Background: Leigh syndrome (LS) is a rare disease caused by mitochondrial defects and has high phenotypic and genotypic heterogeneity. We analyzed the clinical symptoms, neuroimaging, muscular histopathology, and genotypes of 13 Chinese LS patients with mitochondrial DNA (mtDNA) mutations. Methods: Mutations in mtDNA were identified by targeted sequencing. The brain imaging features on magnetic resonance imaging (MRI) were analyzed. The levels of lactate in fasting blood and cerebrospinal fluid (CSF) were routinely tested. The levels of urinary organic acids, plasma amino acids, and acylcarnitines were examined with gas chromatography-mass spectrometry and tandem mass spectrometry. The histopathological traits of skeletal muscles were analyzed under microscope. Results: Among 13 patients, mutations of MT-NDs (n = 8) and MT-ATP6 (n = 4) genes were most common. Strabismus (8/13), muscle weakness (8/13), and ataxia (5/13) were also common, especially for the patients with late-onset age after 2 years old. However, respiratory distress was common in patients with early-onset age before 2 years old. The most frequently affected brain area in these patients was the brain stem (12/13), particularly the dorsal part of midbrain, followed by basal ganglia (6/13), thalamus (6/13), cerebellum (5/13), and supratentorial white matter (2/13). Besides, the elevated lactate levels in CSF (6/6) were more common than those in serum (7/13). However, the analysis of abnormal plasma amino acid and urinary organic acid showed limited results (0/3 and 1/4, respectively). Muscular histopathology showed mitochondrial myopathy in the three late-onset patients but not in the early-onset ones. Conclusions Noninvasive genetic screening is recommended for mtDNA mutations in MT-NDs and MT-ATP6 genes in patients with ophthalmoplegia, muscle weakness, ataxia, and respiratory disorder. Furthermore, the lactate detection in CSF and the brain MRI scanning are suggested as the diagnosis methods for LS patients with mtDNA mutations.
Child ; Child, Preschool ; Creatine Kinase ; blood ; Cytochrome-c Oxidase Deficiency ; DNA, Mitochondrial ; genetics ; Fasting ; blood ; cerebrospinal fluid ; Female ; Humans ; Infant ; Lactic Acid ; blood ; cerebrospinal fluid ; Leigh Disease ; diagnostic imaging ; genetics ; Magnetic Resonance Imaging ; Male ; Mutation ; genetics ; Neuroimaging ; methods

Glucose transport 1 (GLUT-1) deficiency is a rare syndrome caused by mutations in the glucose transporter 1 gene (SLC2A1) and is characterized by early-onset intractable epilepsy, delayed development, and movement disorder. De novo mutations and several hot spots in N34, G91, R126, R153, and R333 of exons 2, 3, 4, and 8 of SLC2A1 are associated with this condition. Seizures, one of the main clinical features of GLUT-1 deficiency, usually develop during infancy. Most patients experience brief and subtle myoclonic jerk and focal seizures that evolve into a mixture of different types of seizures, such as generalized tonic-clonic, absence, myoclonic, and complex partial seizures. Here, we describe the case of a patient with GLUT-1 deficiency who developed infantile spasms and showed delayed development at 6 months of age. She had intractable epilepsy despite receiving aggressive antiepileptic drug therapy, and underwent a metabolic workup. Cerebrospinal fluid (CSF) examination showed CSF-glucose-to-blood-glucose ratio of 0.38, with a normal lactate level. Bidirectional sequencing of SLC2A1 identified a missense mutation (c.1198C>T) at codon 400 (p.Arg400Cys) of exon 9.
Cerebrospinal Fluid ; Codon ; Drug Resistant Epilepsy ; Drug Therapy ; Exons* ; Glucose Transport Proteins, Facilitative ; Glucose Transporter Type 1 ; Glucose* ; Humans ; Infant ; Infant, Newborn ; Lactic Acid ; Movement Disorders ; Mutation, Missense ; Myoclonus ; Seizures ; Spasms, Infantile*

