Cerebral Metabolic Changes Related to Oxidative Metabolism in a Model of Bacterial Meningitis Induced by Lipopolysaccharide

Background

Cerebral mitochondrial dysfunction is prominent in the pathophysiology of severe bacterial meningitis. In the present study, we hypothesize that the metabolic changes seen after intracisternal lipopolysaccharide (LPS) injection in a piglet model of meningitis is compatible with mitochondrial dysfunction and resembles the metabolic patterns seen in patients with bacterial meningitis.

Methods

Eight pigs received LPS injection in cisterna magna, and four pigs received NaCl in cisterna magna as a control. Biochemical variables related to energy metabolism were monitored by intracerebral microdialysis technique and included interstitial glucose, lactate, pyruvate, glutamate, and glycerol. The intracranial pressure (ICP) and brain tissue oxygen tension (PbtO₂) were also monitored along with physiological variables including mean arterial pressure, blood glucose, lactate, and partial pressure of O₂ and CO₂. Pigs were monitored for 60 min at baseline and 240 min after LPS/NaCl injection.

Results

After LPS injection, a significant increase in cerebral lactate/pyruvate ratio (LPR) compared to control group was registered (p = 0.01). This increase was due to a significant increased lactate with stable and normal values of pyruvate. No significant change in PbtO₂ or ICP was registered. No changes in physiological variables were observed.

Conclusions

The metabolic changes after intracisternal LPS injection is compatible with disturbance in the oxidative metabolism and partly due to mitochondrial dysfunction with increasing cerebral LPR due to increased lactate and normal pyruvate, PbtO₂, and ICP. The metabolic pattern resembles the one observed in patients with bacterial meningitis. Metabolic monitoring in these patients is feasible to monitor for cerebral metabolic derangements otherwise missed by conventional intensive care monitoring.

     

Coenzyme Q10, exercise lactate and CTG trinucleotide expansion in myotonic dystrophy.

Steinert's myotonic dystrophy (DM) is a genetic autosomal dominant disease and the most frequent muscular dystrophy in adulthood. Although causative mutation is recognized as a CTG trinucleotide expansion on 19q13.3, pathogenic mechanisms of multisystem involvement of DM are still under debate. It has been suggested that mitochondrial abnormalities can occur in this disease and deficiency of coenzyme Q 10 (CoQ10) has been considered one possible cause for this. The aim of this investigation was to evaluate, in 35 DM patients, CoQ10 blood levels and relate them to the degree of CTG expansion as well as to the amount of lactate production in exercising muscle as indicator of mitochondrial dysfunction. CoQ10 concentrations appeared significantly reduced with respect to normal controls: 0.85 +/- 0.25 vs. 1.58 +/- 0.28 microg/ml (p < 0.05). Mean values of blood lactate were significantly higher in DM patients than controls (p < 0.05) both in resting conditions (2.9 +/- 0.55 vs. 1.44 +/- 1.11 mmol/L) and at the exercise peak (6.77 +/- 1.79 vs. 4.90 +/- 0.59 mmol/L), while exercise lactate threshold was anticipated (30-50% vs. 60-70% of the predicted normal maximal power output, p < 0.05). Statistical analysis showed that serum CoQ10 levels were significantly (p < 0.05) inversely correlated with both CTG expansion degree and lactate values at exercise lactate threshold level. Our data indicates the occurrence of reduced CoQ10 levels in DM, possibly related to disease pathogenic mechanisms associated with abnormal CTG trinucleotide amplification.     

A randomized trial of coenzyme Q10 in mitochondrial disorders

Case reports and open-label studies suggest that coenzyme Q(10) (CoQ(10)) treatment may have beneficial effects in mitochondrial disease patients; however, controlled trials are warranted to clinically prove its effectiveness. Thirty patients with mitochondrial cytopathy received 1200 mg/day CoQ(10) for 60 days in a randomized, double-blind, cross-over trial. Blood lactate, urinary markers of oxidative stress, body composition, activities of daily living, quality of life, forearm handgrip strength and oxygen desaturation, cycle exercise cardiorespiratory variables, and brain metabolites were measured. CoQ(10) treatment attenuated the rise in lactate after cycle ergometry, increased (∽1.93 ml) VO(2)/kg lean mass after 5 minutes of cycling (P < 0.005), and decreased gray matter choline-containing compounds (P < 0.05). Sixty days of moderate- to high-dose CoQ(10) treatment had minor effects on cycle exercise aerobic capacity and post-exercise lactate but did not affect other clinically relevant variables such as strength or resting lactate.     

