Association of Juvenile Dermatomyositis Disease Activity With the Expansion of Blood Memory B and T Cell Subsets Lacking Follicular Markers.

OBJECTIVE: This study was undertaken to identify blood markers of juvenile dermatomyositis (DM) disease activity (DA), which are needed to improve disease management. METHODS: The study comprised a total of 123 juvenile DM patients and 53 healthy controls. Results of laboratory tests (aldolase, creatinine kinase, lactate dehydrogenase [LDH], aspartate aminotransferase) and clinical measures of DA in patients with juvenile DM, including the Manual Muscle Testing in 8 muscles (MMT-8), Childhood Myositis Assessment Scale (CMAS), and disease activity scores (DAS) (total DAS for juvenile DM, the muscle DAS, and the skin DAS), were recorded when available. Surface phenotype of peripheral blood mononuclear cells was assessed using flow cytometry. Whole blood transcriptional profiles were studied using either RNA-sequencing or microarrays. Differential gene expression was determined using DESeq and compared by pathway and gene ontology analyses. RESULTS: Conventional memory (CD27+IgD-) B cells expressing low CXCR5 levels (CXCR5low/- CM B cells) were significantly increased in frequency and absolute numbers in 2 independent cohorts of juvenile DM patients compared with healthy controls. The frequency of CD4+ Th2 memory cells (CD45RA-CXCR5-CCR6-CXCR3-) was also increased in juvenile DM, especially in patients who were within <1 year from diagnosis. The frequency of CXCR5low/- CM B cells correlated with serum aldolase levels and with a blood interferon-stimulated gene transcriptional signature. Furthermore, both the frequency and absolute numbers of CXCR5low/- CM B cells correlated with clinical and laboratory measures of muscle DA (MMT-8, CMAS, aldolase, and LDH). CONCLUSION: These findings suggest that both CM B cells lacking the CXCR5 follicular marker and CXCR5- Th2 cells represent potential biomarkers of DA in juvenile DM and may contribute to its pathogenesis.

Determining an infectious or autoimmune etiology in encephalitis.

OBJECTIVES: Early presentation and workup for acute infectious (IE) and autoimmune encephalitis (AE) are similar. This study aims to identify routine laboratory markers at presentation that are associated with IE or AE. METHODS: This was a multi-center retrospective study at three tertiary care hospitals in New York City analyzing demographic and clinical data from patients diagnosed with definitive encephalitis based on a confirmed pathogen and/or autoantibody and established criteria for clinical syndromes. RESULTS: Three hundred and thirty-three individuals with confirmed acute meningoencephalitis were included. An infectious-nonbacterial (NB) pathogen was identified in 151/333 (45.40%), bacterial pathogen in 95/333 (28.50%), and autoantibody in 87/333 (26.10%). NB encephalitis was differentiated from AE by the presence of fever (NB 62.25%, AE 24.10%; p < 0.001), higher CSF white blood cell (WBC) (median 78 cells/µL, 8.00 cells/µL; p < 0.001), higher CSF protein (76.50 mg/dL, 40.90 mg/dL; p < 0.001), lower CSF glucose (58.00 mg/dL, 69.00 mg/dL; p < 0.001), lower serum WBC (7.80 cells/µL, 9.72 cells/µL; p < 0.050), higher erythrocyte sedimentation rate (19.50 mm/HR, 13.00 mm/HR; p < 0.05), higher C-reactive protein (6.40 mg/L, 1.25 mg/L; p = 0.005), and lack of antinuclear antibody titers (>1:40; NB 11.54%, AE 32.73%; p < 0.001). CSF-to-serum WBC ratio was significantly higher in NB compared to AE (NB 11.3, AE 0.99; p < 0.001). From these findings, the association of presenting with fever, CSF WBC ≥50 cells/µL, and CSF protein ≥75 mg/dL was explored in ruling-out AE. When all three criteria are present, an AE was found to be highly unlikely (sensitivity 92%, specificity 75%, negative predictive value 95%, and positive predictive value 64%). INTERPRETATIONS: Specific paraclinical data at initial presentation may risk stratify which patients have an IE versus AE.

MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines.

BACKGROUND: Among boys with X-Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy. METHODS: To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus. RESULTS: One hundred twenty-three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0-9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI. CONCLUSION: Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.

Clinical and electrographic features of persistent seizures and status epilepticus associated with anti-NMDA receptor encephalitis (anti-NMDARE).

Based on a multicenter cohort of people with anti-NMDA receptor encephalitis (anti-NMDARE), we describe seizure phenotypes, electroencephalographic (EEG) findings, and anti-seizure treatment strategies. We also investigated whether specific electrographic features are associated with persistent seizures or status epilepticus after acute presentation. In this retrospective cohort study, we reviewed records of children and adults with anti-NMDARE between 2010 and 2014 who were included in the Rare Epilepsy of New York City database, which included the text of physician notes from five academic medical centers. Clinical history (e.g., seizure semiology) and EEG features (e.g., background organization, slowing, epileptiform activity, seizures, sleep architecture, extreme delta brush) were abstracted. We compared clinical features associated with persistent seizures (ongoing seizures after one month from presentation) and status epilepticus, using bivariate and multivariable analyses. Among the 38 individuals with definite anti-NMDARE, 32 (84%) had seizures and 29 (76%) had seizures captured on EEG. Electrographic-only seizures were identified in five (13%) individuals. Seizures started at a median of four days after initial symptoms (IQR: 3-6 days). Frontal lobe-onset focal seizures were most common (n=12; 32%). Most individuals (31/38; 82%) were refractory to anti-seizure medications. Status epilepticus was associated with younger age (15 years [9-20] vs. 23 years [18-27]; p=0.04) and Hispanic ethnicity (30 [80%] vs. 8 [36%]; p=0.04). Persistent seizures (ongoing seizures after one month from presentation) were associated with younger age (nine years [3-14] vs. 22 years [15-28]; p<0.01). Measured electrographic features were not associated with persistent seizures. Seizures associated with anti-NMDARE are primarily focal seizures originating in the frontal lobes. Younger patients may be at increased risk of epileptogenesis and status epilepticus. Continuous EEG monitoring helps identify subclinical seizures, but specific EEG findings may not predict the severity or persistence of seizures during hospitalization.

The Landscape of Hematopoietic Stem Cell Transplant and Gene Therapy for X-Linked Adrenoleukodystrophy.

PURPOSE OF REVIEW: To present an updated appraisal of hematopoietic stem cell transplant (HSCT) and gene therapy for X-linked adrenoleukodystrophy (ALD) in the setting of a novel, presymptomatic approach to disease. RECENT FINDINGS: Outcomes in HSCT for ALD have been optimized over time due to early patient detection, improved myeloablative conditioning regimens, and adjunctive treatment for patients with advanced cerebral disease. Gene therapy has arrested disease progression in a cohort of boys with childhood cerebral ALD. New therapeutic strategies have provided the clinical basis for the implementation of Newborn Screening (NBS). With the help of advocacy groups, NBS has been implemented, allowing for MRI screening for the onset of cerebral ALD from birth. Gene therapy and optimized hematopoietic stem cell transplant for childhood CALD have changed the natural history of this previously devastating neurological disease.