Elevated CSF-lactate is a reliable marker of mitochondrial disorders in children even after brief seizures.

BACKGROUND: Increased lactate is an important biochemical marker in diagnosis of children with suspicion of mitochondrial disorders. A diagnostic dilemma may originate if analyses are performed after seizures, when the increased lactate levels may be considered to result from the seizures. To address this problem, we ascertained the diagnostic value of lactate and alanine in blood (B) and cerebrospinal fluid (CSF) in children with mitochondrial disorders (n = 24), epilepsy (n = 32), psychomotor retardation (n = 23), meningitis (n = 12) and meningism (n = 16). METHODS: Lactate concentration was measured using a spectrophotometric method. Amino acids in serum and CSF were analyzed by ion exchange chromatography with ninhydrin detection. RESULTS: Average blood and CSF-lactate levels were significantly higher in children with mitochondrial disorders (3.87 ± 0.48 and 4.43 ± 0.55 mmol/l) and meningitis (2.77 ± 0.45 and 8.58 ± 1.08 mmol/l) than in children with epilepsy (1.72 ± 0.13 and 1.62 ± 0.04 mmol/l), psychomotor retardation (1.79 ± 1.40 and 1.68 ± 0.06 mmol/l) or meningism (1.70 ± 0.13 and 1.64 ± 0.07 mmol/l). Blood and CSF-alanine levels were also higher in children with mitochondrial disorders (558 ± 44 and 51 ± 8 µmol/l) than in children with epilepsy (327 ± 23 and 27 ± 3 µmol/l) or psychomotor retardation (323 ± 27 and 26 ± 3 µmol/l). The CSF-lactate levels of children with epilepsy were similar whether the samples were obtained 3 ± 0.6 h after an attack of brief seizures or from children without history of recent seizures. CONCLUSION: Elevated cerebrospinal fluid lactate level is a reliable marker pointing to mitochondrial origin of disease, even in children who have recently suffered short-lasting seizures. Some children with mitochondrial disorders manifest only mild or intermittent elevation of lactate levels.

A case of 6-pyruvoyl-tetrahydropterin synthase deficiency demonstrates a more significant correlation of L-Dopa dosage with serum prolactin levels than CSF homovanillic acid levels.

6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is a tetrahydrobiopterin (BH4) deficiency that presents as hyperphenylalaninemia. Administration of the neurotransmitter precursors L-Dopa/carbidopa and 5-hydroxytryptophan (5HTP), as well as BH4, is necessary for treatment. It has been reported that serum prolactin levels are elevated in patients with PTPS deficiency indicating that inhibition of prolactin secretion by dopamine is insufficient and is negatively correlated with the CSF level of HVA. Here, we present a case of PTPS deficiency which showed a more significant correlation of dosage of L-Dopa/carbidopa with serum prolactin levels than with CSF HVA levels. Combined treatment of BH4, L-Dopa/carbidopa, and 5HTP was started as the CSF neopterin/biopterin ratio (N/B ratio 7.54, control 0.46-1.59) and serum prolactin level (36.79 ng/ml, control <15) were elevated. The dosage of L-Dopa/carbidopa was adjusted in the range of 9.08-10.5mg/kg/day. The CSF level of HVA stayed within normal limits using these dosages of L-Dopa/carbidopa, and there was no correlation between dose given and HVA level (R=0.230, p=0.71). On the other hand, even in this relatively small dosing range, the serum prolactin level showed significant negative correlation with the dosage of L-Dopa/carbidopa (R=0.645, p=0.023). The patient did not show any neurological symptoms even when the serum prolactin level was elevated. From these results, we suggest that the serum prolactin level may be a more sensitive marker than the CSF HVA level to guide the dose adjustment of L-Dopa/carbidopa in the management of patients with PTPS deficiency.

Serum and CSF levels of cytokines in acute encephalopathy following prolonged febrile seizures.