Hyperthyroidism associated with papilloedema and pyramidal tract involvement

Summary In a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes [MELAS] who had normal mitochondrial enzyme activity, high doses of coenzyme Q₁₀ (CoQ) were administered. Clinical improvement with decreased serum lactate and pyruvate levels was observed. Though the mechanism of action of CoQ is not known, a trial is worthwhile in patients with MELAS.     

Cytochromec oxidase and coenzyme Q in neuromuscular diseases: a histochemical study

Summary Cytochromec oxidase (CCO) has been histochemically studied in 250 muscle biopsies from patients with different neuromuscular diseases. The results were compared with those obtained on serial sections stained with Gomori's trichrome and with the methods for NADH tetrazolium reductase, succinate dehydrogenase and lactate dehydrogenase. In 58 selected cases serial sections were also stained with a method demonstrating coenzyme Q (CoQ) activity. Demonstration of structural alterations was as good with CCO as with the methods for other oxidative enzymes: particularly evident were alterations of the distribution of mitochondria, such as core areas in central core and multiminicore diseases. Unstained fibers were observed in mitochondrial myopathies, in Becker, Emery-Dreifuss, limb-girdle, facio-scapulo-humeral muscular dystrophies, muscle infarction, polymyositis, motor neuron diseases and neuropathies. The histochemical method for CoQ showed only low specificity, since partial staining was also present in areas devoid of mitochondria, such as cores. CoQ deficiency was not observed in any of the 19 mitochondrial myopathies examined.     

Diagnostic accuracy of blood and CSF lactate in identifying children with mitochondrial diseases affecting the central nervous system

Objective: To determine the diagnostic accuracy of blood and cerebrospinal fluid (CSF) lactate and pyruvate concentrations in identifying children with mitochondrial diseases (MD) affecting the central nervous system (CNS). Methods: We studied lactate and pyruvate concentrations in paired samples of blood and CSF collected concurrently from 17 patients with MD (Leigh encephalomyelopathy 10, MELAS 5, Pearson disease 1, PDH deficiency 1) and those from control patients (n = 49). Results: Although blood and CSF variables (lactate, pyruvate concentrations and lactate/pyruvate ratio) were significantly higher in the mitochondrial group than in the control group, there was considerable overlap of individual values between these two groups. The maximum value of the area under the receiver operating characteristic curve (AUC) was observed for the CSF lactate concentration (0.994, optimal cut-off value 19.9 mg/dl, sensitivity 0.941 and specificity 1.00), followed by the CSF pyruvate level (0.983). There was an inverse relationship between blood lactate and lactate CSF/blood ratio. For blood lactate concentrations between 20 and 40 mg/dl, a significant difference was also noted in the lactate CSF/blood ratio between the two groups (AUC 1.0, optimal cut-off value 0.91, sensitivity 1.0 and specificity 1.0). Conclusions: Our study suggests that that CSF lactate level > 19.9 mg/dl is the most reliable variable for identifying patients with MD affecting the CNS. When blood lactate concentrations are marginally elevated (20–40 mg/dl), lactate CSF/blood ratio > 0.91 may also provide diagnostic information.     

