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.     

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.     

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.     

Levels of enolase and other enzymes in the cerebrospinal fluid as indices of pathological change

The activities of enolase, aldolase, pyruvate kinase, lactate dehydrogenase and creatine phosphokinase were measured in cerebrospinal fluid of 121 patients presenting with a range of disorders of the central nervous system. The results from 41 patients undergoing myelography were used as controls. An assessment was made of the relative merits of these five enzymes as markers of brain damage with special reference to brain tumours. Enolase was the most sensitive marker of pathological change and was the only enzyme raised in the CSF of patients with low grade astrocytomas.     

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.     

Carbohydrate metabolites in the blood and CSF of patients with neuromuscular disorders

Summary The concentrations of glucose, pyruvate and lactate were determined in the blood and lumbar CSF of 63 patients with neuromuscular disorders and 40 controls. The glucose/lactate and lactate/pyruvate ratios were also calculated, in addition to the cytoplasmic NADH/NAD⁺ (nicotinamide-adenine dinucleotide-H/nicotinamide-adenine dinucleotide) ratio in the brain. Remarkable deviations from control values were found not only in blood but also in the CSF of patients with different neuromuscular diseases, particularly in Duchenne muscular dystrophy and peroneal muscular atrophy, indicative of disturbance of the carbohydrate metabolism in the central nervous system.

---

Zusammenfassung Die Konzentration von Glukose, Pyruvat und Laktat wurde im venösen Blut und lumbalen Liquor bei 63 Patienten mit neuromuskulären Erkrankungen und bei 40 Kontrollpatienten gemessen. Die Glukose/Laktat- und Laktat/Pyruvat-Quotienten, im weiteren der cerebrale cytoplasmatische NADH/NAD⁺-Quotient, wurden errechnet. Nicht nur im Blut, sondern auch im Liquor der neuromuskulären Patienten, u.a. bei Kranken mit Duchenne-Dystrophie und mit neuronaler peronealer Atrophie, konnten ausgeprägte Abweichungen von den Kontrollen gefunden werden. Diese weisen auf die Störung des Kohlenhydrat-Stoffwechsels im ZNS dieser Kranken hin.

     

The Rett syndrome and CSF lactic acid patterns.

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.     

Dosage of lactate in the cerebrospinal fluid in infectious diseases of the central nervous system.

This paper analyzes the diagnosis aid of the dosage of lactate in the cerebrospinal fluid (CSF) in infectious diseases of the central nervous system (CNS). We analyzed prospectively 130 samples of CSF of 116 patients with diagnoses of infectious processes in the CNS. The 130 samples of CSF were divided into five groups: 28 samples of the control group, 40 of bacterial meningitis, 22 of viral meningitis, 16 of fungal meningitis and 24 of patients presenting acquired immune deficiency syndrome (AIDS). The concentration of lactate in the CSF was elevated in the group of patients with bacterial meningitis (average = 46.2 mg/dL), fungal meningitis (average = 27.3 mg/dL) and in the AIDS group (average = 23.5 mg/dL). In the control group and viral meningitis group the lactate content in the CSF presented the reference rates according to the employed method. The lactate dosage in the CSF presented a negative correlation with glycorrhachia and positive correlation with the cellularity and total proteins of the CSF. We conclude that the lactate dosage in the CSF, although unspecific, helps to distinguish the infectious processes of the CNS.     

Morvan's syndrome: clinical, laboratory, and in vitro electrophysiological studies

Morvan's syndrome is a rare disorder characterized by neuromyotonia, hyperhidrosis, and central nervous system dysfunction. We report a patient with features of this syndrome, but who initially presented with breathing difficulties. Concentric needle electromyography showed an abundance of myokymic and neuromyotonic discharges. Exercise tests and repetitive nerve stimulation showed a decrement-increment response of compound muscle action potentials. Antibodies against voltage-gated potassium channels were not detected on repeated testing, but the presence of oligoclonal bands in the cerebrospinal fluid (CSF) suggested an autoimmune etiology. At follow-up over 3 years, no cancer was found. Electrophysiological in vitro studies of effects of patient serum and CSF on rat nerves provided no evidence of altered voltage-gated sodium or potassium conductances. We conclude that putative humoral factors do not block ion channels acutely but may cause channel dysfunction with chronic exposure.     

