Serum neuron-specific enolase predicting neurological outcomes post-cardiac arrest: a review of the literature.

BACKGROUND: Coronary artery disease is a major problem in the United States, affecting 785 000 individuals, with the most serious event being a cardiopulmonary arrest. Families of post-cardiac arrest patients are left with difficult decisions to be made. OBJECTIVE: This article is a comprehensive literature review examining the current research available to health care professionals about the biomarker serum neuron-specific enolase (NSE) and its use in predicting neurological outcomes in comatose post-cardiac arrest patients. METHODS: Using the bibliographic databases CINAHL, Plus, EBSCOhost, MEDLINE, PubMed, Google Scholar, H. W. Wilson, Cochrane, and NEXUS, from the period 2003 to 2013, revealed there is minimal research or literature on NSE predicting neurological outcomes post-cardiac arrest. RESULTS: Research on this particular biomarker is relatively new, and more research is necessary to establish an adequate amount of support. At this time, an exact NSE cutoff value or its exact ability to help predict neurological outcomes is unable to be established, and further research is necessary. DISCUSSION: This literature review should provide a basic understanding of NSE and its ability to help predict neurological outcomes of post-cardiac arrest patients earlier. The research provides evidence that NSE should be considered in determining outcomes. However, more research is necessary before nursing practice is changed and implemented into patient care.

Bispectral index predicts deaths within 2 weeks in coma patients, a better predictor than serum neuron-specific enolase or S100 protein.

PURPOSE: We assessed the ability of bispectral index (BIS) to predict clinical outcome (dead or alive within 2 weeks). METHODS: In total, 90 coma patients with severe brain injuries underwent BIS monitoring, and serum neuron-specific enolase (NSE) and S100 protein levels were assayed within the first 3 days of admission. Receiver operator characteristic (ROC) curve analysis was used to assess the performance of BIS values for predicting death within 2 weeks. A cutoff value was calculated using the Youden index. RESULTS: A significant negative correlation was found between BIS value and serum NSE and S100 levels. The area under the curve for BIS value was 0.841 (p < 0.001, 95 % CI = 0.751-0.931), and higher than for NSE (0.713) (p = 0.002, 95 % CI = 0.582-0.844) or S100 (0.790) (p < 0.001, 95 % CI = 0.680-0.899). The optimal cutoff of BIS was 32.5. Serum NSE and S100 protein levels and the mortality rate were significantly lower in patients with a BIS value >32.5 than in patients with a BIS value ≤32.5. CONCLUSIONS: Bispectral index values may reflect degree of brain injury, and BIS is an objective and noninvasive monitoring method for helping clinicians to predict death in patients with a BIS value ≤32.5.

Serum neuron-specific enolase as predictor of outcome in comatose cardiac-arrest survivors: a prospective cohort study.

BACKGROUND: The prediction of neurological outcome in comatose patients after cardiac arrest has major ethical and socioeconomic implications. The purpose of this study was to assess the capability of serum neuron-specific enolase (NSE), a biomarker of hypoxic brain damage, to predict death or vegetative state in comatose cardiac-arrest survivors. METHODS: We conducted a prospective observational cohort study in one university hospital and one general hospital Intensive Care Unit (ICU). All consecutive patients who suffered cardiac arrest and were subsequently admitted from June 2007 to February 2009 were considered for inclusion in the study. Patients who died or awoke within the first 48 hours of admission were excluded from the analysis. Patients were followed for 3 months or until death after cardiopulmonary resuscitation. The Cerebral Performance Categories scale (CPC) was used as the outcome measure; a CPC of 4-5 was regarded as a poor outcome, and a CPC of 1-3 a good outcome. Measurement of serum NSE was performed at 24 h and at 72 h after the time of cardiac arrest using an enzyme immunoassay. Clinicians were blinded to NSE results. RESULTS: Ninety-seven patients were included. All patients were actively supported during the first days following cardiac arrest. Sixty-five patients (67%) underwent cooling after resuscitation. At 3 months 72 (74%) patients had a poor outcome (CPC 4-5) and 25 (26%) a good outcome (CPC 1-3). The median and Interquartile Range [IQR] levels of NSE at 24 h and at 72 h were significantly higher in patients with poor outcomes: NSE at 24 h: 59.4 ng/mL [37-106] versus 28.8 ng/mL [18-41] (p < 0.0001); and NSE at 72 h: 129.5 ng/mL [40-247] versus 15.7 ng/mL [12-19] (p < 0.0001). The Receiver Operator Characteristics (ROC) curve for poor outcome for the highest observed NSE value for each patient determined a cut-off value for NSE of 97 ng/mL to predict a poor neurological outcome with a specificity of 100% [95% CI = 87-100] and a sensitivity of 49% [95% CI = 37-60]. However, an approach based on a combination of SSEPs, NSE and clinical-EEG tests allowed to increase the number of patients (63/72 (88%)) identified as having a poor outcome and for whom intensive treatment could be regarded as futile. CONCLUSION: NSE levels measured early in the course of patient care for those who remained comatose after cardiac arrest were significantly higher in patients with outcomes of death or vegetative state. In addition, we provide a cut-off value for NSE (> 97 ng/mL) with 100% positive predictive value of poor outcome. Nevertheless, for decisions concerning the continuation of treatment in this setting, we emphasize that an approach based on a combination of SSEPs, NSE and clinical EEG would be more accurate for identifying patients with a poor neurological outcome.