Comparison of MR spectroscopy and MR imaging with contrast agent in children with cerebral astrocytomas

We studied 33 patients with astrocytomas of different grades (68 examinations) by magnetic resonance imaging (MRI) and proton MR spectroscopy (¹H-MRS). We found that in 80% of the spectra, the presence of signals in the area of 0.8–1.5 ppm, assigned to lipids/lactate in ¹H-MR spectra, correlated with signal enhancement after Gd-DTPA administration. We suggest that visibility of lipid/lactate signals could be due to blood–brain barrier damage, which is characterized by contrast agent enhancement. Received: 16 November 1998     

Brief Report: High Frequency of Biochemical Markers for Mitochondrial Dysfunction in Autism: No Association with the Mitochondrial Aspartate/Glutamate Carrier SLC25A12 Gene

In the present study we confirm the previously reported high frequency of biochemical markers of mitochondrial dysfunction, namely hyperlactacidemia and increased lactate/pyruvate ratio, in a significant fraction of 210 autistic patients. We further examine the involvement of the mitochondrial aspartate/glutamate carrier gene (SLC25A12) in mitochondrial dysfunction associated with autism. We found no evidence of association of the SLC25A12 gene with lactate and lactate/pyruvate distributions or with autism in 241 nuclear families with one affected individual. We conclude that while mitochondrial dysfunction may be one of the most common medical conditions associated with autism, variation at the SLC25A12 gene does not explain the high frequency of mitochondrial dysfunction markers and is not associated with autism in this sample of autistic patients.     

Clinical,biochemical and molecular aspects of cerebellar ataxia and Coenzyme Q10 deficiency

Coenzyme Q₁₀ (CoQ) deficiency is an autosomal recessive disorder presenting five phenotypes: a myopathic form, a severe infantile neurological syndrome associated with nephritic syndrome, an ataxic variant, Leigh syndrome and a pure myopathic form. The third is the most common phenotype related with CoQ deficiency and it will be the focus of this review. This new syndrome presents muscle CoQ deficiency associated with cerebellar ataxia and cerebellar atrophy as the main neurological signs. Biochemically, the hallmark of CoQ deficiency syndrome is a decreased CoQ concentration in muscle and/or fibroblasts. There is no molecular evidence of the enzyme or gene involved in primary CoQ deficiencies associated with cerebellar ataxia, although recently a family has been reported with mutations atCOQ2 gene who present a distinct phenotype. Patients with primary CoQ deficiency may benefit from CoQ supplementation, although the clinical response to this therapy varies even among patients with similar phenotypes. Some present an excellent response to CoQ while others show only a partial improvement of some symptoms and signs. CoQ deficiency is the mitochondrial encephalomyopathy with the best clinical response to CoQ supplementation, highlighting the importance of an early identification of this disorder.     

Chronic corticosteroid administration causes mitochondrial dysfunction in skeletal muscle

Corticosteroid myopathy is a major clinical problem in patients undergoing chronic corticosteroid treatment and shows insidious and progressive muscle atrophy in proximal limbs. Although several mechanisms underlying the pathophysiology of muscle injury have been postulated, precise pathogenesis is still not clear. We evaluated the mitochondrial functions in patients receiving corticosteroids compared with those in healthy controls or patients not receiving corticosteroids. The serum levels and total production of lactate were investigated by an aerobic exercise test using a bicycle ergometer. Mitochondrial respiratory activities and oxidative damage in biopsied skeletal muscles were also studied. The results of aerobic exercise tests revealed a significant overproduction of lactate in patients treated with corticosteroids (p < 0.005), which was positively correlated with total corticosteroid doses administered (p < 0.0001). In these patients, mitochondrial enzyme activity in complex I was significantly decreased (p < 0.05) and oxidative damage of biopsied skeletal muscle was remarkable both in mitochondrial and nuclear DNAs (p < 0.001). The results suggest that chronic corticosteroid administration induces mitochondrial dysfunction and oxidative damage in skeletal muscles, which may be the pathogenesis, at least in part, of corticosteroid-induced myopathy. Received: 5 November 2001 Received in revised form: 4 February 2002 Accepted: 7 February 2002     

Clinical cerebral microdialysis: Brain metabolism and brain tissue oxygenation after acute brain injury