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is caused by impaired glucose transport across the blood-brain barrier (BBB) and characterized by infantile seizures, developmental delay, acquired microcephaly, spasticity, ataxia, and a low cerebrospinal glucose concentration (hypoglycorrhachia). A diagnosis of GLUT1-DS is biochemically established in neurologically impaired patients with hypoglycorrhachia in the normoglycemia. GLUT1-DS can be confirmed by mutation analysis of the solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) gene or reduced 3-O-methyl-D-glucose uptake into erythrocytes. The patient was a 12-year-old boy born at term. He had experienced seizures from 4 months of age. Electroencephalography (EEG) did not show epileptiform activity. Brain magnetic resonance imaging (MRI) revealed mild diffuse cortical atrophy and ventricular dilatation. Furthermore, he showed developmental delay, mental retardation, and ataxia, which all became more apparent with age progression. For 7 years, he had experienced paroxysmal episodes of atonic behavioral changes that were aggravated before meals or when he became tired. When he was 12 years old, cerebrospinal fluid (CSF) analysis revealed a low glucose concentration in the normal serum glucose and lactate levels. Under the impression of GLUT1-DS, mutation analysis of the SLC2A1 gene by direct sequencing was performed using white blood cells, and c.680-2delA of intron 5 was found. We describe a GLUT1-DS patient with a typical natural history of GLUT1-DS through a long term follow-up visits, with a novel splice site mutation (SLC2A1: c.6802delA).
3-O-Methylglucose ; Ataxia ; Atrophy ; Blood Glucose ; Blood-Brain Barrier ; Brain ; Cerebrospinal Fluid ; Child ; Diagnosis ; Dilatation ; Electroencephalography ; Erythrocytes ; Follow-Up Studies ; Glucose ; Glucose Transport Proteins, Facilitative* ; Glucose Transporter Type 1 ; Humans ; Intellectual Disability ; Introns ; Lactic Acid ; Leukocytes ; Magnetic Resonance Imaging ; Male ; Meals ; Microcephaly ; Muscle Spasticity ; Natural History ; Seizures

We evaluated the efficacy of non-competitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine) as an adjuvant therapy in experimental neonal bacterial meningitis. Meningitis was induced by injecting 10(6) colony forming units of Escherichia coli into the cisterna magna. MK-801 3 mg/kg was given as a bolus intravenous injection, 30 min before the induction of meningitis. MK-801 did not down-modulate the inflammatory parameters, such as increased intracranial pressure, cerebrospinal fluid (CSF) leukocytosis, increased lactate and TNF-alpha levels in the CSF, and hypoglycorrhachia observed in the meningitis group. MK-801 did not significantly attenuate the elevated glutamate concentration in the CSF. However, MK-801 showed some neuroprotective effects as evidenced by significant attenuation of cerebral lipid peroxidation products (conjugated dienes) and increase of brain high-energy phosphate compounds (ATP and PCr). Improvement in cerebral cortical cell membrane Na+, K+ -ATPase activity did not reach a statistical significance. These results suggest that MK-801 was effective in ameliorating brain injury in neonatal bacterial meningitis, although it failed to attenuate the inflammatory responses.
Animals ; Animals, Newborn ; Blood Glucose/metabolism ; Brain/cytology ; Brain/drug effects* ; Brain/metabolism ; Cell Membrane/drug effects* ; Cell Membrane/metabolism ; Cerebral Cortex/metabolism ; Dizocilpine Maleate/pharmacology* ; Energy Metabolism* ; Excitatory Amino Acid Antagonists/pharmacology ; Glutamic Acid/cerebrospinal fluid ; Lactic Acid/blood ; Leukocytes/metabolism ; Meningitis, Escherichia coli/drug therapy ; Meningitis, Escherichia coli/metabolism* ; Neurons/drug effects* ; Neurons/metabolism ; Neuroprotective Agents/pharmacology* ; Random Allocation ; Swine ; Tumor Necrosis Factor/cerebrospinal fluid

In this study, we tested the hypothesis that decreased cerebral perfusion pressure (CPP) induces cerebral ischemia and worsen brain damage in neonatal bacterial meningitis. Meningitis was induced by intracisternal injection of 10(9) colony forming units of Escherichia coli in 21 newborn piglets. Although CPP decreased significantly at 8 hr after bacterial inoculation, deduced hemoglobin (HbD), measured as an index of changes in cerebral blood flow by near infrared spectroscopy, did not decrease significantly. In correlation analyses, CPP showed significant positive correlation with brain ATP and inverse correlation with brain lactate levels. CPP also correlated positively with HbD and oxidized cytochrome aa3 (Cyt aa3) by near infrared spectroscopy. However, CPP did not show significant correlation with cerebral cortical cell membrane Na+,K+-ATPase activity, nor with levels of lipid peroxidation products. In summary, decreased CPP observed in this study failed to induce cerebral ischemia and further brain injury, indicating that cerebrovascular autoregulation is intact during the early phase of experimental neonatal bacterial meningitis.
Animal ; Animals, Newborn ; Blood Glucose/metabolism ; Cell Membrane/microbiology ; Cell Membrane/enzymology ; Cerebral Cortex/metabolism ; Cerebral Cortex/chemistry ; Cerebral Cortex/blood supply ; Cerebrovascular Circulation/physiology* ; Energy Metabolism/physiology* ; Escherichia coli Infections/physiopathology* ; Escherichia coli Infections/metabolism* ; Glucose/cerebrospinal fluid ; Glucose/analysis ; Intracranial Pressure ; Lactic Acid/cerebrospinal fluid ; Lactic Acid/blood ; Lactic Acid/analysis ; Lipid Peroxidation/physiology ; Meningitis, Bacterial/physiopathology* ; Meningitis, Bacterial/metabolism* ; Na(+)-K(+)-Exchanging ATPase/metabolism ; Spectroscopy, Near-Infrared ; Swine

