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Background: Pathophysiological mechanisms involved in amyotrophic lateral sclerosis (ALS) are complex and none has identified reliable markers useful in routine patient evaluation. The aim of this study was to analyze the CSF of patients with ALS by (1)H NMR (Nuclear Magnetic Resonance) spectroscopy in order to identify biomarkers in the early stages of the disease, and to evaluate the biochemical factors involved in ALS., Methodology: CSF samples were collected from patients with ALS at the time of diagnosis and from patients without neurodegenerative diseases. One and two-dimensional (1)H NMR analyses were performed and metabolites were quantified by the ERETIC method. We compared the concentrations of CSF metabolites between both groups. Finally, we performed principal component (PCA) and discriminant analyses., Principal Findings: Fifty CSF samples from ALS patients and 44 from controls were analyzed. We quantified 17 metabolites including amino-acids, organic acids, and ketone bodies. Quantitative analysis revealed significantly lower acetate concentrations (p = 0.0002) in ALS patients compared to controls. Concentration of acetone trended higher (p = 0.015), and those of pyruvate (p = 0.002) and ascorbate (p = 0.003) were higher in the ALS group. PCA demonstrated that the pattern of analyzed metabolites discriminated between groups. Discriminant analysis using an algorithm of 17 metabolites revealed that patients were accurately classified 81.6% of the time., Conclusion/significance: CSF screening by NMR spectroscopy could be a useful, simple and low cost tool to improve the early diagnosis of ALS. The results indicate a perturbation of glucose metabolism, and the need to further explore cerebral energetic metabolism.

Localized proton magnetic resonance spectroscopy (MRS) was performed to study the metabolic changes in the brain of a patient with Leigh syndrome, who had a T-->G point mutation at nt 8993 of mitochondrial DNA. In this patient, sodium dichloroacetate therapy normalized the lactate and pyruvate levels in both blood and cerebrospinal fluid (CSF). However, his psychomotor retardation did not improve and magnetic resonance imaging showed progressive cerebral atrophy. In the patient's spectra, elevation of brain lactate was observed throughout the brain with regional variations, predominantly in the basal ganglia and brainstem with an abnormal MRI appearance. Although the lactate/creatine ratio observed on proton-MRS was related to the CSF lactate level, the ratio did not completely parallel the CSF lactate level, i.e. brain lactate was detected even when the CSF lactate level had become normalized. Furthermore, proton-MRS revealed a decrease in the N-acetylaspartate/creatine ratio and an increase in the choline/creatine ratio, representing neuronal loss and breakdown of membrane phospholipids. The clinical and MRI findings were well related to the changes in spectroscopically determined brain metabolites. These results indicate that the brain metabolites observed on proton-MRS are useful indicators of a response to therapy and prognosis in Leigh syndrome.

To clarify the mechanism of action of adrenocorticotropic hormone (ACTH) in treating infantile spasms, we evaluated the effects of ACTH on the metabolism of pyruvate in the central nervous system (CNS) of children with infantile spasms. We measured the levels of lactate and pyruvate in cerebrospinal fluid (CSF) and serum, before and during ACTH treatment in 12 children with infantile spasms. We evaluated statistically any correlation between the observed metabolic changes and the clinical response of ACTH. ACTH therapy significantly elevated the levels of lactate and pyruvate in the CSF and serum. The effect was not dose-dependent. During ACTH therapy, the serum levels of lactate and pyruvate and the ratio of lactate to pyruvate (L:P ratio) were unrelated to these levels in CSF. Patients who showed a good initial response to treatment had a significantly higher CSF level of pyruvate and a lower L:P ratio during therapy than did those with a poor initial response. This is the first report that ACTH therapy administered for infantile spasms alters pyruvate metabolism in the CNS. This metabolic change may be involved in part in the action of ACTH in relieving infantile spasms.