Abstract

While continuous monitoring of brain tissue oxygenation (p_tiO₂) is known as a practicable, safe and reliable monitoring technology supplementing traditional ICP-CPP-monitoring, the impact of cerebral microdialysis, now available bedside, is not proven extensively. Therefore our studies focused on the practicability, complications and clinical impact of microdialysis during long term monitoring after acute brain injury, especially the analysis of the correlation between changes of local brain oxygenation and metabolism. Advanced neuromonitoring including ICP-CPP-p_tiO₂ was performed in 20 patients suffering from acute brain injury. Analysis of the extracellular fluid metabolites (glucose, lactate, pyruvate, glutamate) were performed bedside hourly. No catheter associated complications, like infection and bleeding, occurred. However, longterm monitoring was limited in 5 out of 20 patients caused by obliteration of the microdialysis catheter after 3-4 days. In the individual patients partly a correlation between increased lactate levels as well as lactate pyruvate ratios and hypoxic brain tissue oxygenation could be found. Analysing the data sets of all patients only a low correlation was detected indicating physiological and increased lactate and lactate/pyruvate ratio during sufficient brain oxygenation. Additionally, concentrations of excitatory amino acid glutamate were found in normal and elevated range during periods of hypoxic oxygenation (p_tiO₂ < 10 mmHg) and intracranial hypertension. Our data strongly suggest partly evidence of correlation between hypoxic oxygenation and metabolic disturbances after brain injury. On the other hand brain metabolism is altered without changes of cerebral oxygenation. Further studies are indicated to improve our pathophysiological knowledge before microdialysis is routinely useful in neurointensive care. [Neurol Res 2001; 23: 801-806]     

Long-term coenzyme Q10 therapy for a mitochondrial encephalomyopathy with cytochrome c oxidase deficiency: a 31P NMR study

For 2 years we administered high doses of coenzyme Q10 (CoQ) to a patient having mitochondrial encephalomyopathy with cytochrome c oxidase deficiency. Abnormal elevation of the serum lactate per pyruvate ratio and the increased concentration of serum lactate plus pyruvate induced by exercise decreased with CoQ treatment. This therapeutic effect continued for 2 years. 31P nuclear magnetic resonance spectroscopy showed acceleration of the postexercise recovery of the ratio of phosphocreatine to inorganic phosphate in muscle during CoQ treatment. These observations support the beneficial effect of CoQ on the impaired mitochondrial oxidative metabolism in muscle. Also, impaired central and peripheral nerve conductivities consistently improved during CoQ treatment. These results indicate that CoQ has clinical value in the long-term management of patients with mitochondrial encephalomyopathies, even though there are clinical limitations to the effects of this therapy.     

Intraoperative serum lactate is not a predictor of survival after glioblastoma surgery

BackgroundCancer cells can produce lactate in high concentrations. Two previous studies examined the clinical relevance of serum lactate as a biomarker in patients with brain tumors. Patients with high-grade tumors have higher serum concentrations of lactate than those with low-grade tumors. We hypothesized that serum lactic could be used of biomarker to predictor of survival in patients with glioblastoma (GB).MethodsThis was a retrospective study. Demographic, lactate concentrations and imaging data from 275 adult patients with primary GB was included in the analysis. The progression free survival (PFS) and overall survival (OS) rates were compared in patients who had above and below the median concentrations of lactate. We also investigated the correlation between lactate concentrations and tumor volume. Multivariate analyses were conducted to test the association lactate, tumor volume and demographic variables with PFS and OS.ResultsThe median serum concentration of lactate was 2.3 mmol/L. A weak correlation was found between lactate concentrations and tumor volume. Kaplan–Meier curves demonstrated similar survival in patients with higher or lower than 2.3 mmol/L of lactate. The multivariate analysis indicated that the intraoperative levels of lactate were not independently associated with changes in survival. On another hand, a preoperative T1 volume was an independent predictor PFS (HR 95%CI: 1.41, 1.02–1.82, p = 0.006) and OS (HR 95%CI: 1.47, 1.11–1.96, p = 0.006).ConclusionThis retrospective study suggests that the serum concentrations of lactate cannot be used as a biomarker to predict survival after GB surgery.To date, there are no clinically available serum biomarkers to determine prognosis in patients with high-grade gliomas. These tumors may produce high levels of lactic acid. We hypothesized that serum lactic could be used of biomarker to predictor of survival in patients with glioblastoma (GB). In this study, we collected perioperative and survival data from 275 adult patients with primary high-grade gliomas to determine whether intraoperative serum acid lactic concentrations can serve as a marker of prognosis. The median serum concentration of lactate was 2.3 mmol/L. Our analysis indicated the intraoperative levels of lactate were not independently associated with changes in survival. This retrospective study suggests that the serum concentrations of lactate cannot be used as a biomarker to predict survival after GB surgery.     