PURPOSE: Despite the advent of new and more potent antibiotics, mortality and morbidity rates due to bacterial meningitis remain stagnant. Rapid detection of microorganism and early antibiotics treatment are the most important prognostic factors of bacterial meningitis. For early diagnosis of bacterial meningitis biochemical markers such as lactic dehydrogenase, lactic acid, C-reactive proteia have been measured in cerebrospinal fluid. Ferritin is a large, spherical molecule with propensity for oligomer formation, which causes low concentration in cerebrospinal fluid. METHODS: From May 1996 to July 1999, cerebrospinal fluid(CSF) ferritin was serially measured in 84 children who were admitted to Chonnam Natuional University Hospital Pediatric Department for evaluation of the diagnostic value of CSF ferritin in bacterial meningitis. They were divided into three groups-control(20), aseptic(40), bacterial(24)-according to inclusion criteria for each group. RESULTS: CSF ferritin level in bacterial meningitis(52.94+/-3.19ng/mL) was much higher than those of aseptic(5.26+/-2.07ng/mL), and control(3.01+/-2.52ng/mL) groups(P<0.05). CSF ferritin level of 9.20ng/mL was suggested as a cut-off value for bacterial meningitis on ROC curve(sensitivity: 92 %, specificity:81%). CSF ferritin levels were positively correlated with CSF WBC(r=0.699) and protein(r=0.734) and negatively correlated with CSF glucose(r=-0.609) (P<0.01). CONCLUSION: CSF ferritin could be a good indicator for bacterial meningitis in children.
Anti-Bacterial Agents ; Biomarkers ; Cerebrospinal Fluid* ; Child* ; Early Diagnosis ; Ferritins* ; Humans ; Jeollanam-do ; Lactic Acid ; Meningitis* ; Meningitis, Bacterial ; Mortality ; Oxidoreductases

In two female siblings, growth and developmental retardation, poor sucking, anorexia, floppiness and respiratory difficulty developed around 2 and 4 monthes of age in each, and the respiratory symptoms rapidly aggravated to comatose states and finally into death one month later. On admission at emergency room, severe acidosis and high lactate and pyruvate levels in serum and cerebrospinal fluid were revealed in one. Brain computed tomography and magnetic resonance imaging revealed identical bilateral involvement of putamen in both of the sibs, which made the diagnosis of Leigh disease(subacute necrotizing encephalomyelopathy) possible. There is also a family history of early death in infancy period; an elder sister and a brother of mother died with unknown cause at their 5 and 10 months of age. Mitochondrial enzyme functions could not be assayed.
Acidosis ; Anorexia ; Brain ; Cerebrospinal Fluid ; Coma ; Diagnosis ; Emergency Service, Hospital ; Female ; Growth and Development ; Humans ; Lactic Acid ; Leigh Disease* ; Magnetic Resonance Imaging ; Mothers ; Putamen ; Pyruvic Acid ; Siblings

Cerebrospinal fluid lactate and intracranial pressure were measured in 24 severely head-injured patients with Glasgow coma scale below 8. Cerebral perfusion pressure, vital sign and CVP were also measured simultaneously. Severely head-injured patients revealed increased CSF lactate and intracranial pressure which have been significantly correlated with outcome. But changes of vital sign, cerebral perfusion pressure and CVP were not correlated with outcome. The elevation of intracranial pressure checked on arrival was statistically significant in correlation to outcome. And the elevation of CSF lactate were correlated with statistically significance in correlation with outcome and lactate level checked on time interval(arrival, 12hr, 24hr, 48hr after trauma). And so CSF lactate levels are statistically more significant than intracranial pressure in predicting prognosis. We will expect good prognosis in severely head-injured patient by reducing intracranial pressure and CSF lactate, oxygenation and increasing cerebral perfusion.
Cerebrospinal Fluid ; Glasgow Coma Scale ; Humans ; Intracranial Pressure ; Lactic Acid* ; Oxygen ; Perfusion ; Prognosis* ; Vital Signs