Risk of hyperammonemic coma in the puerperium: two cases of women with diagnosed and undiagnosed deficiency of urea cycle enzymes.

Deficiencies of urea cycle enzymes are rare metabolic disorders. Inadequate function of these enzymes may in worst cases lead to hyperammonemic encephalopathy and death. The danger of urea cycle enzyme deficiencies is that previously healthy adults with no prior medical history suggesting these deficiencies may suddenly develop life-threatening complications during prolonged catabolic situations such as delivery or surgery. Since most of the metabolic disorders are diagnosed during childhood, it may sometimes be difficult to bear in mind these rare diseases as a cause of unconsciousness in adulthood. However, early diagnosis and prompt initiation of ammonia-lowering treatment are essential for survival of these patients. We present two pregnant women with urea cycle disorders: one with a known deficiency and an uncomplicated outcome, and another with a previously undiagnosed disorder and life-threatening course of the postpartum period.

Late-onset ornithine transcarbamylase deficiency: a potentially fatal yet treatable cause of coma.

Hyperammonaemia due to ornithine transcarbamylase (OTC) deficiency is a well-described cause of coma in neonates. Rarely, adults with this disorder may also present with coma. Here we describe the first reported case, to our knowledge, in a pregnant woman. She was successfully treated with metabolic therapy and, contrary to usual paediatric practice, renal replacement therapy. We review the biochemistry of OTC deficiency and other urea cycle disorders, and discuss the physiological rationale and evidence base for treatment of this condition. We highlight the need to consider hyperammonaemia in the differential diagnosis of coma.

Serum neuron-specific enolase predicts outcome in post-anoxic coma: a prospective cohort study.

OBJECTIVE: The aim of this study was to investigate whether serial serum neuron-specific enolase (NSE) can be used to predict neurological prognosis in patients remaining comatose after cardiopulmonary resuscitation (CPR). DESIGN. Observational cohort study. Clinicians were blinded to NSE results. SETTING: Eighteen-bed general ICU. PATIENTS: Comatose patients admitted to the ICU after CPR. INTERVENTIONS: Serum NSE was measured at admission and daily for 5 days. MEASUREMENTS AND RESULTS: Patients received full intensive treatment until recovery or until absence of cortical response to somatosensory evoked potentials more than 48 h after CPR proved irreversible coma. Of the 110 patients included (mean GCS at ICU admission 3, range 3--9), 34 regained consciousness, five of whom died in hospital. Seventy-six patients did not regain consciousness, 72 of whom died in hospital. Serum NSE at 24 h and at 48 h after CPR was significantly higher in patients who did not regain consciousness than in patients who regained consciousness (at 24 h: median NSE 29.9 microg/l, range 1.8-250 vs 9.9 microg/l, range 4.5-21.5, P<0.001; at 48 h: median 37.8 microg/l, range 4.4-411 vs 9.5 microg/l, range 6.2-22.4, P= 0.001). No patient with a serum NSE level >25.0 microg/l at any time regained consciousness. Addition of NSE to GCS and somatosensory evoked potentials increased predictability of poor neurological outcome from 64% to 76%. CONCLUSIONS: High serum NSE levels in comatose patients at 24 h and 48 h after CPR predict a poor neurological outcome. Addition of NSE to GCS and somatosensory evoked potentials increases predictability of neurological outcome.

