Utility of chemokines CCL2, CXCL8, 10 and 13 and interleukin 6 in the pediatric cohort for the recognition of neuroinflammation and in the context of traditional cerebrospinal fluid neuroinflammatory biomarkers.

BACKGROUND: The recognition of active inflammation in the central nervous system (CNS) in the absence of infectious agents is challenging. The present study aimed to determine the diagnostic relevance of five selected chemo/cytokines in the recognition of CNS inflammation and in the context of traditional cerebrospinal fluid (CSF) biomarkers (white blood cell [WBC] counts, oligoclonal bands, protein levels, CSF/serum albumin ratios) and clinical diagnoses. METHODS: C-C and C-X-C motif ligands (CCL2, CXCL8, 10 and 13) and interleukin (IL) 6 levels in the CSF and serum from 37 control and 87 symptomatic children with ten different (mostly noninfectious) inflammatory CNS disorders (16 of which had follow-up samples after recovery) were determined using Luminex multiple bead technology and software. Nonparametric tests were used; p < 0.05 was considered statistically significant. Receiver operating characteristic curves were constructed to analyze controls and 1) all symptomatic samples or 2) symptomatic samples without CSF pleocytosis. RESULTS: Compared with the control CSF samples, levels of all investigated chemo/cytokines were increased in symptomatic CSF samples, and only IL-6 remained elevated in recovery samples (p ≤ 0.001). CSF CXCL-13 levels (> 10.9 pg/mL) were the best individual discriminatory criterion to differentiate neuroinflammation (specificity/sensitivity: 97/72% and 97/61% for samples without pleocytosis), followed by CSF WBC counts (specificity/sensitivity: 97/62%). The clinical utility of the remaining CSF chemo/cytokine levels was determined in descending order of sensitivities corresponding to thresholds that ensured 97% specificity for neuroinflammation in samples without pleocytosis (pg/mL; sensitivity %): IL-6 (3.8; 34), CXCL8 (32; 26), CXCL10 (317; 24) and CCL2 (387; 10). Different diagnosis-related patterns of CSF chemo/cytokines were observed. CONCLUSIONS: The increased CSF level of CXCL13 was the marker with the greatest predictive utility for the general recognition of neuroinflammation among all of the individually investigated biomarkers. The potential clinical utility of chemo/cytokines in the differential diagnosis of neuroinflammatory diseases was identified.

Hypocretin Deficiency Associated with Narcolepsy Type 1 and Central Hypoventilation Syndrome in Neurosarcoidosis of the Hypothalamus.

We report a case of a 53-year-old man presenting with depressed alertness and severe excessive sleepiness in the setting of neurosarcoidosis. Neuroimaging demonstrated hypothalamic destruction due to sarcoidosis with a CSF hypocretin level of 0 pg/mL. The patient also experienced respiratory depression that presumably resulted from hypocretin-mediated hypothalamic dysfunction as a result of extensive diencephalic injury. This is a novel case, demonstrating both hypocretin deficiency syndrome, as well as respiratory dysfunction from destruction of hypocretin neurons and extensive destruction of key diencephalic structures secondary to the underlying neurosarcoidosis.

Experimental infection of goats with Trypanosoma brucei ssp. and effects of treatment with suramin and Mel-B.

A stock of Trypanosoma brucei ssp. isolated from a naturally-infected goat in the Lambwe Valley, Kenya, induced cerebral trypanosomiasis in experimentally-infected goats. Six of nine goats with cerebral trypanosomiasis induced by this stock were cured by a single high dose of suramin (50 mg kg-1). Two other goats appeared to be cured with this dosage of suramin but later developed abnormal central nervous system (CNS) signs and parasitaemia. Parasites first appeared in the cerebrospinal fluid (CSF) and then in the blood and lymph nodes. Mel-B was also effective against primary and relapse cerebral trypanosomiasis in goats.

Calcium, phosphorus, magnesium, and calcitonin concentrations in the serum and cerebrospinal fluid of children.

Mineral metabolism in the cerebrospinal fluid (CSF) of children is poorly understood. Recent reports have suggested a neuroregulatory role for calcitonin. We examined the hypotheses that in children (1) CSF levels of calcium and phosphorus might be low, (2) CSF levels of magnesium might be higher than serum levels of magnesium, and (3) immunoreactive calcitonin might be present in the CSF. We examined serum and CSF samples of 45 children, aged 8 days to 16 years, undergoing spinal taps for suspected meningitis or as part of leukemia therapy. Both serum and CSF levels of calcium correlated with those of magnesium. There was no correlation for CSF levels vs serum levels of calcium, magnesium, or phosphorus. The CSF levels of calcium and phosphorus were lower than the serum levels of these elements, but the CSF levels of magnesium were higher than the serum levels of magnesium. Calcitonin was detected in the CSF of 8% of samples assayed (range, 14 to 175 ng/L [14 to 175 pg/mL]). Two of these five samples had bacteriologically proven meningitis, and two samples were from patients less than 2 months of age. The CSF levels of calcitonin did not correlate with the serum levels of calcitonin. Thus, in children CSF levels of calcium and phosphorus are low, CSF levels of magnesium are higher than the serum levels, and the level of immunoreactive calcitonin is usually not present in the CSF but possibly is elevated in meningitis and early infancy.

Prostaglandins. A review of neurophysiology and psychiatric implications.

This article reviews the function of prostaglandins (PGs) in the nervous system and discusses the possible alterations in PG metabolism as relating to mental illness. The PGs are a unique group of cyclic fatty acids whose immediate precursors are thought to function postsynaptically by inhibition or facillitation of neurotransmission through cyclase inhibition or activation, and by means of a negative feedback loop to inhibit further release of neurotransmitter from the presynaptic nerve. A review of PGs in psychiatric conditions is presented as well as a discussion of the interaction of psychoactive drugs with the PGs. The concluding section of this review discusses possible future strategies to provide insight into PG physiology as it relates to synaptic transmission in normal and pathological conditions in man.

Somatostatin in human cerebrospinal fluid.

To determine whether somatostatin is found in the hypothalamus and extrahypothalamic brain, we studied autopsy brain tissue by specific immunoassay. The hypothalamus contained the highest concentration (16.7 +/- 2.4 S.D. pg per microgram of protein), with small amounts in brainstem, cerebral cortex, cerebellum, pineal gland and spinal cord. Cerebrospinal fluid of seven neurologically normal persons also contained somatostatin in concentrations ranging from 15 to 55 pg per milliliter. To determine whether brain disease leads to abnormal cerebrospinal-fluid somatostatin, we examined 30 patients with neurologic disease, of whom 20 of 24 with cord or cerebral disease had concentrations above the highest normal level. The wide variety of diseases with somatostatin elevation suggests nonspecific leakage from damaged brain tissue. Cerebrospinal-fluid somatostatin may provide a good index of brain damage. Although correlated statistically with cerebrospinal-fluid protein, somatostatin concentration in five of 24 cases exceeded the upper limit of normal by 3 S.D. while protein was normal.