Subcutaneous microdialysis in mitochondrial cytopathy

We present the results of subcutaneous microdialysis, a new minimally invasive biochemical monitoring technique, in mitochondrial cytopathy. We studied 6 ambulatory patients with mitochondrial cytopathy and 6 controls without mitochondrial disease using a subcutaneous probe for continuous microdialysis, and obtained measurements of lactate, pyruvate, and glucose from samples gathered at 30-60 min intervals during the day and at 3-h intervals at night. The lactate:pyruvate ratio (LPR) was calculated and related to disease severity and metabolic stress. Microdialysis was well tolerated. Controls had stable lactate and pyruvate values in the normal range and a low LPR (average values between 0.0114 and 0.0145). Patients had widely fluctuating lactate and pyruvate values, a higher average LPR between 0.0187 and 0.0724, and marked diurnal variation, especially in the severely affected patients. Increases in the LPR coincided with metabolic stress in individual cases. We conclude that subcutaneous microdialysis is well tolerated and enables continuous metabolic monitoring of patients with mitochondrial cytopathy. It has particular potential for use in the identification of metabolic risk factors and may help to assess the impact of therapeutic regimens.     

Binding characteristics of the glucocorticoid receptor in peripheral blood lymphocytes in multiple sclerosis

Although the exact etiology of multiple sclerosis (MS) remains unresolved, immune reactions are believed to be the central pathogenic mechanisms. Endogenous and therapeutic steroid hormones affect the immune system, and inflammatory diseases are associated with activation of the hypothalamic-pituitary-adrenal axis, providing evidence of an immune-endocrine interplay. Function tests in MS have revealed dysregulation of the hypothalamic-pituitary-adrenal system in a substantial proportion of patients. We characterized glucocorticoid receptor (GR) binding in peripheral blood lymphocytes from 39 MS patients and 14 age- and sex-matched controls with respect to dissociation constant and binding capacity, using a whole-cell binding assay with [³H]dexamethasone as the ligand. GR binding parameters did not differ significantly between patients (K _d 8.98 ± 1.07 nM, B _max 183 ± 29.8 fmol/mg) and controls (K _d 9.36 ± 1.17 nM, B _max 158 ± 16 fmol/mg). No effect of age, sex, course, duration or severity of disease, or prior steroid treatments was detected. GR binding parameters were analyzed in relation to the results of the combined dexamethasone-CRH test, which reflects corticosteroid receptor function at the hypothalamus, in 30 patients and 9 controls. While controls showed a moderate correlation between binding affinity of the GR in lymphocytes and regulatory function at the hypothalamic level, the patients did not. These data suggest that the physiological relationship between binding and function of the glucocorticoid receptor is disturbed in MS. Received: 23 December 1997 Received in revised form: 12 August 1998 Accepted: 18 August 1998     

31P NMR spectroscopy and ergometer exercise test as evidence for muscle oxidative performance improvement with coenzyme Q in mitochondrial myopathies.

Two patients with mitochondrial encephalomyopathy due to complexes I and IV deficiencies received 150 mg/d of coenzyme Q10 (CoQ). We studied them with a bicycle ergometer exercise test and 31P NMR spectroscopy before and after 10 months of treatment. Before treatment, we observed a low phosphocreatine/inorganic phosphate (PCr/P(i)) resting value along with abnormally high resting lactate concentration. During exercise, there was a pronounced acidosis with delayed kinetics of postexercise recovery for blood lactate, pH, PCr, and PCr/P(i) ratio. Oxygen uptake during exercise was reduced while the lowering of the ventilatory threshold indicated an early activation of glycolysis. After treatment, the bicycle ergometer exercise test indicated a significant improvement with a decrease in resting blood lactate level, an increase in oxygen consumption during exercise, and an increase in the kinetics of lactate disappearance during the recovery period. A shift of the ventilatory threshold to higher workload was present. 31P NMR spectroscopy confirmed the improvement, showing a significant increase in the PCr/P(i) ratio at rest and in the kinetics of recovery for pH, PCr, and PCr/P(i) ratio following exercise in patient 1. For patient 2, we observed a less pronounced acidosis correlated with a lesser amount of Pi produced during exercise. These observations indicate an improvement of mitochondrial function and a shift from high to low glycolytic activity in both patients consequent to CoQ treatment.     

