Prevalence of Alternative Diagnoses and Implications for Management in Idiopathic Normal Pressure Hydrocephalus Patients.

BACKGROUND: Following Bayes theorem, ventriculomegaly and ataxia confer only a 30% chance of idiopathic Normal Pressure Hydrocephalus (NPH). When coupled with positive responses to best diagnostic testing (extended lumbar drainage), 70% of patients recommended for shunting will not actually have NPH. This is inadequate clinical care. OBJECTIVE: To determine the proportion of alternative and treatable diagnoses in patients referred to a multidisciplinary NPH clinic. METHODS: Patients without previously diagnosed NPH were queried from prospectively collected data. At least 1 neurosurgeon, cognitive neurologist, and neuropsychologist jointly formulated best treatment plans. RESULTS: Of 328 total patients, 45% had an alternative diagnosis; 11% of all patients improved with treatment of an alternative diagnosis. Of 87 patients with treatable conditions, the highest frequency of pathologies included sleep disorders, and cervical stenosis, followed by Parkinson disease. Anti-cholinergic burden was a contributor for multiple patients. Of 142 patients undergoing lumbar puncture, 71% had positive responses and referred to surgery. Compared to NPH patients, mimickers were statistically significantly older with lower Montreal Cognitive Assessment (MoCA) score and worse gait parameters. Overall, 26% of the original patients underwent shunting. Pre-post testing revealed a statistically significant improved MoCA score and gait parameters in those patients who underwent surgery with follow-up. CONCLUSION: Because the Multidisciplinary NPH Clinic selected only 26% for surgery (corroborating 30% in Bayes theorem), an overwhelming majority of patients with suspected NPH will harbor alternative diagnoses. Identification of contributing/confounding conditions will support the meticulous work-up necessary to appropriately manage patients without NPH while optimizing clinical responses to shunting in correctly diagnosed patients.

Use of positive airway pressure in mild cognitive impairment to delay progression to dementia.

STUDY OBJECTIVES: The aim was to assess the relationship between continuous positive airway pressure (CPAP) therapy and cognitive function in patients with mild cognitive impairment (MCI) and obstructive sleep apnea (OSA). METHODS: This was a retrospective chart review of patients with MCI and OSA. CPAP therapy compliance was defined as average use of CPAP therapy for at least 4 hours per night. Kaplan-Meier estimates, log-rank tests, and Cox proportional hazards regression were done to compare the compliance groups in terms of progression to dementia, defined as a Clinical Dementia Rating of 1 or greater. Linear mixed models were used to assess the relationships between CPAP therapy compliance and neurological cognitive function outcomes over time. RESULTS: Ninety-six patients were included with mean age at MCI diagnosis of 70.4 years, mean apnea-hypopnea index of 25.9 events/h, and mean duration of neurology follow-up of 2.8 years. Forty-two were CPAP compliant, 30 were noncompliant, and 24 had no CPAP use. No overall difference between the groups was detected for progression to dementia (P = .928, log-rank test). Patients with amnestic MCI had better CPAP use (P = .016) and shorter progression time to dementia (P = .042), but this difference was not significant after adjusting for age, education, and race (P = .32). CONCLUSIONS: CPAP use in patients with MCI and OSA was not associated with delay in progression to dementia or cognitive decline.

Development of a culture system that supports adult microglial cell proliferation and maintenance in the resting state.

Microglial cells constitute what is considered to be a fixed macrophage population in the central nervous system (CNS), which are broadly implicated in the regulation of neuroinflammation. In the normal adult CNS, microglial cells exist in a resting state characterized by a minimal or negative expression of MHC class II and the co-stimulatory molecules CD80, CD86 and CD40 and exhibit a unique ramified morphology. Microglial cell activation is associated with many inflammatory and neurogenerative CNS pathologies and is characterized by the transformation of resting microglia into cells with a macrophage morphology and up-regulation of MHC class II and co-stimulatory molecules. The cellular and molecular mechanisms required for microglial cell activation and their immunological functions in the adult brain still remain enigmatic, primarily due to the lack of an appropriate culture system that both facilitates microglial survival and expansion in the resting state. Here, we describe a new M-CSF-dependent culture system that overcomes these barriers and allows the long-term proliferation and maintenance of resting adult microglial cells isolated from the CNS. These cultured microglial cells retain their plasticity as indicated by their ability to up-regulate MHC class II and differentiate into cells with a macrophage morphology following the addition of IFN-gamma and GM-CSF, or activated T cells, which produce both cytokines. By measuring the proliferation of the T cells, we were also able to demonstrate that the microglial cells differentiated into fully functional antigen presenting cells. In addition, the replacement of the M-CSF with GM-CSF resulted in the differentiation of microglial cells into cells morphologically and phenotypically similar to dendritic cells. Our microglial cell culture system is the first described that allows the expansion of adult cells in the resting state and will facilitate studies examining the specific mechanisms of microglial cell activation and functions involved in a variety of CNS pathologies.

Gamma delta T cell regulation of IFN-gamma production by central nervous system-infiltrating encephalitogenic T cells: correlation with recovery from experimental autoimmune encephalomyelitis.

Interferon-gamma has been shown to be important for the resolution of inflammation associated with CNS autoimmunity. Because one of the roles of gamma delta T cells is the regulation of inflammation, we asked whether gamma delta T cells were able to regulate CNS inflammation using the autoimmune disease mouse model experimental autoimmune encephalomyelitis (EAE). We show that the presence of gamma delta T cells was needed to promote the production of IFN-gamma by both CD4 and CD8 T cells in the CNS before the onset of EAE. This regulation was shown to be independent of the ability of gamma delta T cells to produce IFN-gamma, and was specific to T cells in the CNS, as no alterations in IFN-gamma production were detectable in gamma delta T cell-deficient mice in the spleen and lymph nodes of mice with EAE or following immunization. Analysis of TCR gamma delta gene usage in the CNS showed that the only TCR delta V gene families present in the CNS before EAE onset are from the DV7s6 and DV105s1 gene families. We also show that the primary IFN-gamma-producing cells in the CNS are the encephalitogenic T cells, and that gamma delta T cell-deficient mice are unable to resolve EAE disease symptoms like control mice, thus exhibiting a long-term chronic disease course similar to that observed in IFN-gamma-deficient mice. These data suggest that CNS resident gamma delta T cells promote the production of IFN-gamma by encephalitogenic T cells in the CNS, which is ultimately required for the recovery from EAE.