Elevated cerebrospinal fluid tau protein levels in Wernicke's encephalopathy.

OBJECTIVE: Limited neuronal cell loss is seen in the neuropathology of Wernicke's encephalopathy (WE), but the extent of neuronal damage has not been well studied. Moreover, there is still a debate as to whether alcohol itself causes brain damage in humans. Although, it is difficult to examine the extent of neuronal damage in living patients, recent studies have revealed that total tau protein levels in the cerebrospinal fluid (CSF) reflect the rate of neuronal degeneration. Therefore, we hypothesized that the elevated CSF total tau in patients with WE was due to neuronal damage and thus we examined CSF total tau protein in patients with WE, as well as in those with alcohol withdrawal delirium (WD) and Korsakoff syndrome (KS). We also examined CSF total tau in nonalcohol dependent patients with Alzheimer's disease (AD) as a disease control. METHODS: CSF samples were obtained from 13 acute WE patients with alcohol dependence, 9 WD patients with alcohol dependence and 16 KS patients with alcohol dependence, and from 20 nonalcohol dependent AD patients. CSF was also obtained from 10 of the WE patients after their disease had progressed to the chronic stage. CSF tau protein levels in all samples were determined by sandwich enzyme-linked immunosorbent assay. Tau phosphorylated at threonine 181 (p-tau(181)) and amyloid beta-protein ending at amino acid 42 (A beta 42) in CSF were also determined for comparison between acute WE with AD. RESULTS: Total tau was significantly elevated in acute WE and decreased on long-term follow-up, but was not elevated in WD or KS. The patterns of p-tau(181) and A beta 42 differed between acute WE and AD. CONCLUSIONS: Intense neuronal cell death occurs transiently in WE, and the mechanism differs from that in AD. Neuronal damage is generally unaccompanied in WD. These results suggest that CSF total tau is a useful biological marker for WE.

5-Hydroxyindolacetic acid and homovanillic acid are not involved in the cerebrospinal fluid after a seizure in patients with Delirium Tremens.

Little is known about 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA) levels in cerebrospinal fluid of patients with Delirium Tremens revealed at onset by seizures. The aim of the study is to understand the biochemical abnormalities induced by seizures in the cerebrospinal fluid of patients involved by Delirium Tremens. Nine patients 42-62 years of age, who had experienced a Delirium Tremens after alcohol withdrawal, with one or two seizures at onset, were included in this study. The lumbar puncture (and a CT scan) were performed after the last seizure. Nine patients with neither Delirium Tremens nor seizure, needing a lumbar puncture for their medical problem, were matched by sex and by age. For the measures of 5-HIAA and HVA, we systematically took the first cm3. The mean value of 5-HIAA levels were 12.70 ng ml(-1) in the group of nine patients with Delirium Tremens versus 13.45 ng ml(-1) in the control group. The mean value of HVA levels were 19.81 ng ml(-1) in the group of nine patients with Delirium Tremens versus 25.25 ng ml(-1) in the control group. The differences were not statistically significant. During a Delirium Tremens with seizure at onset, there are no statistically significant changes in 5-HIAA and HVA levels in the cerebrospinal fluid. Our work raises the question of the role of Delirium Tremens in the normalization of the levels of neuro-mediators that usually decrease soon after seizures.

Levels of gamma-aminobutyric acid in cerebrospinal fluid and plasma during alcohol withdrawal.

Aminobutyric acid (GABA) is implicated in the biochemical pathophysiology of alcohol intoxication, dependence and withdrawal. We therefore measured GABA in both cerebrospinal fluid (CSF) and plasma from 14 male alcohol-dependent patients during acute alcohol withdrawal (day 1) and again after 21 days of inpatient treatment (day 21). Plasma GABA levels on admission correlated with indices of liver function. When corrected for differences in liver function, plasma levels of GABA levels on day 1 were significantly higher than on day 21. CSF GABA concentrations were also significantly higher during withdrawal compared with concentrations after 3 weeks of abstinence. The change in plasma GABA levels correlated significantly with the change in CSF GABA levels, although there was no correlation between plasma and CSF levels at either time. These findings demonstrate that changes in CSF GABA may be reflected in plasma GABA, and they highlight the potential importance of the GABA system in alcohol dependence and withdrawal.

Elevated cerebrospinal fluid histidine in alcohol withdrawal.