Elevated cerebrospinal fluid lactate/pyruvate ratio in Machado-Joseph disease

To identify the metabolic alterations related to mitochondrial functions in Machado-Joseph disease (MJD), we analyzed the cerebrospinal fluid (CSF) levels of lactate, pyruvate, and citric acid cycle intermediates by high performance liquid chromatography (HPLC) in 7 Japanese patients with that disease and then measured some mitochondrial enzymes. Their mean age was 46 years. Diseased controls were matched by age to the patients studied. The CSF level of lactate was significantly elevated, pyruvate was significantly decreased, and the lactate/pyruvate (L/P) ratio was significantly elevated in the patients with MJD. There were no significant differences of citric acid cycle intermediates of the CSF between the patients and the controls. We measured the native and dichloroacetate (DCA)-activated pyruvate dehydrogenase complex (PDHC) activities, and mitochondrial electron transport activities in 3 patients with MJD, and found these activities to be normal. Therefore, the increased CSF lactate, increased lactate/pyruvate ratio, and decreased pyruvate may reflect the decreased regional cerebral blood flow rather than metabolic derangement of the mitochondria.     

Effect of coenzyme Q(10) on biochemical and morphological changes in experimental ischemia in the rat brain

The aim of the work was to evaluate an influence of CoQ(10) on lactate acidosis, adenosine-5'-triphosphate (ATP) concentrations, oxidized to reduced glutathione ratio and on superoxide dismutase activity in endothelin model of cerebral ischemia in the rat. Light microscopic studies in the central nervous system and morphometric analysis of pyramidal cells in the hippocampus were also performed. Endothelins (ET-1 or ET-3; 20 pmoles) were injected into the right lateral cerebral ventricle (intracerebroventricularly). CoQ(10) was given intraperitoneally (i.p.) just before the operation (i.p. 10 mgkg b. wt.). More severe changes of investigated biochemical parameters were observed in the animals treated with ET-1 in comparison with ET-3. Recovery was noted earlier in the group subjected to ET-3 and CoQ(10) administration, than in the animals subjected to ET-1 and CoQ(10) treatment. Histopathological observations showed sparse foci of a neuronal loss in the cerebral cortex and in the hippocampus only in the ET-1 model of ischemia. Additionally more numerous dark neurons were present in above brain structures following ET-1 administration comparing with ET-3 one. Morphometrical studies demonstrated that CoQ(10) diminished neuronal injury in the hippocampal CA1, CA2 and CA3 zones. Above data indicate on neuroprotective effect of CoQ(10) as a potent antioxidant and oxygen derived free radicals scavenger in the cerebral ischemia.     

Cerebrospinal fluid studies in the Rett syndrome: biogenic amines and beta-endorphins.

The etiology of the Rett syndrome (RS) is unknown. Reduced function of biogenic amines has been described. Symptoms of central apnea, hyperventilation, hypothermia, peripheral analgesia, muscle rigidity, myoclonic jerks, hand stereotypy and seizures occur in RS and have been suggested as a result of elevated central beta-endorphins. It was hypothesized that a dysfunctional modulation of endogenous opiate systems and biogenic amines may be present. Cerebrospinal fluid (CSF) from 12 girls with RS was studied for beta-endorphin immunoreactivity, and biogenic amines. Lactates and pyruvate levels were measured. Eleven of the 12 girls had elevated beta-endorphin immunoreactivity in CSF, 4 girls had reduced biogenic amines and 6 girls had elevated pyruvate and lactate levels. Whether the elevated beta-endorphin immunoreactivity is a primary disorder or is a result of secondary feedback mechanisms is unknown. Naltrexone, an antiopioid drug, may reduce symptoms.     

Clinical and biochemical correlations in mitochondrial myopathies treated with coenzyme Q10

We tested the efficacy of coenzyme Q10 (ubidecarenone, CoQ10) therapy in patients with Kearns-Sayre syndrome and other mitochondrial myopathies with chronic progressive external ophthalmoplegia (CPEO). We treated seven patients for 1 year with daily oral administration of 120 mg of CoQ10. Throughout the treatment most of our patients showed a progressive reduction of serum lactate and pyruvate levels following standard muscle exercise and generally improved neurologic functions. The ECG and echocardiogram showed no significant changes in our patients. None of our patients showed any improvement in ptosis and CPEO.     

A case of Kearns-Sayre-Shy syndrome with abnormal signal intensity on MRI in cerebral white matter and brainstem

A 42-year-old woman was admitted for complaining of gait disturbance lasting for 2 years. She had a past history of hearing loss and bilateral ocular ptosis since her age of 21 years. Neurological examinations revealed severe external ophthalmoplegia, ptosis and muscular weakness of neck and extremities, but no dementia. Laboratory examinations showed high level of serum CK and slight elevations of CSF protein, lactate and pyruvate. The QT interval on ECG was prolonged. The EEG finding was slightly abnormal. The neurogenic pattern on EMG was noted. Muscle biopsy was performed at the quadriceps muscle. Its specimens demonstrated mixed changes of muscular atrophy and ragged red fibers. From these findings, Kearns-Sayre-Shy syndrome was diagnosed. It was noted in this case that brain MRI (T2-weighted image) revealed bilateral diffuse high signal intensity areas on cerebral white matter and brainstem. It seems that the lesions of central nervous system may progress subclinically for many years in cases of KSS, as our case shows.     