Objective: This study was undertaken to assess the relationships among CSF concentrations of substrates of mitochondrial energy metabolism, neuroleptic medication, and neurological side effects., Method: CSF was obtained from 25 patients with schizophrenia; seven were unmedicated and 11 had tardive dyskinesia. CSF concentrations of four substrates of mitochondrial energy metabolism (Krebs cycle)--alanine, aspartate, lactate, and pyruvate--were determined. Tardive dyskinesia was measured with the Abnormal Involuntary Movement Scale (AIMS), and parkinsonism was measured with the Simpson-Angus Rating Scale., Results: CSF concentrations of alanine were significantly elevated in the medicated patients when tardive dyskinesia status was controlled for. CSF aspartate concentrations were significantly elevated in patients with tardive dyskinesia when medication status was controlled for and were significantly correlated with total scores on the AIMS., Conclusions: These results are consistent with a model linking neuroleptic-induced neurological side effects with impairment of mitochondrial energy metabolism, possibly mediated by inhibition of complex 1 of the electron transport chain.

A chromatographic method base don a combination of ion-exclusion chromatography separation and bulk acoustic wave series piezoelectric quartz crystal detector quantification for the determination of pyruvic acid and lactic acid in serum and cerebrospinal fluid (CSF) was developed. The separation was carried out using a Shim-pak SCR-102H ion-exclusion column with phosphoric acid solution as eluent. The method shows an acceptable detection limit and anti-interference ability. Serum and CSF from healthy individuals and patient were analysed successfully.

Impaired energy metabolism is an early, predominant feature in Alzheimer's disease. In order to find out simple, reliable 'in vivo' markers for the clinical-biological typization of the disorder, we measured cerebrospinal fluid (CSF) glucose, lactate and pyruvate levels in patients suffering from dementia of Alzheimer type (DAT) and in healthy elderly controls. DAT group showed remarkably higher levels of pyruvate (P = 0.01), with no overlap with the values obtained in controls. CSF pyruvate levels were also significantly associated with the severity of dementia. Therefore, CSF pyruvate levels neatly separate DAT patients from controls, having also pathogenetic value.

The etiology of Rett syndrome (RS) remains a mystery. The clinical phenotype has similarities to that of patients with mitochondrial defects of oxidative metabolism. There is evidence of lactate and pyruvate elevations in blood and CSF in some patients. Over the last 10 years we have studied girls with RS looking for evidence of a defect in oxidative metabolism. We present data on lactate and pyruvate blood measurements in 30 patients with RS with repeated measurements performed over time in many. Taken as a whole the means of measurements of lactate and pyruvate fall within the control range, however, individual patients have marked elevation of both lactate and pyruvate with considerable fluctuation over time. Nine girls with typical RS were studied in detail using a clinical protocol designed to identify disorders of oxidative metabolism. These patients underwent fasting for 24 hours, glucose loading and alanine loading tests. Seven girls had skin and muscle biopsies performed. One patient admitted with particularly high blood lactate levels underwent hourly blood collections over a 24 hour period during which state of alertness was noted and respiratory monitoring was performed. In this patient serial blood sampling for lactate performed. In this patient serial blood sampling for lactate performed with oxypneumocardiogram recording demonstrated a fall in plasma lactate to normal levels during sleep when the respiratory pattern was normal. Such fluctuations of plasma lactate apparently correlated with sleep/wake state and respiration suggest that in some patients with RS lactate elevations may arise from respiratory abnormalities. Other positive findings included prediabetic glucose responses in three girls. Ammonia levels following alanine loading were normal in all patients.

Organic acids in cerebrospinal fluid (CSF) from patients with various central nervous system (CNS) diseases were determined by capillary zone electrophoresis (CZE). Under one of the two sets of conditions employed, several anionic components of CSF were separated into corresponding peaks on the electropherograms and determined. The other conditions employed were also useful in measurement of the lactate contents in CSF. The CSF levels of lactate and pyruvate and the ratios of lactate to pyruvate were elevated in patients with cerebral infarction and bacterial meningitis, whereas CSF ascorbate was reduced mainly in inflammatory disorders of the CNS. The results showed that CZE can become a powerful tool in the biochemical diagnosis of CNS diseases.