It is well known that an acute encephalopathy occasionally follows prolonged febrile seizures. We measured the concentrations of interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in serum and CSF during the acute stage in 13 children with acute encephalopathy following prolonged febrile seizures (AEPFS) and 23 with prolonged febrile seizures without encephalopathy (PFS) to investigate the pathogenesis of AEPFS. Serum IL-6, IL-10, sTNFR1, and CSF IL-6 levels were significantly higher in AEPFS and PFS compared with control subjects. CSF IL-6 levels in AEPFS were significantly higher than those in PFS, but not serum IL-6, IL-10, or sTNFR1. The CSF IL-6 levels were significantly higher than the serum levels in AEPFS, but not PFS. The serum levels of sTNFR1 and IL-10 were significantly higher than those in the CSF in AEPFS and PFS. The serum IL-10 and sTNFR1 levels in patients who did not experience a second seizure were significantly higher than those in patients who experienced a second seizure, which was characterized by clusters of complex partial seizures several days after the initial prolonged febrile seizure. Our results suggest that serum IL-6, IL-10, TNF-alpha, and CSF IL-6 are part of the regulatory system of cytokines in AEPFS.

Reversible dementia and corresponding CSF alterations due to intraspinal lumbosacral metastasis of a prostate carcinoma.

We report, for the first time, how intraspinal carcinoma metastasis can cause reversible dementia accompanied by distinct cerebrospinal fluid (CSF) alterations. A 73-year-old male patient who suffered from rapidly progressive dementia and gait disturbance showed marked abnormalities of CSF tau protein, amyloid beta(1-42), and prostate-specific antigen. A lumbosacral, intraspinal metastasis from a prostate carcinoma was found, and after microsurgical removal, CSF alterations normalized and the clinical symptoms regressed. This case illustrates how malignant tumors can disturb brain function via indirect mechanisms.

Gadolinium encephalopathy in a patient with renal failure.

Gadolinium chelates are extensively used in MRI studies. Neurotoxicity due to gadolinium chelates is minimal and uncommon. A 57-year-old woman in renal failure developed a subacute encephalopathy after inadvertent repetitive gadolinium contrast administration. An unusual MRI appearance with CSF hyperintensity due to gadolinium diffusion into the CSF is also shown.

Relationship of white matter hyperintensities to cerebrospinal fluid glucose polyol pathway metabolites-a pilot study in treatment-resistant affective disorder patients.

BACKGROUND: Magnetic resonance imaging (MRI) white matter hyperintensities (WMHs) are found at higher rates in patients with affective disorders, particularly late-life or treatment-resistant disorders. Studies support a vascular pathogenesis for WMHs in late-life onset disorders; however, pathogenesis in typical early-life onset disorders is less clear. Based on associations between diabetes mellitus and both WMHs and affective disorders, this study investigated the relationship between WMHs and brain glucose metabolism by the polyol pathway-a pathway linked to nervous tissue disease in diabetes. METHODS: Burdens of fluid-attenuated inversion recovery (FLAIR) WMHs were quantified and correlated with cerebrospinal fluid (CSF) concentrations of glucose metabolites in 10 nondiabetic inpatients with treatment-resistant bipolar, unipolar, and schizoaffective disorders and 10 nondiabetic control patients who had been investigated clinically for transient neurological symptoms. RESULTS: Deep but not periventricular WMH burden correlated positively and significantly with elevated CSF concentrations of sorbitol, the specific polyol pathway metabolite of glucose (rho=0.86, p=0.002), in the affective disorders but not the control group. LIMITATIONS: This was a pilot study with a relatively small number of subjects; therefore, conclusions are tentative. Controls were not healthy subjects; they were patients with transient neurological symptoms. CONCLUSIONS: This is the first reported evidence of a relationship between WMHs and increased brain glucose metabolism by the polyol pathway in patients with affective disorders. More extensive studies are necessary to determine whether this preliminary finding represents a pathogenetic relationship.

Severe hypomyelination associated with increased levels of N-acetylaspartylglutamate in CSF.

