No abstract

Objective To update the 2001 American Academy of Neurology (AAN) guideline on mild cognitive impairment (MCI). MethodsThe guideline panel systematically reviewed MCI prevalence, prognosis, and treatment articles according to AAN evidence classification criteria, and based recommendations on evidence and modified Delphi consensus.Results MCI prevalence was 6.7% for ages 60-64, 8.4% for 65-69, 10.1% for 70-74, 14.8% for 75-79, and 25.2% for 80-84. Cumulative dementia incidence was 14.9% in individuals with MCI older than age 65 years followed for 2 years. No high-quality evidence exists to support pharmacologic treatments for MCI. In patients with MCI, exercise training (6 months) is likely to improve cognitive measures and cognitive training may improve cognitive measures. Major recommendationsClinicians should assess for MCI with validated tools in appropriate scenarios (Level B). Clinicians should evaluate patients with MCI for modifiable risk factors, assess for functional impairment, and assess for and treat behavioral/neuropsychiatric symptoms (Level B). Clinicians should monitor cognitive status of patients with MCI over time (Level B). Cognitively impairing medications should be discontinued where possible and behavioral symptoms treated (Level B). Clinicians may choose not to offer cholinesterase inhibitors (Level B); if offering, they must first discuss lack of evidence (Level A). Clinicians should recommend regular exercise (Level B). Clinicians may recommend cognitive training (Level C). Clinicians should discuss diagnosis, prognosis, long-term planning, and the lack of effective medicine options (Level B), and may discuss biomarker research with patients with MCI and families (Level C). Glossary AAN = American Academy of Neurology; AD = Alzheimer disease; aMCI = amnestic mild cognitive impairment; CI = confidence interval; CIND = cognitively impaired, no dementia; FDA = Food and Drug Administration; IADL = instrumental activities of daily living; MCI = mild cognitive impairment; RR = relative risk.Mild cognitive impairment (MCI) is a condition in which individuals demonstrate cognitive impairment with minimal impairment of instrumental activities of daily living (IADL).

No abstract

Objective To develop recommendations for disease-modifying therapy (DMT) for multiple sclerosis (MS).Methods A multidisciplinary panel developed DMT recommendations, integrating findings from a systematic review; followed an Institute of Medicine-compliant process to ensure transparency and patient engagement; and developed modified Delphi consensus-based recommendations concerning starting, switching, and stopping DMTs pertinent to people with relapsingremitting MS, secondary progressive MS, primary progressive MS, and clinically isolated syndromes of demyelination. Recommendations were supported by structured rationales, integrating evidence from one or more sources: systematic review, related evidence (evidence not from the systematic review), principles of care, and inference from evidence. ResultsThirty recommendations were developed: 17 on starting DMTs, including recommendations on who should start them; 10 on switching DMTs if breakthrough disease develops; and 3 on stopping DMTs. Recommendations encompassed patient engagement strategies and individualization of treatment, including adherence monitoring and disease comorbidity assessment. The panel also discussed DMT risks, including counseling about progressive multifocal leukoencephalopathy risk in people with MS using natalizumab, fingolimod, rituximab, ocrelizumab, and dimethyl fumarate; and made suggestions for future research to evaluate relative merits of early treatment with higher potency DMTs vs standard stepped-care protocols, DMT comparative effectiveness, optimal switching strategies, long-term effects of DMT use, definitions of highly active MS, and effects of treatment on patient-specified priority outcomes. This guideline reflects the complexity of decisionmaking for starting, switching, or stopping MS DMTs. The field of MS treatment is rapidly changing; the Academy of Neurology development process includes planning for future updates.

Anti-N-methyl-D-aspartate receptor (anti-NMDA-R) encephalitis is an immune-mediated syndrome that remains under-recognized despite a growing body of literature. This syndrome has been predominantly described in young females with a constellation of symptoms, including personality changes, autonomic dysfunction and neurologic decompensation. It is commonly associated with mature ovarian teratomas. We describe the classic presentation of anti-NMDA-R encephalitis in three dramatically different patients: Case A, a young woman with ovarian teratoma; Case B, the eldest case reported to date; and Case C, a young male with no identifiable tumor. We review the literature summarizing the differential diagnosis, investigative approach, treatment options and challenges inherent to this disorder. We advocate good supportive care, involvement of multiple health disciplines and use of immune-modulating therapies in patient management. These cases underscore the need for increased awareness and high diagnostic suspicion when approaching the patient with suspected viral encephalitis.