We studied both cerebrospinal fluid (CSF) and serum of 11 patients suffering from Huntington's disease (HD) and 12 control subjects by combining high resolution proton NMR spectroscopy and HPLC. NMR spectroscopy analysis of the CSF shows a significant increase (60%) in pyruvate concentration in HD patients. No unexpected molecules were detected. Glutamate, glutamine, aspartate, proline and GABA levels were found unchanged in the CSF of HD patients, using HPLC analysis. Conversely, a significant increase (30%) in the CSF level of glycine was detected. These observations are in agreement with the metabolic hypothesis of HD physiopathogenesis. In addition, the protocol combining NMR spectroscopy and HPLC provides a straightforward evaluation of brain metabolic status and blood-brain-barrier function.

By studying early postmortem changes in cerebrospinal fluid (CSF) it is possible to draw conclusions as to premortem focal brain cell injury and terminal brain ischemia. Cisternal fluid (CF) from 40 different adult cadavers with no known neurological disorder was analyzed and compared with known in vivo values. They were divided into four groups (n = 10 in each group), CF samples taken 2, 4, 10, and 24 h after death. The enzyme activity of CK and CK-BB (EC 2.7.3.2) increased linearly and statistically significantly 4-24 h postmortem (P < 0.001) the 2 h values being already 10 to 20 times higher than in vivo, LD and its isoenzymes 1 to 3 (EC 1.1.1.27) distinctly 10 to 24 h after death. Glucose and pyruvate concentrations in the CF declined, as did Na+ and Cl-. Lactate and K+ increased over time. The earliest statistically significant changes between different timepoints were seen in lactate, pyruvate and K+ concentrations. The GABA concentration was already more than 170 times at 2 h postmortem, and glutamate more than 20 times higher than in vivo. The concentrations of alanine, glycine, lysine, histidine, isoleucine, phenylalanine, and tyrosine were 2 to 3 times higher at 2 h postmortem than during life. The concentrations of all amino acids and ammonia increased linearly and statistically significantly (P < 0.001) in the CF 4 to 24 h postmortem.

A female neonate with pyruvate dehydrogenase (PDH) deficiency is presented with clinical, radiologic, biochemical, neuropathologic, and molecular genetic data. She was dysmorphic, with a high forehead, lowset ears, thin upper lip, upturned nose, and rhizomelic limbs. Cranial MRI revealed severe cortical atrophy, ventricular dilatation, and corpus callosum agenesis. Pyruvate and lactate levels were increased in CSF and blood. Urinary organic acid profile was compatible with PDH deficiency. PDH activity was normal in fibroblasts, lymphocytes, and muscle. The PDH E1-alpha gene was sequenced and a single base mutation was found within the regulatory phosphorylation site in exon 10. It is postulated that this mutation causes a cerebral form of PDH deficiency. Tissue-specific expression of the disease could be explained by differential X chromosome inactivation because the PDH E1-alpha gene is located on this chromosome. Dysmorphism with severe cerebral malformations in female patients merits a metabolic evaluation, including determination of lactate and pyruvate levels in CSF.

Ventricular cerebrospinal fluid (CSF) lactate concentrations and lactate/pyruvate (L/P) ratios were measured daily in 20 patients from day 1 to day 12 after subarachnoid haemorrhage due to ruptured aneurysms. Patients without symptomatic vasospasm were classified in Group 1, patients with symptomatic vasospasm were classified in Group 2, and patients who were Hunt and Kosnik grade 4 on admission clinically were classified in Group 3. Patients in all three groups had high CSF lactate concentrations on day 1, and, especially in Group 3, the high lactate was accompanied by an increased L/P ratio and a decreased CSF bicarbonate. Lactate concentrations in Group 1 decreased throughout the observation period. Lactate concentrations in Group 2 also decreased but then began to increase again on days 5 to 7, correlating well with the onset of cerebral vasospasm. The delayed increase of CSF lactate in Group 2 was also accompanied by increases in the CSF pyruvate level and the CSF L/P ratio. Daily monitoring of CSF lactate may thus serve as a chemical marker for cerebral vasospasm.

