Neuron-specific Enolase Levels In Cerebrospinal Fluid Research Articles

Value of Biochemical Markers for Outcome in Term Infants With Asphyxia

Perinatal asphyxia remains a common cause of neonatal deaths and morbidity as well as long-term neurologic disability. Numerous biochemical markers have been proposed for evaluating infants having perinatal asphyxia. This prospective study evaluated 3 putative markers of outcome in term infants with perinatal asphyxia: interleukin-6 (IL-6), neuron-specific enolase (NSE), and the urinary uric acid/creatinine ratio (UA/Cr ratio). Marker levels were estimated simultaneously in blood and cerebrospinal fluid (CSF) within 1 to 3 days after birth in 21 infants with hypoxic\Nischemic encephalopathy (HIE). They subsequently were monitored for development and neurologic function over the first 2 years of life using the Denver Developmental Screening Test II. Twelve infants were diagnosed as having mild and 9 moderate to severe HIE. Two infants died in the neonatal intensive care unit. The overall outcome was thought to be adverse in 7 infants (33%). Five surviving infants, all of whom had moderate to severe HIE, developed severe motor deficits (spastic hemiparesis in 3 infants and spastic diapiresis and spastic hemiparesis in 1 infant each). Four of the 21 infants had postneonatal seizures. Of 7 infants with moderate to severe HIE, 9 (78%) had an adverse outcome, whereas all of those with mild HIE had a favorable outcome. Levels of IL-6 in both serum and CSF were significantly higher in infants with moderate to severe HIE than in the mildly affected infants. Moderate to severe HIE invariably predicted higher IL-6 levels in CSF. Serum and CSF concentrations of IL-6 correlated to a high degree. Levels of NSE in CSF were significantly higher in cases of moderate to severe HIE than in mildly affected infants. Serum NSE levels did not correlate significantly with the degree of HIE. CSF levels of NSE correlated relatively strongly with CSF levels of IL-6. UA/Cr ratios did not correlate significantly with the degree of HIE. Of all the parameters, IL-6 in CSF best predicted the outcome at age 2 years. A cutoff value of 25.9 pg/mL was 100% sensitive and 79% specific for an adverse outcome, and had positive and negative predictive values of 100% and 86%, respectively. Levels of NSE in CSF also had high predictive value They were 86% sensitive and 64% specific, with positive and negative predictive values of 90% and 55%, respectively. Neither serum NSE nor the urinary UA/Cr ratio was a good predictor of adverse outcomes. Should these predictive markers of later neurodevelopmental outcome be found accurate in further samples of infants in the neonatal intensive care unit, they might become a routine part of the workup of infants having perinatal asphyxia.

Use of neuron-specific enolase for assessing the severity and outcome in patients with neurological disorders.

Neuron-specific enolase (NSE) is a glycolytic enzyme present almost exclusively in neurons and neuroendocrine cells. NSE levels in cerebrospinal fluid (CSF) are assumed to be useful to estimate neuronal injury and clinical outcome of patients with serious clinical manifestations such as those observed in stroke, head injury, anoxic encephalopathy, encephalitis, brain metastasis, and status epilepticus. We compared levels of NSE in serum (sNSE) and in CSF (cNSE) among four groups: patients with meningitis (N=11), patients with encephalic injuries associated with impairment of consciousness (ENC, N=7), patients with neurocysticercosis (N=25), and normal subjects (N=8). Albumin was determined in serum and CSF samples, and the albumin quotient was used to estimate blood-brain barrier permeability. The Glasgow Coma Scale score was calculated at the time of lumbar puncture and the Glasgow Outcome Scale (GOS) score was calculated at the time of patient discharge or death. The ENC group had significantly higher cNSE (P=0.01) and albumin quotient (P=0.005), but not sNSE (P=0.14), levels than the other groups (Kruskal-Wallis test). Patients with lower GOS scores had higher cNSE levels (P=0.035) than patients with favorable outcomes. Our findings indicate that sNSE is not sensitive enough to detect neuronal damage, but cNSE seems to be reliable for assessing patients with considerable neurological insult and cases with adverse outcome. However, one should be cautious about estimating the severity of neurological status as well as outcome based exclusively on cNSE in a single patient.

Neuron-specific enolase levels and neuroimaging in asphyxiated term newborns.

