaging revealed unilateral (n = 12, 63%) or bilateral (n = 7, 37%) cortical T2 hyperintensity and leptomeningeal enhancement (n = 17, 89%). N‐Methyl‐D‐aspartate receptor autoantibodies coexisted in 2 of 15 tested (13%). CCE pathology (n = 2) showed extensive subpial cortical demyelination (n = 2), microglial reactivity (n = 2), and inflammatory infiltrates (perivascular, n = 1; meningeal, n = 1). Most received high‐dose steroids (n = 17, 89%), and all improved, but 3 had CCE relapses. This study highlights the CCE spectrum and provides insight into its pathogenesis. ANN NEUROL 2023;93:297–302

Abstract Objective To report the clinical presentations and outcomes of patients with seizure and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD). Methods We retrospectively reviewed the electronic medical records for clinical and paraclinical features among patients with seizures and MOG‐IgG (immunoglobulin G) seropositivity. Results We identified 213 patients with MOG‐IgG seropositivity who fulfilled criteria for MOGAD. Seizures attributed to central nervous system (CNS) autoimmunity were observed in 10% of patients ( n = 23: 19 children, 4 adults). The majority ( n = 19, 83%) had pediatric disease onset. Focal motor seizures were the most common seizure semiology (16/23; 70%). Focal to bilateral tonic‐clonic seizures were present in 12 patients (53%), and 3 patients (13%) developed status epilepticus. All patients had features of encephalitis at onset of seizures. Cerebral cortical encephalitis (CCE) was the most common radiological finding (10 unilateral and 5 bilateral cases). Eight of 23 patients (35%) had only CCE, six of 23 patients (26%) had only acute disseminated encephalomyelitis (ADEM), and seven of 23 patients (30%) had features of both. Fifteen patients (65%) had leptomeningeal enhancement. Three patients (13%) had coexistence of N ‐methyl‐ d ‐aspartate receptor (NMDAR) IgG. Only 3 of 23 patients (13%) developed drug‐ resistant epilepsy. Although the majority had MOGAD relapses (14/23, 60%) had only 5 of 23 patients had recurrence of episodes of encephalitis with associated seizures. Twenty‐one of 23 patients (91%) had seizure freedom at last follow‐up. Significance MOG‐IgG evaluation should be considered in patients who present with encephalitis and focal motor and/or focal to bilateral tonic‐clonic seizures, especially pediatric patients with magnetic resonance imaging (MRI) brain findings consistent with CCE, ADEM, or other MOGAD presentations. The majority of these seizures are self‐limited and do not require maintenance/chronic antiseizure medications. Although seizure recurrence is uncommon, many patients have MOGAD relapses in the form of encephalitis and optic neuritis.

Objective The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)‐IgG and aquaporin‐4 (AQP4)‐IgG among patients with pediatric‐onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG‐IgG‐associated disease (MOGAD), and identify clinical features associated with final diagnosis. Methods Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case–control study on POMS risk factors. Serum AQP4‐IgG and MOG‐IgG were assessed using live cell‐based assays. Results AQP4‐IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG‐IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty‐five of 30 patients positive with MOG‐IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re‐review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein–Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). Interpretation MOG‐IgG and AQP4‐IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4‐IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271–284