Parkinson's disease (PD) is a common degenerative disease, but its etiology is still unknown. However, since the discovery of MPTP, many investigators have been interested in the mitochondrial function in PD. We investigated mitochondrial functions in PD patients using the methods which have successfully been applied to mitochondrial myopathies (MM), i.e. assay of lactate and pyruvate, measurement of muscle mitochondrial respiratory enzyme activities and Southern blot analysis of muscle mitochondrial DNA. Parkinson's disease patients did not differ from controls in the mean blood and CSF (cerebrospinal fluid) lactate and pyruvate levels at the basal resting state or during an aerobic exercise. But mitochondrial complex I activity of the skeletal muscle was significantly decreased in PD. In the Southern blot analysis, we could not find major deletions or insertions of mitochondrial DNA in PD. Our studies disclosed a differential mitochondrial impairment between PD and MM. We discuss the implication of our observation.

We investigated both blood and cerebrospinal fluid (CSF) lactate and pyruvate levels in seven girls with the Rett syndrome (RS) and evaluated the relationship between CSF lactate and pyruvate levels and the clinical manifestations, particularly seizures, anticonvulsant medication, and breathing dysfunction including breath holding, apnea and hyperventilation. Elevated lactate and pyruvate levels in CSF with normal serum lactate were found in two RS patients. Elevated CSF lactate correlated significantly with the clinical occurrence of hyperventilation (P0 = 0.048, Fisher exact probability). We measured native and dichloroacetate (DCA)-activated pyruvate dehydrogenase (PDH) complex activities in two patients (#1 and 2) using cultured lymphoblastoid cell lines which were transformed by EB virus and the results were normal. We also analyzed CSF citric acid intermediates from 7 RS patients including citric acid, cis-aconitate, alpha-ketoglutarate, succinate, fumarate, malate and oxaloacetate. These concentrations were not significantly different from those control patients (N = 21). An elevated lactate level may be a clue to clarify the etiology of RS.

Many CoQ trials for mitochondrial encephalomyopathy are reported, however, the action of CoQ in the central nervous system is unknown. We administered CoQ to a patient with MELAS, and decreasing CSF lactate and pyruvate levels were revealed. This reduction in CSF lactate and pyruvate may be evidence that CoQ acts directly on the CNS. There have been no other descriptions of evidence of CoQ effective action in the central nervous system, a finding unique to this report.

We present two unrelated MELAS patients, and compare them with 24 patients derived from the literature. In most patients the stroke-like features of the MELAS syndrome occur late in the course of the disease. The diagnosis is based on characteristic clinical symptoms, presence of lactic acidemia, mitochondriopathy in muscle, and low density lesions on cerebral CT, most frequently occurring in the posterior and parieto-temporal regions. In some cases, a metabolic defect could not be demonstrated, in other cases a partial deficiency of various respiratory chain enzymes was found.

This investigation was designed to study the dynamics of energy-related metabolites (i.e., lactate, pyruvate, inosine, and hypoxanthine) in the extracellular fluid (ECF) of the striatum and in cisternal cerebrospinal fluid (CSF) during the first 6 h after middle cerebral artery occlusion (MCAO) using microdialysis. Ischemia induced a dramatic increase in the ECF levels of lactate, inosine, and hypoxanthine, while pyruvate did not change significantly. The major part of these changes occurred during the first 10 min after MCAO. Inosine tended to normalize towards the end, while lactate and hypoxanthine remained elevated throughout the experiment. There was no increase of the energy-related metabolites in CSF during the experiment. It was concluded that lactate, inosine, and hypoxanthine appear to be useful ECF markers of the compromised energy state of the brain during ischemia. Because the metabolites did not appear in CSF during the first 6 h after MCAO, such measurements seem not to be useful for early detection of a disturbance in energy metabolism.

Lactic acid accumulation has been implicated in the evolution of brain damage after ischemia. Since compartmentation of lactate may play a role in acid-base balance, lactate release from gerbil hippocampal slices was examined during a number of metabolic stresses including elevated [K+]e, ischemia, anoxia, and aglycemia. Slices were preincubated for 1 hr in artificial cerebrospinal fluid (ACSF) equilibrated with 95% O2/5% CO2 (pH 7.4 at 37 degrees C) and then transferred to tubes containing 300 microliters of test medium. The rate of lactate release in control slices was 9.64 nmol/min/mg protein and increased 2.6- and 3.2-fold in the presence of 60 mM potassium and anoxia, whereas the rate of lactate release was decreased by 50 and 25% during ischemia and aglycemia. Lactate release was temperature dependent and was only minimally influenced by removing Ca2+ or by adding 5 mM d-lactate to the ACSF. In contrast, pyruvate inhibited lactate release with an apparent Ki of 2.4 mM. The results suggest that lactate can be released from cells via a saturable and stereospecific lactate transporter with an apparent Km of 10.7 mM and Vmax of 43.7 nmol/mg protein/min. Such a relatively high-capacity transporter system can rapidly equilibrate brain lactate but is probably not involved in regulating intracellular acid-base balance.