The study was designed to investigate the cerebrospinal fluid and serum levels of neuron-specific enolase, along with cranial ultrasonography, magnetic resonance imaging (MRI), and electroencephalography (EEG), for predicting the clinical state and neurologic outcome of 26 asphyxiated term newborns. The babies were graded according to the Sarnat and Sarnat classification. Cerebrospinal fluid neuron-specific enolase levels of the 18 babies in the whole hypoxic-ischemic encephalopathy group were higher than the 8 babies in the "no encephalopathy" group. Cerebrospinal fluid neuron-specific enolase levels of 13 cases in the hypoxic-ischemic encephalopathy grade 2 and 3 groups (high-risk group) were higher than both the no encephalopathy and hypoxic-ischemic encephalopathy grade 1 groups when pooled. Cerebrospinal fluid neuron-specific enolase levels of the 7 newborns in the hypoxic-ischemic encephalopathy grade 3 group were also significantly higher than the 5 in the hypoxic-ischemic encephalopathy grade 1 group. The findings of cranial MRI, EEG, and cerebrospinal fluid neuron-specific enolase levels were correlated with each other and the clinical grade of the patients and also were predictive of the neurologic outcome at 1 year of age. Cerebrospinal fluid neuron-specific enolase levels, cranial MRI, and EEG are predictive of outcome of hypoxic-ischemic brain damage in asphyxiated newborns, and this predictivity would increase with the combination of these diagnostic parameters.

Biochemical Alterations in Cerebrospinal Fluid During Thoracoabdominal Aortic Cross-clamping in Dogs

Spinal cord damage during and after thoracoabdominal aortic cross-clamping continues to be a major problem. Somatosensory and motor evoked potentials have been used to monitor spinal cord function but their value for predicting paraplegia has been controversial. The aim of this study was to measure biochemical markers in the cerebrospinal fluid (CSF) and correlate changes with spinal cord ischemia. Since neural tissue utilizes only glucose as substrate for its metabolism and energy supply, we measured changes of metabolites of anaerobe glycolysis. In a canine model in which general anesthesia was used, the thoracoabdominal aorta was cross-clamped proximally and distally for 60 min. Hemodynamic parameters, blood gases, and glucose level were monitored continuously. Blood and CSF sampling were performed at baseline, at 15, 30, and 55 min during cross-clamping, and at 5 and 15 min after aortic declamping. Levels of lactate (1.7 +/- 0.1 to 3.2 +/- 0.3 mmol/L), pCO2 (43 +/- 2 to 35 +/- 1.6 mmHg), and neuron-specific enolase (NSE) (5.17 +/- 0.5 to 13.0 +/- 3.5 mg/L) in CSF showed significant changes (p < 0.05) during clamping and reperfusion. Changes in CSF lactate and NSE levels correlate with the duration of spinal cord ischemia. These markers of ischemic metabolism appear suitable to monitor the degree of spinal cord ischemia during thoracoabdominal cross-clamping and may be useful to predict the efficacy of preventive methods.

Elevation of neuron-specific enolase in serum and cerebrospinal fluid of early stage Creutzfeldt-Jakob disease.

To investigate the levels of neuron-specific enolase (NSE) in serum and cerebrospinal fluid (CSF) of patients with early stage Creutzfeldt-Jakob disease (CJD). The levels of NSE in serum and CSF were examined in 6 cases with CJD patients. The levels of NSE in CSF were measured in 8 age matched control patients with other neurological diseases and the levels of serum NSE were also measured in another 8 age matched control patients with other neurological diseases. The groups of 8 age matched control patients consisted of 1 same patient and 7 different patients in the 2 control groups both for serum and CSF. The level of serum NSE in CJD (17.3 +/- 7.0 ng/ml, mean +/- SD) was significantly higher than that of controls (6.5 +/- 1.6) (P < 0.02) as was the case in CSF (79.3 +/- 53.3 ng/ml) vs (9.6 +/- 2.9) (P < 0.03). Although mean NSE levels of CJD were higher in CSF than in the serum, there still is a case with higher serum NSE level than CSF. These results suggest that the mechanism of elevation of serum NSE may not be a simple leakage from CSF, and that the measurement of serum NSE level may be useful for diagnosis of early stage CJD.