BACKGROUND: Two unrelated girls had early onset of nystagmus and epilepsy, absent psychomotor development, and almost complete absence of myelin on cerebral MRI. The clinical features and MR images of both patients resembled the connatal form of Pelizaeus-Merzbacher disease (PMD), which is an X-linked recessive disorder caused by duplications or mutations of the proteolipid protein gene (PLP). OBJECTIVE: To define a unique neurometabolic disorder with failure of myelination. METHOD: S AND RESULTS: 1H-NMR of CSF in both girls was performed repeatedly, and both showed highly elevated concentrations of N-acetylaspartylglutamate (NAAG). The coding sequence of the gene coding for glutamate carboxypeptidase II, which converts NAAG to N-acetylaspartate (NAA) and glutamate, was entirely sequenced but revealed no mutations. Even though both patients are girls, the authors sequenced the PLP gene and found no abnormality. CONCLUSIONS: NAAG is an abundant peptide neurotransmitter whose exact role is unclear. NAAG is implicated in two cases of unresolved severe CNS disorder. Its elevated concentration in CSF may be the biochemical hallmark for a novel neurometabolic disorder. The cause of its accumulation is still unclear.

Cerebrospinal fluid investigations for neurometabolic disorders.

Careful clinical delineation and advances in analytical methods have opened new possibilities for the detection of inherited neurometabolic disorders, some of which require specific CSF analyses for diagnosis. Although patients suffering from these disorders have recognizable phenotypes, there are strong indications that remain many undiagnosed, leading to a continuation of futile diagnostic searches and, for most disorders, withholding of available rational therapy. As there is still widespread uncertainty about when to perform specialist CSF investigations, it is the aim of this paper to define the place for CSF investigations in the diagnostic work-up of a child with an encephalopathy of unknown origin. Most neurometabolic disorders can be identified through serum, plasma and urine analyses in conjunction with neuroradiological investigations. Whenever CSF investigations are performed, the analysis should include quantitative determination of lactate, pyruvate and amino acids, the latter by methods especially suited for CSF, in addition to cells, glucose, protein, immunoglobulin classes, specific immunoglobulins, and an evaluation of the blood-brain barrier. If the disease course is non-progressive or if extracerebral symptoms are present in addition to an encephalopathy, e.g. endocrinological, hepatic, muscular or renal symptoms, investigations of metabolites in CSF over and above lactate, pyruvate and amino acids are generally noncontributary. Specific CSF investigations, which are discussed in detail, test metabolic pathways of brain metabolism, especially of neurotransmission. For a successful diagnosis of these defects, analyses must be planned individually, before CSF samples are taken, based on family history, clinical findings and disease course. Different determinations require different logistics from taking of the sample to shipment. One indication for specialized CSF analyses including biogenic monoamines and GABA is severe neonatal/infantile epileptic encephalopathy. In addition to a therapeutic trial of B6, folinic acid should be tried empirically for two to three days as the emerging syndrome of folinic acid responsive seizures appears to be the underlying cause in a sizable proportion of patients. In later infancy and childhood, defects in the metabolism of the biogenic monoamines may be suspected in patients with (fluctuating) extrapyramidal disorders, in particular Parkinsonism dystonia or more general "athetoid cerebral palsy", and vegetative disturbances. A severe epileptic encephalopathy and progressive mental retardation may be present. Neuroimaging findings do not show specific lesions. Determinations of folates and organic acids in CSF appear at present only warrantable individually in special constellations, e.g. classical clinical findings and disease course suggestive of glutaryl-CoA dehydrogenase deficiency with repeated negative quantitative analyses of organic acids in urine. The diagnosis of disorders, which require specific analyses of CSF, can only be achieved by conscious diagnostic decisions based on a concept of the respective disease and repeated scrupolous expert clinical evaluation aided by an array of investigations in blood and urine as well as neuroimaging findings. No single one investigation in CSF can serve as a "selective screening" test. A growing awareness of these disorders is needed and should lead to increased and earlier diagnosis of patients through fewer rather than more lumbar punctures.

Cerebrospinal fluid as a tool in the diagnosis of neurometabolic diseases: amino acid analysis before and after acid hydrolysis.