[3-hydroxy-3-methylglutaric aciduria and recurrent Reye-like syndrome]. / Aciduria 3-hidroxi-3-metilglutárica y síndrome Reye-like recurrente.

INTRODUCTION: 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMG-CoA lyase) is an inborn error of ketogenesis and Leucine catabolism. HMG-CoA lyase catalyses the final step in leucine degradation, converting HMG-CoA to acetyl-CoA and acetoacetic acid. Clinical manifestations include hepatomegaly, lethargy or coma and apnoea. Biochemically there is a characteristic absence of ketosis with hypoglycemia, acidosis, hipertransaminasemia and variable hyperammoniemia. The urinary organic acid profile includes elevated concentrations of 3-hydroxy-3-isovaleric, 3-hydroxy-3-methylglutaric, 3-methylglutaconic and 3-methylglutaric acids. CLINICAL CASE: Here, we report the case of a 17-year-old girl who presented in both ten months and five years of age a clinical picture characterized by lethargy leading to apnea and coma, hepatomegaly, hypoglycemia, metabolic acidosis, hyperammoniemia, elevated serum transaminases and absence of ketonuria. Diagnostic of Reye syndrome was suggested by hystopathologic finding of hepatic steatosis and clinical and biochemical data. As of 11 years old, laboratory investigations revealed carnitine deficiency and characteristic aciduria. Confirmatory enzyme diagnosis revealing deficiency of HMG-CoA lyase was made in cultured fibroblasts. CONCLUSION: Our report constitutes an example of the presentation of HMG-CoA lyase deficiency as recurrent Reye-like syndrome.

Serum pancreatic enzymes in patients with coma due to head injury or acute stroke.

Serum amylase and lipase were measured in 32 patients with cerebral ischemia, 19 with spontaneous cerebral hemorrhage, 15 with head injury and intracranial bleeding, and 22 with head injury without intracranial bleeding; 20 healthy subjects were also studied as controls. Serum pancreatic isoamylase concentrations were assayed in hyperamylasemic sera. The overall incidence of hyperamylasemia was 14% (12 of 88 patients: 4 with cerebral ischemia, 4 with spontaneous cerebral hemorrhage, 1 with head injury and intracranial bleeding, and 3 with head injury without intracranial bleeding). In 4 of the 12 patients the hyperamylasemia was of pancreatic origin: 1 patient with cerebral ischemia, 1 patient with spontaneous cerebral hemorrhage, 1 patient with head injury and intracranial bleeding, and 1 patient with head injury without intracranial bleeding. The incidence of hyperlipasemia was 7% (6 of the 88 patients: 1 patient with cerebral ischemia, 2 with spontaneous cerebral hemorrhage, and 3 with head injury without intracranial bleeding). We conclude that hyperamylasemia is more frequent than hyperlipasemia in patients with an altered state of consciousness due to head injury or stroke and is usually of non-pancreatic origin. This knowledge may save these patients from invasive and costly examinations.

An assessment of cerebrospinal fluid's total creatine-kinase activity in the differential diagnosis of metabolic and organic causes of coma.