The authors compared the changes of morphology, blood brain barrier alteration, pathology, arterial blood lactate content and cerebrospinal fluid lactate content between an intermittent brain retraction group and a continuous brain retraction group in 56 mongrel cats. The results were as follows ; 1) Microscopically, hemorrhages were punctate in 15 cases among 25 cases in the intermittent retraction group. However, there were multiple or large hemorrhages in 13 cases among the 25 cases in the continuous brain retraction group. 2) All cases of the intermittent retraction group showed 0~25% Evans blue staining of the coronal section crossing the retraction site. However, 8 cases among the 25 cases of the continuous retraction group showed 51~75% Evans blue staining and 4 cases of this group showed 76~100% staining. 3) With photomicroscopy, the authors noted small hemorrhage and cellular swelling in the intermittent retraction group instead of pyknosis, hemorrhagic necrosis, vacuolation in the continuous retraction group. 4) The change of arterial blood lactate content was from 1.22+/-0.24mmol/L at preretraction time to 1.42+/-0.26mmol/L at 90 minutes after release of retractor in the intermittent retraction group(p<0.01). In the continuous retraction group, the authors noted a change in the lactate content from 1.20+/-0.38mmol/L to 3.15+/-0.97mmol/L for the same time as above(p<0.001). 5) The change of CSF lactate content in the intermittent retraction group was from 1.39+/-0.29mmol/L at preretraction time to 1.43+/-0.23mmol/L at 90 minutes after release of retractor(p>0.05). In the continuous retraction group, this author noted change in the lactate content from 1.37+/-0.28mmol/L to 2.11+/-0.52mmol/L for the same time as described above(p<0.01). From the above results, the superiority of the intermittent brain retraction was demonstrated as compared with the continuous brain retraction. Also the possible utilization of this experimental method was discussed for other wxperimental studies on ischemia.
Animals ; Blood-Brain Barrier ; Brain* ; Cats* ; Cerebrospinal Fluid ; Evans Blue ; Hemorrhage ; Ischemia ; Lactic Acid ; Necrosis ; Pathology

The use of controlled hyperventilation during neurosurgical procedures prevents the deleterious effects of hypercarbia on the cerebral blood flow and intracranial pressure. hyperventilation with hypocarbia produces cerebral vasoconstriction, reduced cerebral blood flow and a reduction in brain size in the majority of patients with increased intracranial pressure. But since excessive cerebral vasoconstriction might induce cerebral ischemia, there has been much discussion concerning the optimal level of hypocarbia. Several studies have shown biochemical evidence of a change in cerebral glucose utilization to anaerobic metabolism during hypocarbia. In our investigation, the effect of hyperventilation on 10 neurosurgical patients was evaluated by blood gas analysis and the estimation of lackate and pyruvate in arterial blood and the cerebrospinal fluid. The results were as follows: 1) PaCO2 decreased from a prearesthetic value of 38+/-2.2 mmHg to 22+/-2.1mmHg 1 hour postinduction and 24+/-2.2mmHg at 2 hours due to hyperventilation. pH was 7.58+/-0.047 1 hour postinduction and 7.56+/-0.018 at 2 hours. PaO2 was 251+/-33.0mmHg 1 hour postinduction 1 hour and 215+/-20.9mmHg at 2 hours under a 50% inspired oxygen concentration(FiO2=0.5). 2) The arterial blood lactate value increased statistically significantly from a preanesthetic value of 9.3+/-1.5mg% to 11.8+/-1.47mg% 1 hour postinduction(p<0.01) to 12.5+/-1.53mg% at 2 hours(p<0.005). However all values were within the normal range(4.7+/-15.1mg%), and the lacte/pyruvate ratio did not change. 3) In the cerebrospinal fluid, pH was 7.45+/-0.057, PCO2 was 34+/-3.5mmHg and PO2 was 91+/-6.7mmHg following hyperventilation for 1 hour. The lactate value of the cerebrospinal fluid was 19.2+/-3.14mg%(normal range: 11.0~27.0mg%) and the lactate/pyruvate ration was 14.5+/-2.39. 4) No evidence of an excessive increase in CSF lactate was seen in any case. The above findings suggest that maintenance of an adequate oxygen concentration and a carbon dioxide value over 20mmHg would prevent cerebral ischemia following hypocarbia due to hyperventilation.
Anesthesia* ; Blood Gas Analysis ; Brain ; Brain Ischemia ; Carbon Dioxide ; Cerebrospinal Fluid* ; Glucose ; Humans ; Hydrogen-Ion Concentration ; Hyperventilation* ; Intracranial Pressure ; Lactic Acid ; Metabolism ; Neurosurgical Procedures ; Oxygen ; Pyruvic Acid ; Vasoconstriction