We perform systematically amino acid analysis of the CSF before and after strong acid hydrolysis in children with unexplained neurological disease. By comparing the amino acid pattern before and after hydrolysis, defects can be traced in the metabolism not only of amino acids but also of purines, peptides, N-acetylated amino acids and peptides, and probably other compounds. This method has yielded important information such as the identification of two "new" diseases, GABA transaminase deficiency and adenylosuccinase deficiency, and the discovery of a peculiar, acid-labile double peak in the CSF of patients with the transient neonatal hyperammonaemia syndrome and with urea cycle defects. This substance was subsequently identified by others as gamma-glutamylglutamine. As a consequence, we strongly recommend incorporating of this approach in the investigation of all children with unclear neurological disease.

CSF copper concentration: a new parameter for diagnosis and monitoring therapy of Wilson's disease with cerebral manifestation.

In five patients with cerebral manifestation of Wilson's disease, copper was measured in CSF, serum, urine and liver, and ceruloplasmin was determined in CSF and serum. CSF copper was found to be elevated in all cases, especially in the four examined before therapy. Two patients were followed up for a period of 3 years, while undergoing therapy with chelating substances. In case 1, the data and the clinical course are presented in detail: prior to therapy, the daily urinary copper excretion had been elevated, and this increased during the initial treatment stages. The serum copper concentration, which was already low, decreased quickly the during the initial stages of therapy, and remained at a low level during further treatment. In contrast to its level in serum, the copper level in the CSF was up to 3-fold the normal range and fell only very slowly as clinical symptoms improved. These findings suggest transport of copper from the CNS to the CSF. The copper concentration in CSF appears to be a valuable parameter for diagnosis and monitoring therapy in patients with cerebral manifestation of Wilson's disease.

Increased concentrations of cholestanol and apolipoprotein B in the cerebrospinal fluid of patients with cerebrotendinous xanthomatosis. Effect of chenodeoxycholic acid.

We investigated the effect of chenodeoxycholic acid on cerebrospinal fluid sterol and protein composition in six patients with cerebrotendinous xanthomatosis, a progressive neurologic disease, and in 11 control subjects. In the cerebrospinal fluid from the controls, the mean (+/- SD) levels of cholesterol and cholestanol were 400 +/- 300 and 4 +/- 7 micrograms per deciliter, respectively. The levels were almost 1.5 and 20 times higher in cerebrospinal fluid from untreated patients with cerebrotendinous xanthomatosis. Cholestanol levels were also markedly elevated in the plasma of untreated patients, but their plasma cholesterol levels (215 +/- 61 mg per deciliter) were not different from control values. Treatment with chenodeoxycholic acid reduced cerebrospinal fluid cholesterol by 34 percent and cholestanol threefold. Plasma cholestanol levels also decreased sharply. Normal cerebrospinal fluid contained small quantities of albumin, apolipoproteins, and lecithin:cholesterol acyltransferase. In cerebrospinal fluid from untreated patients with cerebrotendinous xanthomatosis, immunoreactive apolipoprotein B or apolipoprotein B fragment was increased about 100-fold and albumin about 3.5-fold; apolipoprotein AI, apolipoprotein D, and lecithin:cholesterol acyltransferase were 1.5 to 3 times more concentrated. Apolipoprotein AIV and apolipoprotein E concentrations were comparable to those in controls, and apolipoprotein AII was considerably decreased. During treatment, the concentrations of albumin and apolipoproteins AI and B declined. These results suggest that increased cerebrospinal fluid sterols are derived from plasma lipoproteins by means of a defective blood-brain barrier in patients with cerebrotendinous xanthomatosis. Therapy with chenodeoxycholic acid reestablished selective permeability of the blood-brain barrier and normalized the concentrations of sterol and apolipoprotein in the cerebrospinal fluid.

Cerebrospinal fluid hypoxanthine and xanthine concentrations as indicators of metabolic damage due to raised intracranial pressure in hydrocephalic children.

Intracranial pressure and cerebrospinal fluid hypoxanthine and xanthine concentrations were measured in hydrocephalic children with suspected raised intracranial pressure. There was a highly significant correlation between intracranial pressure and cerebrospinal fluid hypoxanthine and xanthine levels.