The objective of the study was to assess total cerebrospinal creatinine-kinase activity (CSF-CK) measurement in differential diagnosis of "metabolic" and organic causes of coma. The setting for the study was a tertiary care reference medical center and community general hospital. The design of the study was a series of consecutive patients with profound coma (Glasgow scale ratings between 3 and 6) as the presenting complaint to the emergency room and controls. Measurements and main results were as follows: CSF-CK was measured in 103 consecutive patients including 18 patients with metabolic causes of coma, 27 patients with organic causes of coma, 18 patients scheduled for elective orthopedic surgery with epidural anesthesia and 27 patients with compressive myelopathy and radiculopathy. CSF-CK activities were significantly different between groups (H = 29.48, p < 0.001, Kruskal-Wallis test), controls had a median of 0 mU/ml (range 0-16 mU/ml), patients with metabolic causes of coma had a median of 0 mU/ml (range 0-65 mU/ml), patients with compressive myelopathy or radiculopathy had a median of 19 mU/ml (range 0-80 mU/ml), and patients with organic causes of coma had a median of 20 mU/ml (range 0-400 mU/ml). The test sensitivity was 83% (95% confidence interval (CI 65-100%) specificity 62% (CI 43-80%) positive predictive value 60% (CI 49-79%) and negative predictive value 85% (CI 75-95%). The conclusion of the study was that the test is useful for ruling out metabolic causes of coma when CSF-CK activity is high (i.e., above 16 mU/ml).

Brain membrane serine protease activity in human cortex compared with rat: implication for Alzheimer's disease.

Cerebral cortex from humans and rats was extracted sequentially with detergent-containing and low-ionic-strength buffers. The resulting pellet was extracted with detergent/high-ionic-strength buffer to yield a soluble enzyme preparation. This was incubated with substrate prepared from rat cerebral cortical membranes containing amyloid precursor protein-like immunoreactivity (APPLIR) of 116 kD approximate apparent molecular mass. The effectiveness of various enzyme preparations to degrade APPLIR was: routine-post-mortem (pm)-delay human samples > rat pup > short-pm-delay human samples >> adult rat. In incubations with human samples only a 100-kD product accumulated. The activity in human brain was inhibited by phenylmethylsulphonylfluoride, insensitive to Ca2+, correlated with pyramidal neurone numbers but not those of astrocytes and was not significantly higher in Alzheimer's disease compared with controls. These data are discussed in terms of other approaches for studying proteolytic activity to explain the deposition of beta-amyloid protein in this disease.

Increased serum phospholipase A2 activity in Malawian children with falciparum malaria.

Some clinical manifestations of severe malaria resemble those of sepsis and there may be mediators of the host response that are common to both sepsis and malaria. Phospholipase A2 (PLA2), a proinflammatory enzyme whose expression is induced by tumor necrosis factor (TNF), has been implicated in the pathogenesis of complications of the sepsis syndrome. We examined levels of circulating PLA2 in Plasmodium falciparum malaria and studied the association of PLA2 with disease severity. Plasma PLA2 and TNF were measured in 75 Malawian children with P. falciparum malaria. The mean (SD) plasma PLA2 activity in children with acute malaria was 53,804 (37,256) units/ml as compared with 424 (349) units/ml in 34 healthy controls (P < 0.00001). The mean PLA2 activity in 45 convalescent patients was 2,546 (7,372) units/ml (P < 0.00001). In 48 patients with pretreatment PLA2 activity less than 60,000 units/ml, mortality was 8.3%, while in 27 patients with pretreatment PLA2 levels greater than 60,000 units/ml, mortality was 33.3% (P = 0.008). There were significant correlations between PLA2 and TNF (r = 0.471, P < 0.01), density of parasitemia (r = 0.443, P < 0.0001) and a decrease in hematocrit (r = 0.352, P < 0.005). These data show that P. falciparum malaria is associated with a markedly increased circulating PLA2, especially in patients with severe disease, as manifested by high parasite burden, anemia, coma, and death.

Hyperammoniemic coma in an adolescent girl: an unusual case of ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTCD) is caused by an alteration of urea synthesis, linked with partial modification of the X-chromosome, whose clinical manifestations are: lethargy, nausea, vomiting and cerebral edema. While in newborn males OTCD presents with hyperammoniemia leading to cerebral palsy with profound neurological impairment and eventually death, in women who are healthy carriers, it is possible to detect the disorder only through specific tests, since heterozygote women are rarely symptomatic. We describe the case of a young woman admitted to the hospital after an episode of mental confusion with vomiting and psychomotor restlessness, which had previously occurred several times during the premenstruum and lasted a few hours. A 2 day history of stupor made admission mandatory. Tests carried out during the hospital stay showed marked hyperammoniemia and unconjugated hyperbilirubinemia, marked cerebral edema documented by a CT scan. Liver biopsy and CSF test were normal. Screening of plasma and urinary aminoacids, level of orotic acid in the urine and OTC activity in the liver, confirmed the diagnosis of OTCD. The possibility of early diagnosis and therapy of a disease which otherwise leads to death, emphasizes the importance of precise evaluation of a possible organic cause of anorexia and behaviour disorders in young women.