Brain metabolism in deep controlled hypotension in neurosurgical patients

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.     

Different effects of monocarboxylates on neuronal survival and beta-amyloid toxicity

Glucose is a principal metabolic fuel in the central nervous system, but, when glucose is unavailable, the brain can utilize alternative metabolic substrates such as monocarboxylates to sustain brain functions. This study examined whether the replacement of glucose with monocarboxylates (particularly pyruvate and lactate) had an equivalent effect of glucose on neuronal survival in rat hippocampal organotypic slice cultures, or ameliorate the neurotoxicity induced by amyloid beta-peptide (Abeta). The possible mechanism was also explored. We found that pyruvate and lactate alone increased cell death in the hippocampal slice cultures at 24 and 48 h. Supplementation of glucose-containing culture media and Abeta-treated culture media with pyruvate, but not lactate, attenuated cell death as strong as with trolox, known as a reactive oxygen species scavenger, and niacinamide, an NAD(+) precursor, and this protective effect was reversed by alpha-cyano-4-hydroxycinnamic acid. Pyruvate significantly increased the aconitase activity and the NAD(+) levels in the hippocampal slices in the presence of Abeta, but did not maintain the ATP levels. Our results indicate that pyruvate and lactate alone cannot replace glucose as an alternative energy source to preserve the neuronal viability in the hippocampal slice cultures. Pyruvate, in the presence of glucose, improves neuronal survival in the hippocampal slice cultures and also protects neurons against Abeta-induced cell death in which mitochondrial NAD(P) redox status may play a central role.     

Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy

We used a standardized bicycle ergometry protocol with a stepwise increasing workload (30–100 W) to evaluate various metabolic factors for the diagnosis and metabolic monitoring of mitochondrial encephalomyopathies. All patients (n = 9) showed pathological venous lactate/pyruvate (L/P) ratios, which normalized in three patients after 6 months of coenzyme Q₁₀ (CoQ) therapy. Thus, the L/P ratio proved to be the clinically most useful parameter in the evaluation and monitoring of mitochondrial diseases, showing higher sensitivity than lactate measurements only. CoQ may exert a favourable effect in some patients with mitochondrial diseases. Received: 15 October 1997 Received in revised form: 6 February 1998 Accepted: 20 March 1998     

Cerebrospinal fluid gamma-aminobutyric acid in neurologic disease.

Cerebrospinal fluid gamma-aminobutyric acid (CSF GABA) was analyzed in 151 patients who underwent evaluation for central nervous system disease. CSF GABA was not detected in 19 of these patients, who had no evidence of neurologic disease and who served as controls. GABA was most frequently detected in patients with cerebrovascular disease, and was detected only in Parkinson's syndrome of atherosclerotic origin and dementia of multi-infarct type. CSF GABA was not detected in Alzheimer's disease or Huntington's disease. Patients with grand mal seizures exhibited CSF GABA elevation within 24 hours of the ictus. In patients with multiple sclerosis GABA detection was related to the presence or exacerbation of spinal cord lesions. Further study is necessary to evaluate the significance of elevated CSF GABA in central nervous system disease.     

Cerebrospinal fluid pyruvate levels in Alzheimer's disease and vascular dementia

Increased amounts of CSF pyruvate and lactate were found in patients with AD and patients with vascular dementia (VaD). In the AD group, CSF pyruvate values did not show any overlap with those obtained in controls; within the VaD group, the highest values were observed in possible VaD cases. A significant correlation between the severity of dementia and these biochemical parameters was also observed in both AD and possible VaD. The similarities of CSF pyruvate patterns observed in AD and possible VaD patients implicate a neurodegenerative component in this VaD subgroup.     

Oligoclonal IgG bands in cerebrospinal fluid and serum during asymptomatic human immunodeficiency virus infection

Serum and cerebrospinal fluid (CSF) samples from asymptomatic patients seropositive for human immunodeficiency virus (HIV) showed frequent evidence of intrathecal IgG synthesis and oligoclonal IgG bands, with different isoelectric focusing patterns in serum and CSF; 2 of 7 had a CSF pleocytosis. The results suggest frequent, early, chronic central nervous system infection following HIV infection.