Cerebrospinal fluid (CSF) histidine concentration was significantly elevated in seven patients early in the alcohol withdrawal syndrome (206.3 +/- 74.4 (SEM) nanomols/ml CSF). When these same patients were restudied an average of six days later when alcohol withdrawal was clinically resolved, their mean CSF histidine concentration continued to be significantly elevated (164.7 +/- 24.7) when compared to normal (12.0 +/- 0.5 nanomols/ml CSF). Other amino acids (aspartic acid, serine, alanine, methionine, leucine, tyrosine, phenylalanine, lysine and arginine) showed no definite changes from normal, and no change during the course of alcohol withdrawal. Possible reasons for these high concentrations and the extreme variability (especially early in alcohol withdrawal) are discussed.

Cerebrospinal fluid monoamine metabolites during alcohol withdrawal syndrome and recovered state.

The aim of the study was to examine changes in cerebrospinal fluid (CSF) monoamine concentrations related to alcohol withdrawal. Lumbar puncture was performed in 8 healthy volunteers (control group) and 36 chronic alcoholic patients following alcohol withdrawal. A second lumbar puncture was performed in 20 of these patients after recovery from the withdrawal. CSF 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were measured. Alcohol withdrawal phenomena in all patients were classified in the following three groups: (i) major withdrawal syndrome: alcohol-withdrawal delirium, (ii) minor withdrawal syndrome: evident autonomic nervous hyperactivity without hallucination or clouding of consciousness, and (iii) asymptomatic type: a withdrawal period without overt symptoms. MHPG concentration was significantly increased in the major withdrawal syndrome, as compared with other groups, including the controls. No change in MHPG was found in the patients without overt autonomic nervous syndrome. A positive correlation between CSF-MHPG and intensity of withdrawal symptoms (r = 0.60, p less than 0.02) was found. A higher correlation between CSF-MHPG and intensity of autonomic nervous disturbances was also found (r = 0.86, p less than 0.001). CSF-HVA was significantly low during the alcohol delirium. It is suggested that a close relationship may exist between autonomic nervous disturbances and increase in central noradrenergic activity, as well as between the alcohol delirium and decrease in central dopaminergic activity.

Changes in cerebrospinal fluid cyclic nucleotides in alcohol-dependent patients suffering from delirium tremens.

In eight patients with a history of alcoholism (on average 9 years), cyclic 3',5'-monophosphate (AMP) and cyclic 3',5'-monophosphate (GMP) were determined in CSF in the acute untreated phase of delirium tremens and at 2 weeks later when clinical symptoms had vanished. Before the second lumbar puncture a drug-free period of 1 week had existed. The results were compared with an age- and sex-matched neurological control group. CSF cyclic AMP concentrations were markedly reduced by 62% (p less than 0.005) in the acute state of delirium tremens and remained at the same level 2 weeks later; cyclic GMP concentrations were increased by 37% (p = 0.05) and showed a small further increase (p less than 0.05) at the second lumbar puncture. A negative correlation existed between age and cyclic AMP content of CSF (r = -0.756; p less than 0.05) in the patients group. The data indicate that the earlier observed increase in norepinephrine turnover in the acute state of delirium tremens (Athen et al., 1977) seems not to induce an increase of cyclic AMP content in CSF.

CSF levels of norepinephrine during alcohol withdrawal.

Cerebrospinal fluid norepinephrine (NE) levels were determined by radioenzymatic assay in 21 patients with a variety of neurological diseases and 49 patients in acute alcohol withdrawal. A second determination was made in 19 patients who had recovered from the alcohol withdrawal syndrome. Cerebrospinal fluid NE concentration was higher in the patients during alcohol withdrawal (192.3 plus or minus 22.3 pg/mL) and decreased during recovery to 137.8 plus or minus 15.9 pg/mL. The CSF NE level was higher in both groups than in patients with other neurological disorders. This may help explain the adrenergic signs observed during alcohol withdrawal.

Cerebrospinal fluid amine metabolites in delirium tremens.

Cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5HIAA), homovanillic acid (HVA) and tryptophan (TRY) were measured in 14 male alcohol-dependent patients with delirium tremens. Lumbar punctures were performed immediately after admission following a standardized psychiatric examination and symptom rating in a drug-free state. Results were compared with a control group consisting of 32 neurological patients with only peripheral disorders, excluding spinal processes and abnormal routine CSF findings. All three substances were significantly increased in delirium tremens; 5HIAA showed the most marked and TRY the least pronounced increase. The statistical correction for age, height and body weight did not decrease but somewhat increased the differences. Duration of alcohol abuse did not account for the observed metabolic changes; severity of delirium tremens, however, correlated significantly with the 5HIAA and to a lesser degree with the HVA level. The further analysis revealed a differential relationship of the amine metabolite concentrations to some prominent symptoms: agitation was significantly dependent only on the HVA level while disorientation and hallucination seemed to be determined mostly by the serotonin metabolite 5HIAA in the CSF. TRY concentration proved to be unrelated to either global severity or any of these symptoms.