Two sisters with chronic progressive external ophthalmoplegia (CPEO) and their in all 7 healthy children were investigated. Both ophthalmoplegic patients had histopathological changes typical of mitochondrial myopathy. The same type of muscular pathology was also found among the healthy children. The most common muscular changes were subsarcolemmal accumulation of pathological mitochondria, including vacuoles, abnormal cristae and sometimes also inclusion bodies. Biochemical studies showed partial complex III deficiency, with low succinate-cytochrome c reductase activity in 1 of the ophthalmoplegic patients. These findings suggest that CPEO is a slowly progressive muscle disease, starting early in life. The widespread occurrence among the children may indicate maternal inheritance.

The central nervous system (CNS) is frequently affected by systemic lupus erythematosus (SLE). Other causes, especially infection, may also originate CNS disease in SLE patients. Our findings indicate that measurement of lactic acid and pyruvic acid in cerebrospinal fluid (CSF) may be of help in separating inactive CNS-SLE from active CNS-SLE. Also it may be of help in differentiating sterile meningitis caused by SLE from bacterial meningitis. Because of the special risk on tuberculous and fungal infections in SLE patients, also some findings concerning these specific forms of meningitis are given.

Cerebrospinal fluid (CSF) lactate and pyruvate concentrations were determined in 16 patients with hepatic encephalopathy before and/or after treatment. CSF lactate was significantly increased to 1.92 +/- 0.11 mmol/l in hepatic encephalopathy before the treatment in comparison to 1.40 +/- 0.05 mmol/l in control subjects. In 9 of 11 patients with moderate or stage 2 encephalopathy, CSF lactate levels were below 2 mmol/l. In contrast, in 4 of 5 patients with stage 3-4 encephalopathy, CSF lactate levels were higher than 2 mmol/l. CSF lactate was decreased with the recovery of neurological symptoms by the treatment. These findings indicate that CSF lactate levels reflect the severity of metabolic impairment of the brain. Hypocapnia was frequently observed in these encephalopathic patients, and arterial PCO2 correlated inversely with CSF lactate and linearly with CSF HCO3-, suggesting that CSF lactic acidosis contributes to hyperventilation in hepatic encephalopathy. It is concluded from present results that metabolic disorder of neuronal cells might be one of the important factors for the development of hepatic encephalopathy.

The metabolic effects of Vincamine were studied in eight cases of cranial trauma. The lactate/pyruvate ratio in venous blood and cerebrospinal fluid was observed for a period of six hours immediately following intravenous injection of Pervincamine (1 mg/kg) and the results compared with values obtained in the six hours following injection of a placebo. The injections were administered in 20 minutes, at intervals of 24 hours. A statistically significant change was observed in the lactate/pyruvate ratio after injection of Pervincamine. No effect was observed after administration of the placebo.

Cerebrospinal fluid (CSF) electrolytes, lactate, pyruvate, total proteins, and osmolality, together with arterial plasma electrolytes, total proteins, osmolarity, and systemic arterial blood pressure were monitored during 2 mg/kg and 5 mg/kg E coli endotoxin shock in spontaneously breathing dogs. During four hours of shock, Na+, K+ osmolarity, and total proteins did not change in either plasma or CSF. CSF lactate and lactate/pyruvate ratio were significantly elevated, whereas pyruvate was decreased throughout the four hours of shock. Systemic arterial blood pressure was below control during the entire shock period. Saline control experiments yielded no significant changes in all parameters monitored. These data show that during four hours of shock the brain has shifted form aerobic to anaerobic metabolism the degree of which is not sufficient to cause any detectable changes in membrane permeability or alterations in Na+/K+ active processes.