Carbamyl phosphate synthetase-1 deficiency discovered after valproic acid-induced coma.

Valproic acid induced coma is presented in an adult patient without a history of metabolic disease. Liver biopsy revealed a reduction in activity of carbamyl phosphate synthetase-I, an enzyme obligated for transformation of ammonia to urea in the urea cycle. After recovery CT scan follow-up showed marked cerebral atrophy which did not exist prior to the state of coma. Risk factors are discussed.

Neuropsychiatric manifestations of defect in mitochondrial beta oxidation response to riboflavin.

A 29 year old woman is described with severe hyperemesis gravidarum, atypical migraine, numerous admissions to hospital for psychiatric illness, non-epileptic seizures, and valproate-induced coma. Metabolic studies and measurement of [9,10(n)-3H]palmitate oxidation by cultured fibroblasts suggested a multiple acyl-CoA dehydrogenation disorder. Treatment with riboflavin abolished headaches and abnormal behaviour and normalised the plasma free carnitine level. Subtle defects in mitochondrial beta oxidation may be a treatable cause of disordered behaviour in adults.

Fructose 2,6-bisphosphate in hypoglycemic rat brain.

Fructose 2,6-bisphosphate has been studied during hypoglycemia induced by insulin administration (40 IU/kg). No changes in content of cerebral fructose 2,6-bisphosphate were found in mild hypoglycemia, but the level of this compound was markedly decreased in hypoglycemic coma and recovered after 30 min of glucose administration. To correlate a possible modification of the concentration of the metabolite with selective regional damage occurring during hypoglycemic coma, we have analyzed four cerebral areas (cortex, striatum, cerebellum, and hippocampus). Fructose 2,6-bisphosphate concentrations were similar in the four areas analyzed; severe hypoglycemia decreased levels of the metabolite to the same extent in all the brain areas studied. The decrease in content of fructose 2,6-bisphosphate was not always accompanied by a parallel decrease in ATP levels, a result suggesting that the low levels of the bisphosphorylated metabolite during hypoglycemic coma could be due to the decreased 6-phosphofructo-2-kinase activity, mainly as a consequence of the fall in concentration of its substrate (fructose 6-phosphate). These results suggest that fructose 2,6-bisphosphate could play a permissive role in cerebral tissue, maintaining activation of 6-phosphofructo-1-kinase and glycolysis.

The prognostic value of the brain sodium-potassium ATPase enzyme concentration in head injury.

Sodium-potassium adenosine triphosphatase (ATPase) enzyme was determined in the brain tissue of 11 patients with head injury and 6 control patients. Patients with head injury included in this study were selected from two categories: (a) patients in deep coma due to severe head injury [Glasgow Coma Scale (GCS) less than 8; 6 cases]; (b) patients with depressed skull fractures with dural tears who were conscious and able to give an adequate verbal response (GCS greater than 10; 5 cases). The level of the enzyme was significantly reduced in comatose patients with severe head injury as compared to the controls (P less than 0.001) or to conscious patients with depressed fractures (P less than 0.001). In the group of conscious patients with depressed fractures, the enzyme level was no different from that of the controls (P = 0.4215). All comatose patients with severely reduced enzyme levels subsequently died, whereas those with depressed fractures with normal enzyme levels survived. The relationship between a low enzyme level and brain edema in severe head injury is discussed.

Neuron-specific enolase in comatose children.

Sequential examination of neuron-specific enolase in cerebrospinal fluid and serum was performed in 20 comatose children with acute encephalitis, acute encephalopathy, or Reye's syndrome. Neuron-specific enolase activities corresponded to the degree of brain damage. As neuron-specific enolase levels increased to greater than 80 ng/mL, patients had more severe impairment or died. Neuron-specific enolase may be a useful marker for evaluating the degree of neuronal damage and prognosis.