IMPORTANCE Ovarian teratomas are frequently described in patients with N-methyl-Daspartate receptor (NMDAR) encephalitis, yet NMDAR encephalitis is rarely described in patients with ovarian teratomas. Understanding why a minority of patients with teratomas are seen with autoimmune encephalitis may improve the management of NMDAR encephalitis and other teratoma-associated autoimmune diseases. OBJECTIVE To characterize the unique organization of neuroglial elements within ovarian teratomas resected from patients with NMDAR encephalitis. DESIGN Case-control study comparing the pathological features of ovarian teratomas resected from consecutively accrued cases with NMDAR encephalitis SETTING Pathology tissue database at a tertiary academic care center. PARTICIPANTS Five cases with teratoma-associated NMDAR encephalitis and serum or cerebrospinal fluid autoantibodies against central nervous system (CNS) NMDAR and 38 controls (39 ovarian teratomas) without neurological symptoms or signs.EXPOSURES Formalin-fixed, paraffin-embedded ovarian teratomas were examined for the presence of CNS tissue and inflammatory infiltrates using direct microscopy, enhanced with standard histopathological and immunological stains.MAIN OUTCOMES AND MEASURES Frequency of detection of atypical (dysplastic) CNS neuronal elements in ovarian teratomas resected from cases vs controls, as well as characterization of the relationship between atypical neurons and immune infiltrates. RESULTS Central nervous system neuronal elements were detected in 4 of 5 teratomas resected from cases with NMDAR encephalitis and in 20 of 39 controls (P = .36). Atypical neurons were seen within teratomas resected from 4 of 5 cases but not in 39 controls, reliably distinguishing teratomas associated with NMDAR encephalitis (P < .001). If found within the CNS, these histological abnormalities would have received the diagnosis of gangliogliomas (n = 3) and ganglioneuroblastoma (n = 1). Reactive changes were present in teratomas from controls, including ferruginated neurons and Rosenthal fibers. Abnormal neuroglial elements were closely related to immune infiltrates in teratomas resected from 4 of 4 cases. Inflammatory infiltrates were not associated with neuroglial tissue in 20 controls, further differentiating these populations (P < .001).CONCLUSIONS AND RELEVANCE Abnormal neurons within teratomas distinguish cases with NMDAR encephalitis from controls and may promote the development of autoimmunity. quantify rates of cellular proliferation. Inflammatory cell lineages were characterized using stains specific for leukocyte common antigen, B cells, T cells, and histiocytes. Pathological diagnoses and classification or staging of ovarian teratomas were based on accepted critiera. 11 Abnormal neuronal elements within teratomas were described using World Health Organization terminology for neuroglial tumors, 12,13 acknowledging that this terminology was developed for the diagnosis of CNS tumors.

Antibody-mediated encephalitis defines a class of diseases wherein antibodies directed at cellsurface receptors are associated with behavioral and cognitive disturbances. One such recently described encephalitis is due to antibodies directed at alpha-amino-3-hydroxy-5methyl-4isoxazolepropionic acid receptors (AMPAR). This entity is exceptionally rare and its clinical phenotype incompletely described. We present findings from two cases of AMPAR encephalitis that exemplify variability in the disease spectrum, and summarize findings in published cases derived from a systematic literature review. When all patients are considered together, the presence of psychiatric symptoms at presentation portended a poor outcome and was associated with the presence of a tumor. Furthermore, we provide evidence to suggest that the topography of magnetic resonance imaging abnormalities in reported cases mirrors the distribution of AMPARs in the human brain. The potential for neurological improvement following immunomodulatory therapy together with the favorable outcome reported in most cases emphasizes the importance of testing for autoantibodies against neuronal cell-surface proteins, including AMPAR, in patients with clinical and neuroimaging findings suggestive of autoimmune encephalitis. Close attention to the clinical phenotype may inform the presence of malignancy and long-term prognosis.

Objectives:To determine whether neuronal and neuroaxonal injury, neuroinflammation and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals.Methods:Biomarkers of neuronal (total-tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40) and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n=34) or LGI1/CASPR-2 (n=11) AME, and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scores were evaluated in a subset (n=20) of longitudinally followed patients.Results:Biomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, while markers of neuronal injury and synaptic function were stable (total-tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated cases from cognitively normal individuals (AUC=0.99; 95%CI: 0.97, >0.99). Younger age (ρ=-0.56; p=0.01), lower VILIP-1 (ρ=-0.60; p<0.01) and SNAP-25 (ρ=-0.54; p=0.01), and higher log10(YKL-40/SNAP-25) [(ρ=0.48; p=0.04] associated with greater disease severity (higher modified Rankin Score) in prospectively followed patients. Higher YKL-40 (ρ=0.60; p=0.02) and neurogranin (ρ=0.55; p=0.03) at presentation were associated with higher modified Rankin Scores 12-months following hospital discharge.Conclusions:CSF biomarkers suggest that neuronal integrity is acutely maintained in AME patients, despite neuroaxonal compromise. Low-levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell-surface receptors, and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.