Acute and transient increase of lipocalin-type prostaglandin D synthase (β-trace) level in cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage

We measured the concentration of lipocalin-type prostaglandin D synthase (PGDS) in cerebrospinal fluid (CSF) and serum in patients 1, 3, 5, 7, 9, 11, 14 and 17 days after subarachnoid hemorrhage (SAH) due to ruptured cerebral aneurysms. The PGDS level in lumbar CSF increased about two-fold at day 3 (20.85±2.71 μg/ml, mean±SE) and at day 5 (25.24±3.76), as compared with the level at day 1 (11.25±1.07). The CSF level gradually decreased and returned to the day 1 level at day 17. The serum PGDS level was much lower than the CSF level (0.39±0.06 at day 1) and almost unchanged until day 17. The neuron-specific enolase level in CSF, as an index of brain damage, was maximum at day 1 (29.83±7.32 ng/ml) and decreased at day 3 and at day 5 (18.28±2.65 and 11.95±1.82, respectively). These results suggest that the transient and delayed increase in the PGDS level in CSF is due to its induction of PGDS in the arachnoid membrane after SAH.

Astroglial and neuronal proteins in cerebrospinal fluid as markers of CNS involvement in Lyme neuroborreliosis.

Is Lyme neuroborreliosis, even in its early phase, a parenchymatous disorder in the central nervous system (CNS), and not merely a meningitic process? We quantified cerebrospinal fluid (CSF) levels of four nerve and glial cell marker proteins in Lyme neuroborreliosis patients with pretreatment durations of 7-240 days. All 23 patients had meningoradiculitis, and six had objective signs of encephalopathy. Glial fibrillary acidic protein (GFAp) pretreatment levels in CSF, and the light subunit of neurofilament protein (NFL) levels were related to clinical outcome and declined significantly after treatment (P < 0.001 and P < 0.01, respectively). NFL was detectable in 11 out of 22 patients, and pre- and post-treatment NFL levels were associated with the duration of neurological symptoms within 100 days prior to treatment. Neuron-specific enolase (NSE) concentrations also decreased after therapy (P < 0.001), while CSF levels of glial S-100 protein remained unchanged. The pretreatment duration of disease was related to postinfectious sequelae. GFAp, NSE and NFL levels in CSF are unspecific indicators of astroglial and neuronal involvement in CNS disease. The findings in the present study are in agreement with the hypothesis that early and late stages of Lyme neuroborreliosis damage the CNS parenchyma.

Neuron-specific enolase levels in the cerebrospinal fluid of neurologically healthy children

Levels of neuron-specific enolase (NSE) levels in the cerebrospinal fluid (CSF) of children without neurological disease were assessed. CSF samples were obtained from 37 subjects aged between 1 month and 13 years. All subjects had undergone lumbar puncture for diagnostic purposes, and were subsequently shown not to be suffering any form of neurological disease. NSE levels in CSF were determined by an enzyme immunoassay method. NSE level ranged from below the detection limit to 4.8 ng/ml (1.52±1.01 ng/ml). The present results may be useful as a basis for defining reference levels of NSE in CSF in post-neonatal children.

Serum and CSF levels of neuron-specific enolase (NSE) in cardiac surgery with cardiopulmonary bypass: a marker of brain injury?

We investigated whether neuron-specific enolase (NSE) in serum or cerebrospinal fluid (CSF) reflects subtle or manifest brain injury in children undergoing cardiac surgery using cardiopulmonary bypass (CPB). NSE was measured in serum (s-NSE) before, and up to, 102 h after surgery in 27 children undergoing cardiac surgery with CPB. In 11 children, CSF-NSE was also measured 48 or 66 h post-surgery. As erythrocytes contain NSE, hemoglobin concentration in the samples was determined spectrophotometrically at 550 nm (cut-off limit: absorbance 0.4=560 mg/l) in 14 children and in a further 13 children by spectroscopic multicomponent analysis (cut-off limit 5 μmol/l=80 mg/l). One hundred and one of 214 post-operative serum samples (47%) had to be discarded because of hemolysis (18% spectrophotometrically at 550 nm and 88% with spectroscopic multicomponent analysis). On the first and second post-operative day, the median s-NSE values were significantly higher when compared with samples taken after 54 h or longer ( P=0.008 and P=0.002). All CSF-NSE levels were within the normal range and below the s-NSE measured in the same patient. Although in our study elevated s-NSE seems to indicate brain injury in CPB-surgery, the low concentration of NSE in the post-operative CSF of 11 children puts the neuronal origin of s-NSE in question. NSE from other non-neuronal tissues probably contributes to the elevated s-NSE. Additionally, normal post-operative CSF-NSE values in two children with post-operative neurological sequelae might question the predictive value of CSF-NSE with regard to brain injury.