Survivors of perinatal intraventricular hemorrhage often develop a distinct clinical syndrome characterized by hydrocephalus and biochemical abnormalities in cerebrospinal fluid. The authors investigated six neonates with post-hemorrhagic obstructive hydrocephalus in order to identify cerebral metabolic disturbances responsible for the hypoglycorrhachia observed in this disorder. Lactic acid concentraions and lactate/pyruvate ratios in ventricular fluid were significantly elevated in infants with post-hemorrhagic hydrocephalus compared with the values in five with congenital (non-hemorrhagic) obstructive hydrocephalus. Comparable degrees of ventricular dilatation and intracranial hypertension were present in the two groups. There is evidence that neither residual cellular elements in ventricular fluid nor a disrupted blood-CSF barrier can fully explain the observed alterations in ventricular-fluid glucose, lactate or lactate/pyruvate ratios. It is suggested that when periventricular hemorrhage occurs, the associated cerebral ischemia leads to focal anaerobic glycolysis and increased glucose requirement. With inadequate cerebral glucose glycolysis and increased glucose requirement. With inadequate cerebral glucose delivery from the blood, glucose diffuses into the brain from the ventricular fluid, resulting in hypoglycorrhachia. Cerebral lactic acid production is enhanced, which accumulates in ventricular fluid in the presence of ventricular obstruction.

Cisternal CSF specimens were obtained from 144 fasted individuals free from organic brain disease (42 males and 102 females; mean age 41 +/- 10.3 years, range 16-69 years). In 30 cases a simultaneous lumbar puncture was also performed. The concentration of CSF glucose (G1) was measured by the o-toluidine method, and that of lactate (La) and pyruvate (Py) by enzymatic tests. No significant difference was found between the mean G1 and Py values of the lumbar and cisternal CSF but the lumbar La was somewhat higher than the cisternal one (P less than 0.10). In the cisternal CSF the frequency distribution of G1, La and Py samples was a Gaussian one (P less than 0.05). The normal ranges, as mean +/- 2SD, were for La 0.680-2.100 mM/1, and for Py lower limits of the range (between mean +/- 2 SD and mean +/- 1 SD) are considered to be potentially pathological. No significant difference was found between the mean G1, La and Py values in males and females. Consistent age-related changes could not be detected either in the G1 or Py levels, however, a tendency for La increase was observed in the oldest-age-group (over 54 years). A negative correlation was found between the G1 and La concentrations of the cisternal CSF (r = 0.375; P less than 0.001).

We studied a child with a rapidly progressive neurologic disorder, with psychomotor retardation, hypotonia, seizures, and respiratory disturbances. Laboratory studied showed elevated levels of lactate and pyruvate in cerebrospinal fluid (CSF), without notable elevated levels in serum. In liver, muscle, leukocytes, and cultured fibroblasts we found no abnormality in pyruvate oxidation; biochemical studies of a brain biopsy showed an isolated deficiency of pyruvate dehydrogenase complex in brain tissue with the morphologic picture of progressive poliodystrophy with hypomyelination.

Twenty-two infants and children were studied after convulsions of varied cause and duration. Arterial and CSF acid-base variables, lactate and pyruvate concentrations, and lactate/pyruvate ratios were measured between 3 and 18 hours after convulsive episodes. Biochemical signs of cerebral hypoxia were found in 7 patients with prolonged (greater than 30 minutes) or recurrent short convulsions. These signs were absent in patients with single short convulsions. These findings indicate that cerebral hypoxia and possible brain damage is a hazard of prolonged or rapidly recurring short convulsions.

Changes in the lactate and pyruvate levels and lactic dehydrogenase activity in the cerebrospinal fluid were followed in 56 patients anaesthetised for neurosurgery. Mean arterial blood pressure (MAP) was reduced in these patients from about 90 to about 35 mm Hg. This allowed to safely place a clip at a brain artery aneurysm. In spite of deep hypotension, ischaemia described by other authors in such cases was never observed. Changes in lactate and pyruvate concentrations, lactate/pyruvate ratio and lactic dehydrogenase activity justify the conclusion that we were dealing with an undisturbed metabolism of the brain tissue. The levels of metabolic parameters, even when increased in hypotension, fell well within the range of physiological values. Attention is called to the fact that partial oxygen pressure in arterial blood during controlled hypotension was about 100 mm Hg, a value considered as limiting to oxygen metabolic transformation within the central nervous system in deep hypotension. We also suggest a different mechanism of passage of lactates and pyruvates through the blood-brain barrier.