Delirium tremens: some clinico-chemical features. A study of alanine-aminotransferase, alcaline phosphatase, prothrombine and enolase.

The relationship between variables reflecting liver disease (serum-alanine-aminotransferase (SGPT), serum alcaline phosphatase and plasma prothrombine) and the clinical signs and symptoms during delirium tremens (DT; grade 3) and related clinical states (grade 2) was studied. Furthermore, it was investigated whether the two isoenzymes of enolase which predominante in brain tissue were present in plasma or cerebrospinal fluid (CSF) in DT patients. A correlation between SGPT and clinical state was not observed, which indicates that a causal relationship does not exist between acute liver cell damage and clinical state during DT of grade 3 or 2. In grade 2 patients, but not in grade 3 patients, both SGPT and serum alcaline phosphatase decreased between admission and recovery. This difference between the groups may be due to a higher alcohol consumption and a shorter interval between last drink and admission in grade 3. The difference in recent drinking history may also account for the finding of a higher plasma prothrombine index in grade 3 compared with grade 2, because chronic ethanol intoxication may be accompanied by enhanced hepatic protein synthesis. "Brain-enolase" was not present in detectable amounts in blood or CSF during DT thus suggesting that brain cell damage resulting in leakage of this enzyme from the cells did not prevail during DT.

Blood-brain barrier selectivity and synaptic turnover during delirium tremens and related clinical states. A study of brain and blood proteins in the cerebrospinal fluid.

The synaptic membrane protein D2 was measured in the cerebrospinal fluid (CSF) from patients with delirium tremens and related clinical states immediately after admission to the hospital before treatment was initiated and again after recovery. during this period of on average 5 days duration the concentration of D2 increased to double normal value possible indicating increased breakdown of old synapses during the process of readaptation to the alcohol free state. IgG, albumin and alpha 2-macroglobulin were measured in plasma and in CSF and the results indicated a decreased selectivity of blood-CSF-barrier permeability to proteins in the clinically recovered patients; this was probably due to increased micropinocytotic activity also occurring during readaptation to the alcohol free state.

Magnesium concentrations in blood and cerebrospinal fluid during delirium tremens.

Magnesium in plasma, erythrocytes, and cerebrospinal fluid (CSF) was measured immediately after hospital admission in 9 patients with delirium tremens (DT) and 11 patients with impending DT. Blood samples were taken daily during the acute state; a second lumbar puncture was performed when the patient's condition had improved. Plasma magnesium was low in patients with DT during the first days of the acute state and then spontaneously normalized. Normal plasma magnesium was consistently seen among patients with impending DT. Magnesium in erythrocytes and CSF was normal in both diagnostic categories. Patients with a high blood-alcohol concentration (BAC) at admission had a decreasing plasma magnesium, patients with a low BAC had a moderately increasing plasma magnesium, and patients with a BAC at nil had a more marked increase in plasma toms or with their duration. This finding, combined with the normal CSF magnesium and the lack of correlation between plasma and CSF magnesium, indicates that disturbances in magnesium metabolism do not play a role in the etiology or pathogenesis of DT; but it may be that disturbances in magnesium metabolism contribute to the development of alcoholic encephalopathy.

Pathophysiology of delirious states.

MHPG concentration in CSF, urinary excretion of NA and A as well as activity of serum DBH were significantly elevated during alcohol delirium as compared to the recovery period. Urinary DA and HVA in CSF did not show any constant change. One single dosage of clozapine (100 mg orally) induces higher urinary NA and A excretion. There is a time course of clozapine action. MHPG in rat brain a single dosage (50 mg/kg) is elevated; after repeated administration (11 days) a decrease is observed. After 10 days of treatment with clozapine (300 mg/day) a decrease of MHPG in CSF can be seen. It is hypothesized that there is a relationship between delirious states and increases central NA turnover.

Cerebrospinal fluid acid-base and lactate changes after seizures in unanesthetized man II. Alcohol withdrawal seizures.

Acid-base changes in arterial blood and lumbar cerebrospinal fluid were correlated with simultaneously determined lactate levels in patients admitted after alcohol withdrawal seizures. Arterial and cerebrospinal fluid lactate was elevated in association with a marked respiratory alkalosis in 13 patients studied 5 to 12 hours after the seizure. Similar elevations of arterial and cerebrospinal fluid lactate were found in five patients during delirium tremens without antecedent withdrawal seizure. The cerebrospinal fluid lactate determined on admission appeared to correlate best with the length and severity of the alcohol withdrawal syndrome that developed in patients after a withdrawal seizure.