Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.

Myelin-specific T lymphocytes are considered essential in the pathogenesis of multiple sclerosis. The myelin basic protein peptide (a.a. 83-99) represents one candidate antigen; therefore, it was chosen to design an altered peptide ligand, CGP77116, for specific immunotherapy of multiple sclerosis. A magnetic resonance imaging-controlled phase II clinical trial with this altered peptide ligand documented that it was poorly tolerated at the dose tested, and the trial had therefore to be halted. Improvement or worsening of clinical or magnetic resonance imaging parameters could not be demonstrated in this small group of individuals because of the short treatment duration. Three patients developed exacerbations of multiple sclerosis, and in two this could be linked to altered peptide ligand treatment by immunological studies demonstrating the encephalitogenic potential of the myelin basic protein peptide (a.a. 83-99) in a subgroup of patients. These data raise important considerations for the use of specific immunotherapies in general.

IMPORTANCEIn multiple sclerosis (MS), chronic active lesions, which previously could only be detected at autopsy, can now be identified on susceptibility-based magnetic resonance imaging (MRI) in vivo as non-gadolinium-enhancing lesions with paramagnetic rims. Pathologically, they feature smoldering inflammatory demyelination at the edge, remyelination failure, and axonal degeneration. To our knowledge, the prospect of long-term in vivo monitoring makes it possible for the first time to determine their contribution to disability and value as a treatment target.OBJECTIVE To assess whether rim lesions are associated with patient disability and long-term lesion outcomes. DESIGN, SETTING, PARTICIPANTS We performed 3 studies at the National Institutes of Health Clinical Center: (1) a prospective clinical/radiological cohort of 209 patients with MS (diagnosis according to the 2010 McDonald revised MS criteria, age Ն18 years, with 7-T or 3-T susceptibility-based brain MRI results) who were enrolled from January 2012 to March 2018 (of 209, 17 patients [8%] were excluded because of uninterpretable MRI scans); (2) a radiological/pathological analysis of expanding lesions featuring rims; and (3) a retrospective longitudinal radiological study assessing long-term lesion evolution in 23 patients with MS with yearly MRI scans for 10 years or more (earliest scan, 1992). MAIN OUTCOMES AND MEASURES(1) Identification of chronic rim lesions on 7-T or 3-T susceptibility-based brain MRI in 192 patients with MS and the association of rim counts with clinical disability (primary analysis) and brain volume changes (exploratory analysis). (2) Pathological characterization of 10 expanding lesions from an adult with progressive MS who came to autopsy after 7 years of receiving serial in vivo MRI scans. (3) Evaluation of annual lesion volume change (primary analysis) and T1 times (exploratory analysis) in 27 rim lesions vs 27 rimless lesions. RESULTSOf 209 participants, 104 (50%) were women and 32 (15%) were African American. One hundred seventeen patients (56%) had at least 1 rim lesion regardless of prior or ongoing treatment. Further, 84 patients (40%) had no rims (mean [SD] age, 47 [14] years), 66 (32%) had 1 to 3 rims (mean [SD] age, 47 [11] years), and 42 (20%) had 4 rims or more (mean [SD] age, 44 [11] years). Individuals with 4 rim lesions or more reached motor and cognitive disability at an earlier age. Normalized volumes of brain, white matter, and basal ganglia were lower in those with rim lesions. Whereas rimless lesions shrank over time (−3.6%/year), rim lesions were stable in size or expanded (2.2%/year; P < .001). Rim lesions had longer T1 times, suggesting more tissue destruction, than rimless lesions. On histopathological analysis, all 10 rim lesions that expanded in vivo had chronic active inflammation.CONCLUSIONS AND RELEVANCE Chronic active lesions are common, are associated with more aggressive disease, exert ongoing tissue damage, and occur even in individuals treated with effective disease-modifying therapies. These r...

Objective: To determine the frequency and nature of leptomeningeal contrast enhancement in multiple sclerosis (MS) via in vivo 3-tesla postcontrast T2-weighted, fluid-attenuated inversion recovery (FLAIR) MRI and 7-tesla postmortem MRI-pathology correlation.Methods: Brain MRI, using the postcontrast T2-weighted, FLAIR technique, was prospectively collected in 299 MS cases and 37 age-matched neurologically healthy controls. Expert raters evaluated focal gadolinium enhancement in the leptomeningeal compartment. Two progressive MS cases came to autopsy after in vivo MRI characterization. Pathologic and immunohistochemical examination assessed the association of enhancement with leptomeningeal inflammation and adjacent cortical demyelination.Results: Focal contrast enhancement was detected in the leptomeningeal compartment in 74 of 299 MS cases (25%) vs 1 of 37 neurologically healthy controls (2.7%; p 5 0.001). Enhancement was nearly twice as frequent (p 5 0.009) in progressive MS (39/118 cases, 33%) as in relapsingremitting MS (35/181, 19%). Enhancing foci generally remained stable throughout the evaluation period (up to 5.5 years). Pathology showed perivascular lymphocytic and mononuclear infiltration in the enhancing areas in association with flanking subpial cortical demyelination. Conclusion:Leptomeningeal contrast enhancement occurs frequently in MS and is a noninvasive, in vivo marker of inflammation and associated subpial demyelination. It might therefore enable testing of new treatments aimed at eliminating this inflammation and potentially arresting progressive MS. Neurology ® 2015;85:18-28 GLOSSARY MS 5 multiple sclerosis; T2-FLAIR 5 T2-weighted, fluid-attenuated inversion recovery.

BACKGROUND.In some active multiple sclerosis (MS) lesions, a strong immune reaction at the lesion edge may contain growth and thereby isolate the lesion from the surrounding parenchyma. Our previous studies suggest that this process involves opening of the blood-brain barrier in capillaries at the lesion edge, seen on MRI as centripetal contrast enhancement and a colocalized phase rim. We hypothesized that using these features to characterize early lesion evolution will allow in vivo tracking of tissue degeneration and/or repair, thus improving the evaluation of potential therapies for chronic active lesions. METHODS.Centripetally and centrifugally enhancing lesions were studied in 17 patients with MS using 7-tesla MRI. Highresolution, susceptibility-weighted, T1-weighted (before/after gadolinium), and dynamic contrast-enhanced scans were acquired at baseline and months 1, 3, 6, and 12. For each lesion, time evolution of the phase rim, lesion volume, and T1 hypointensity were assessed. In autopsies of 3 progressive MS cases, the histopathology of the phase rim was determined. RESULTS.In centripetal lesions, a phase rim colocalized with initial contrast enhancement. In 12 of 22, this phase rim persisted after enhancement resolved. Compared with centripetal lesions with transient rim, those with persistent rim had less volume shrinkage and became more T1 hypointense between months 3 and 12. No centrifugal lesions developed phase rims at any time point. Pathologically, persistent rims corresponded to an iron-laden inflammatory myeloid cell population at the edge of chronic demyelinated lesions. CONCLUSION.In early lesion evolution, a persistent phase rim in lesions that shrink least and become more T1 hypointense over time suggests that the rim might mark failure of early lesion repair and/or irreversible tissue damage. In later stages of MS, phase rim lesions continue to smolder, exerting detrimental effects on affected brain tissue.

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Objective: To reassess the role of plasmapheresis in the treatment of neurologic disorders. Methods:We evaluated the available evidence based on a structured literature review for relevant articles from 1995 through September 2009. In addition, due to revision of the definitions of classification of evidence since the publication of the previous American Academy of Neurology assessment in 1996, the evidence cited in that manuscript was reviewed and reclassified.

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