An Enzyme Immunoassay for Neuron-Specific Enolase in Cerebrospinal Fluid

A direct (as opposed to competitive) enzyme immunoassay (EIA) was developed to detect neuron-specific enolase (NSE) in cerebrospinal fluid (CSF). Most common methods of evaluating NSE levels have utilized radioimmunoassay. These are highly sensitive, but cannot be employed in laboratories not equipped or licensed for the use of radioisotopes. The EIA developed here shows sensitivity within the physiological range of values for CSF-NSE (>1 ng/ml) and can be used in laboratories with appropriate densitometric scanning capabilities. The assay was applied to CSF samples obtained from patients with a variety of diagnoses at the time of surgical intervention for their respective disorders. While there were no diagnostically significant differences between the levels of NSE in CSF from patients with different neurological disorders utilized in the development of this procedure, we were able to differentiate between marginally different levels of NSE. We conclude that we have developed a safe, fast, reliable, and sensitive assay for NSE in the CSF that can be used to study NSE levels in a variety of neurological cases.

Cerebrospinal fluid neuron-specific enolase in Alzheimer's disease and vascular dementia

Levels of neuron-specific enolase (NSE), a glycolytic enzyme localized in neurons, were measured in serum and cerebrospinal fluid (CSF) of patients with early-onset (e-AD) and late-onset (1-AD) Alzheimer's disease, vascular dementia (VD) and controls. Mean CSF NSE levels in patients with Alzheimer's disease did not significantly differ from those in controls, although in the AD group a correlation was found between NSE levels and severity of cognitive deficits. In VD patients, CSF NSE was lower than in controls or in AD patients. These findings are of physiopathological interest but suggest that CSF NSE is not a useful biological marker in dementia disorders.

Cerebrospinal fluid levels of superoxide dismutases in neurological diseases detected by sensitive enzyme immunoassays

We measured cerebrospinal fluid (CSF) levels of Cu/Zn superoxide dismutase (Cu/Zn SOD) and Mn superoxide dismutase (Mn SOD) using enzyme immunoassays in 196 neurological patients and 44 controls. The mean Cu/Zn SOD level was 55.8 ± 27.6 (SD) ng/ml and the Mn SOD, 8.0 ± 2.5 ng/ml in the controls. Cu/Zn SOD or Mn SOD levels showed neither age-nor sex-related differences in the controls. Both SODs were markedly elevated in cerebrovascular diseases, bacterial meningitis and encephalitis. Mn SOD alone was significantly elevated in neurodegenerative diseases. We compared SODs with CSF levels of neuron-specific enolase (NSE) and S-100b protein (S-100b) in cerebral infarction and bacterial meningitis. Both SODs were correlated with NSE and S-100 in patients with cerebral infarction, but not in those with bacterial meningitis. This means that elevations of SODs in CSF may not only be due to leakage from damaged nervous tissues, but also to the induction of SOD in lesions. We conclude that the mean SOD levels were elevated in various neurological diseases, and their varied magnitudes may be associated with the underlying diseases.

Changes in piglet auditory brainstem response amplitudes without increases in serum or cerebrospinal fluid neuron-specific enolase.

We studied the relationship between changes in auditory brainstem responses (ABR) and serum and cerebrospinal fluid levels of neuron-specific enolase (NSE) in hyperbilirubinemic 2- to 8-d-old piglets. Infusion of a stabilized solution of bilirubin resulted in serum bilirubin levels of 571.1 +/- 48.8 mumol/L (mean +/- SEM) after 6 h. ABR were obtained at baseline and then hourly until the piglets were killed. We measured peak amplitudes and latencies for waves I-V, as well as latency for the post-V trough. Changes in amplitudes and latencies were analyzed as slopes because of heterogeneous variances. Over time, a significant reduction was observed in peak II-V amplitudes of bilirubin-infused piglets, but not in those of corresponding controls. No change was observed in latencies. NSE was analyzed by RIA. Serum NSE remained stable throughout the experiment (means 5.1-6.6 micrograms/L) and did not differ between the groups. Cerebrospinal fluid NSE values also remained stable, and no differences that could be ascribed to hyperbilirubinemia were detected. We conclude that hyperbilirubinemia induced significant changes in piglet ABR amplitudes without concomitant evidence of severe neuronal compromise, as might have been indicated by significant increases in serum and/or cerebrospinal fluid NSE levels. This provides further support to the clinical impression that early ABR changes during hyperbilirubinemia may be reversible.