The concentration of pyruvate in the venous blood of 31 patients with stroke was determined by the enzymatic spectrophotometric method. The pyruvate concentration was raised on the 1st, 3rd and 10th days after stroke and this increase was statistically significant. Pyruvate concentration changes in venous blood were associated with severe clinical condition of the patients.

Forty infants delivered by vacuum extraction have been studied in the neonatal period--neurological examination, neonatal CSF-examinations, skull X-ray examination, transillumination and sonoencephalography --and at 14 months of age--developmental and behavioural evaluation, neurological examination, skull X-ray examination, sonoencephalography and electroencephalography. Two infants died in the neonatal period but in both cases a life-threatening situation of the fetus required immediate delivery. CSF cytological signs of haemorrhage were observed in 42% of the 26 infants who had a successful lumbar tap, compared to 10% found in normal deliveries. The result of the neonatal neurological study did not differ from that in a control group. The result of the skull X-ray examination and sonoencephalography were also within normal limits. In the follow-up study behavioural problems were found in 25%, but otherwise very few abnormalities were found. The deviatiosn found do not for the present indicate any later signs of brain lesions. It is concluded that this prospective study has shown that VE-delivery in fullterm babies seem to imply no risk fo serious cerebral sequelae. Further follow-up studies at a later age in order to evaluate the incidence of so-called minimal brain damage in VE-delivered children are required.

Thirty-eight patients in coma due to head trauma, cerebrovascular accidents, hypoxia, hypoglycaemia, or barbiturate intoxication, and 15 cases of brain death were studied. Cerebral metabolic rate of oxygen (CMRO(2)) was obtained from the arteriovenous oxygen difference and cerebral blood flow (CBF) measured by intra-arterial (133)Xenon method. If hypothermia and CNS depressants were excluded, CMRO(2) below one-third of normal was incompatible with regaining of consciousness, but this was seen in only three comatose patients. Irrespective of the clinical outcome (death, vegetative survival, or recovery), CMRO(2) values of one-third to two-thirds of normal were seen in the majority of coma patients. CMRO(2) measurements were of no practical value to predict the prognosis in coma, even when the effect of temperature and sedatives were considered. In brain death the CBF studies gave indirect evidence of cerebral circulatory arrest. The cerebrospinal fluid (CSF) was obtained for analysis of lactate, pyruvate, and bicarbonate in 29 cases. Increased CSF lactate levels were found in all groups except barbiturate intoxication. The finding of a negative correlation between CSF bicarbonate and log CBF suggests that the CSFpH determines the wide range of CBF in coma.

The study was conducted in 80 patients with ischaemic and 29 with haemorrhagic cerebral stroke. Lactate, pyruvate, the lactate/pyruvate ratio and glucose were determined in the arterial blood and lumbar CSF. A high prognostic value of the CSF lactate content was found in cases of ischaemic stroke. According to the data obtained, an elevation of the CSF lactate concentration above 4.0 mEq/l should be considered life-threatening. Haemorrhagic stroked was found to be accompanied by a reduced CSF glucose level and an elevated lactate content, as well as by a significant proportional elevation of the lactate and red blood cells count in the CSF. The conducted calculations demonstrated that 1/4 to 1/3 of the CSF lactate is formed at the expense of the glycolytic metabolism in the CSF erythrocytes. This constitutes the main reason of the discordance between the CSF lactate content in haemorrhagic stroke and the routine criteria of prognosis in ischaemic stroke. The lactate/pyruvate ratio in the CSF is of no prognostic importance in both forms of cerebral stroke.