Ubidecarenone in the treatment of mitochondrial myopathies: a multi-center double-blind trial

Forty-four patients with mitochondrial myopathies were treated with Ubidecarenone (CoQ10) for 6 months in an open multi-center trial. No side effects of the drug were observed. Sixteen patients showing at least 25% decrease of post-exercise lactate levels were selected as responders. Responsiveness was apparently not related to CoQ10 level in serum and platelets or to the presence or absence of mtDNA deletions. The responders were treated for a further 3 months with CoQ10 or placebo in the second blind part of the trial; no significant differences were observed between the 2 groups. It is not clear why CoQ10 had therapeutic effects in some patients and not in others with the same clinical presentation and biochemical defect, and we failed to identify candidate responders before treatment. At the dose of CoQ10 used in this study (2 mg/kg/day) the therapy requires a long administration time before a response is seen.     

Can the efficacy of electrically stimulated pedaling using a commercially available ergometer BE improved by minimizing the muscle stress–time integral?

Introduction: The cardiorespiratory and muscular strength benefits of functional electrical stimulation (FES) pedaling for spinal cord injury (SCI) subjects are limited because the endurance of electrically stimulated muscle is low. Methods: We tested new electrical stimulation timing patterns (Stim3, designed using a forward dynamic simulation to minimize the muscle stress–time integral) to determine whether SCI subjects could increase work and metabolic responses when pedaling a commercial FES ergometer. Work, rate of oxygen uptake (V?O ₂), and blood lactate data were taken from 11 subjects (injury level T4–T12) on repeated trials. Results: Subjects performed 11% more work pedaling with Stim3 than with existing stimulation patterns (StimErg) (P = 0.043). Average (V?O ₂) and blood lactate concentrations were not significantly different between Stim3 (442 ml/min, 5.9 mmol/L) and StimErg (417 ml/min, 5.9 mmol/L). Conclusion: The increased mechanical work performed with Stim3 supports the use of patterns that minimize the muscle stress–time integral to prolong FES pedaling. Muscle Nerve, 2012     

Treatment of Kearns-Sayre syndrome with coenzyme Q10

We studied the metabolism of coenzyme Q10 (CoQ) and the effects of CoQ therapy in five patients with Kearns-Sayre syndrome (KSS). Although the mitochondrial fraction was increased in muscles from KSS patients, CoQ content was slightly low. CoQ synthesis was normal in fibroblasts from KSS patients. Administration of 120 to 150 mg/d of CoQ improved abnormal metabolism of pyruvate and NADH oxidation in skeletal muscle. CoQ therapy decreased CSF protein concentration and CSF lactate/pyruvate ratio. ECG abnormalities and neurologic symptoms also improved.     

Serum levels of neuron-specific enolase and s-100 protein after single tonic-clonic seizures

Serum neuron-specific enolase (s-NSE) and s-100 protein (s-100) are sensitive markers of various brain diseases. We investigated both of these markers in nine patients within 5 min, 6 h, 12 h, and 48 h after a single tonic-clonic seizure. The mean peak s-NSE level was significantly higher after 5 min (11.97 ± 8.56 μg/l) and 48 h (10.31 ± 8.92 μg/l, P < 0.05) than the levels of seizure-free, age-matched controls. Five patients had increased s-NSE levels regarding the upper limit of normal as mean + 3 SD. s-100 was not detected either in controls or epileptic patients. These data indicate that s-NSE in contrast to s-100 may be an in vivo marker after generalized seizures in some patients. Received: 2 April 1997 Received in revised form: 22 September 1998 Accepted: 4 November 1998