Cerebrospinal fluid and serum levels of neuron-specific enolase in patients with schizophrenia.

Some patients with schizophrenia appear to have brain abnormalities, including enlarged third and lateral ventricles and reduced volumes of temporal lobe structures. These abnormalities could be attributed to a developmental abnormality or a neurodegenerative process. Neuron-specific enolase (NSE), a protein that is found primarily in neurons and neuroendocrine cells, has been used as an index of neuronal damage or degeneration. Levels of NSE in cerebrospinal fluid (CSF) and serum from 50 patients with acute and chronic schizophrenia were compared with those in normal and neurological control subjects. A double-antibody, solid phase iodinated radioimmunoassay was used to determine NSE levels. There was no evidence of elevated levels in patients with schizophrenia, whereas control subjects with neurological illnesses had increased levels of NSE in CSF. Because NSE is rapidly cleared from CSF, however, elevated levels could have been missed. Unmedicated patients tended to have lower levels than medicated patients.

Detection of neuron specific enolase concentrations in cerebrospinal fluid from patients with neurological disorders by means of a sensitive enzyme immunoassay

An enzyme linked immunosorbent assay (ELISA) for the detection of neuron specific enolase (NSE) in cerebrospinal fluid (CSF) was developed. The sensitivity of the ELISA was less than 1 μg/ml. This sensitivity is comparable with radioimmunoassays which have the disadvantage that radiolabelled products are used. The developed assay was used to measure cerebrospinal fluid neuron specific enolase (CSF-NSE) levels in 1178 patients with neurological disorders to establish its potential usefulness and clinical application. CSF-NSE levels in this group of patients were independent of sex and no correlation with age was found. CSF-NSE was significantly increased in Creutzfeldt-Jacob disease, meningeal hemorrhage, thrombosis, Guillain-Barré syndrome and in schizophrenia.

S-100 protein and neuron-specific enolase in CSF after experimental traumatic or focal ischemic brain damage.

Cerebrospinal fluid (CSF) markers of brain damage are potentially capable of providing quantitative information about the extent of certain neurological injury. The presence of such markers in CSF after brain damage is transient and it is essential to understand their kinetics if they are to be used in clinical practice. In the present study, the CSF concentrations of two neurospecific proteins. S-100 protein and neuron-specific enolase (NSE), were determined in rats before and repeatedly after one of two types of experimental brain damage: traumatic cortical injury and focal cerebral ischemia induced by middle cerebral artery (MCA) occlusion. The two types of experimental brain damage resulted in significant differences in the kinetics of S-100 and NSE concentrations in CSF. Cortical contusion was followed by a rapid increase in both S-100 and NSE and a peak occurred in both after about 7 1/2 hours, at which time the values declined toward normal. A second, smaller peak was seen after about 1 1/2 days. The increase and decrease in S-100 and NSE levels in CSF was slower after MCA occlusion; a peak was seen after 2 to 4 days. Furthermore, S-100 was generally higher than NSE after trauma, whereas after MCA occlusion the NSE concentration was slightly higher than the S-100 value. These results support the use of CSF markers for estimation of the extent of brain damage in experimental models and forms a basis for the understanding of their kinetics, which is important for their use in clinical practice.

A more sensitive radioimmunoassay for neuron-specific enolase suitable for cerebrospinal fluid determinations.

Neuron-specific enolase (NSE) and non-neuronal enolase (NNE) have been shown to be highly specific neuronal and glial products respectively and are therefore useful as biochemical markers of the two major cell types in the vertebrate central nervous system. An iodinated radioimmunoassay (RIA) procedure for human NSE (NSE-H) with approximately 50-fold greater sensitivity than the previously available tritiated assay is described. This assay is capable of detecting 100 pg of NSE-H per assay. NSE levels in human cerebrospinal fluid (CSF) which were previously undetectable with the tritiated RIA are now easily measured and have been shown to be approximately 2 ng/ml of CSF. Furthermore, results obtained with the newly described assay procedure on more concentrated brain tissue extracts are comparable to the tritiated RIA. The iodinated NSE RIA is also shown to be capable of accurately detecting added amounts of NSE in human CSF, indicating the potential clinical usefulness of this assay in determining elevated levels of NSE in CSF.