Morphological study of the choroid plexuses of two patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) revealed an enormously increased number of mitochondria with structural abnormalities in almost all of the choroidal epithelial cells. The majority of the cells also showed loss of microvilli and collapsed or attenuated apical cytoplasmic processes with increased electron density and lysosome-like dense bodies. The blood vessels of the choroid plexus showed the features of mitochondrial angiopathy previously described in the pial arteries of the same patients. These findings are interpreted as the morphological expression of a primary biochemical defect of the mitochondrial function in the choroid plexus, and as the probable explanation for increased CSF lactate and pyruvate levels in this disease.

The glucose, lactate, and pyruvate levels, the lactate/pyruvate ratio and pH were studied in serum and CSF of patients with schizophrenia, reactive psychosis, symptomatic or circular psychosis under the effect of atropine coma, ES and pentetrazole convulsions, tranquilizer treatment and combined therapy. Convulsive therapy caused a disorder in cerebral carbohydrate metabolism while no similar changes were induced by atropine coma. Anaerobic carbohydrate metabolism was stimulated by combined therapy. This treatment had the best effect and the changes caused by it were slighter than in the case of convulsive therapy. The changes in EEG frequency corresponded to the biochemical changes.

Cerebral metabolism in 21 hydrocephalic patients was studied. Preoperative and postoperative specimens of cerebrospinal fluid (CSF) were obtained and the cerebral perfusion pressure (CPP) was calculated in each instance. The specimens of CSF were analyzed for lactate and pyruvate and the lactate/pyruvate (L/P) ratio was calculated for each sample. The L/P ratio, which reflects the redox state of the cell, was used to determine the extent of anaerobic metabolism. An inverse relationship was noted between CPP and lactate as well as the L/P ratio. In general, the level of anaerobic metabolism was decreased after insertion of a shunt.

We studied lactate and pyruvate concentrations in CSF and blood of a patient with Kearns-Sayre syndrome (KSS), 3 patients with ocular myopathy and 11 normal control subjects. We found significant elevation of lactate and pyruvate in the CSF of the patient with KSS, suggesting a disorder of CNS lactate-pyruvate metabolism.

Lactate and pyruvate were studied comparatively in perilymph (PL), blood, and cerebrospinal fluid (CSF) of anesthetized guinea pigs. Arterial blood pressure, heart and respiration rate (Fig. 1), and arterial blood-gas state (Table 2) were simultaneously checked in a group of the animals. The metabolites were determined enzymatically by using the fluorometric technique. The studies have shown (Table 1) that both the lactate and the pyruvate concentrations are in PL at a similar rate (about 3:1) higher than in native blood and also higher than in CSF. The metabolite values of blood, especially the lactate values, were lower when blood was taken alone, e.g., more physiological, than in the case when CSF and PL had been sampled before. The lactate/pyruvate ratios of Pl are somewhat higher than the blood ratios. The ratio of CSF was found to be lower. The high metabolite levels in PL suggest an intracochlear origin. A direct perilymphatic lactate origin could not be detected.

We have studied the lactate-level in the CSF of 40 patients with a severe head injury. After a first group of 20 patients we concluded that those levels were usefull for predicting the outcome of those patients. After receiving new informations about the normal metabolism of lactate in the CSF of man and animals, we became more suspicious. Therefore we have studied a new group of 20 patients. The levels of lactate, pyruvate, pH, pC02 and p02 were checked both in the CSF and in the blood for a longer period. An own coma-scale was used. The results are discussed.

In 18 unconscious patients with traumatic brain injury, the cerebral autoregulation was tested during the first 2-3 weeks after the acute trauma. Regional cerebral blood flow (rCBF) was measured by the intra-arterial 133xenon washout method before and after an increase of about 20% in the mean arterial blood pressure (MABP) by angiotensin. The difference between MABP and intraventricular pressure (IVP) was used as cerebral perfusion pressure (PP). Simultaneously, ventricular fluid pH, lactate and pyruvate were measured. Regional loss of autoregulation indicated by a 20% flow increase was observed in 29 out of 35 studies (83%), while hemispheric loss of autoregulation was observed in only one study. The results of the autoregulation tests were unrelated to the clinical outcome, the presence of brain-stem lesion, and the ventricular fluid pH, lactate and lactate/pyruvate ratio. In repeated studies, a gradual normalization of the autoregulation was observed about 5 days after the acute trauma.