Pellagra and alcoholism: a biochemical perspective.

Historical and clinical aspects of pellagra and its relationship to alcoholism are reviewed from a biochemical perspective. Pellagra is caused by deficiency of niacin (nicotinic acid) and/or its tryptophan (Trp) precursor and is compounded by B vitamin deficiencies. Existence on maize or sorghum diets and loss of or failure to isolate niacin from them led to pellagra incidence in India, South Africa, Southern Europe in the 18th century and the USA following the civil war. Pellagra is also induced by drugs inhibiting the conversion of Trp to niacin and by conditions of gastrointestinal dysfunction. Skin photosensitivity in pellagra may be due to decreased synthesis of the Trp metabolite picolinic acid → zinc deficiency → decreased skin levels of the histidine metabolite urocanic acid and possibly also increased levels of the haem precursor 5-aminolaevulinic acid (5-ALA) and photo-reactive porphyrins. Depression in pellagra may be due to a serotonin deficiency caused by decreased Trp availability to the brain. Anxiety and other neurological disturbances may be caused by 5-ALA and the Trp metabolite kynurenic acid. Pellagra symptoms are resolved by niacin, but aggravated mainly by vitamin B6. Alcohol dependence can induce or aggravate pellagra by inducing malnutrition, gastrointestinal disturbances and B vitamin deficiencies, inhibiting the conversion of Trp to niacin and promoting the accumulation of 5-ALA and porphyrins. Alcoholic pellagra encephalopathy should be managed with niacin, other B vitamins and adequate protein nutrition. Future studies should explore the potential role of 5-ALA and also KA in the skin and neurological disturbances in pellagra.

Protective effects of nimodipine on cerebrovascular function in chronic alcoholic encephalopathy.

In the present study, we used chronic gavage administration of alcohol with gradual increases in alcohol concentration and volume to generate a rat model of chronic alcohol intoxication. We measured the changes in biological, behavioral, pathological and vascular injury-related molecular biological markers, and explored the effects of nimodipine intervention on alcohol intoxication. We found that chronic alcohol consumption induced a variety of behavioral abnormalities, accompanied by severe pathological changes in cerebral arterioles, prefrontal cortex and cerebellar tissue, as well as an upregulation of vascular endothelial growth factor (VEGF), leptin receptor (ob-R) and endothelin-1 (ET-1). Treatment with mimodipine for 15 days significantly improved behavioral abnormalities, alleviated the pathological changes in blood vessels and brain tissues, increased VEGF expression, decreased ob-R expression, reduced plasma ET-1 leakage and protected vascular and neuronal functions.

A rare case of alcoholic pellagra encephalopathy with startle myoclonus and marked response to niacin therapy: time for a new dictum?

We report a case of 56-year-old man, chronic alcoholic, presented to us with progressive weakness in all the four limbs with stiffness and gait disturbance since 1-year associated with cognitive impairment. On examination he had mild confusion, spastic quadriparesis with brisk reflexes, extensor plantars and cerebellar features. During the hospital stay myoclonus was noticed in the patient, which was startle in nature. He did not have dermatitis, ascites or any stigmata of liver failure. MRI of brain revealed bilateral subdural effusion, left focal subarachnoid haemorrhage at perisylvian area and diffuse cortical atrophy. He was treated with supportive measures including thiamine with which his condition worsened. His serum niacin was low. With a possibility of alcoholic pellagra encephalopathy (APE) the patient was treated with niacin. His clinical condition improved drastically over next 1 week and startle myoclonus disappeared, favouring the diagnosis of APE though multiple confounding factors were present.

Anti-retroviral therapy-induced status epilepticus in "pseudo-HIV serodeconversion".

Diligence in the interpretation of results is essential as information gained from the psychiatric patient's history might often be restricted. Nonobservance of established guidelines may lead to a wrong diagnosis, induce a false therapy and result in life-threatening situations. Communication errors between hospitals and doctors and uncritical acceptance of prior diagnoses add substantially to this problem. We present a patient with alcohol-related dementia who received anti-retroviral therapy that promoted a non-convulsive status epilepticus. HIV serodeconversion was considered after our laboratory result yielded a HIV-negative status. Critical review of previous diagnostic investigations revealed several errors in the diagnosis of HIV infection leading to a "pseudo-serodeconversion." Finally, anti-retroviral therapy could be discontinued.

Suppression of neuro-inflammatory signaling cascade by tocotrienol can prevent chronic alcohol-induced cognitive dysfunction in rats.

Chronic alcohol intake is known to induce the selective neuronal damage associated with increase oxidative-nitrosative stress and activation of inflammatory cascade finally resulting in neuronal apoptosis and thus dementia. In the present study, we investigated the comparative effect of both the isoforms of vitamin E, alpha-tocopherol and tocotrienol against chronic alcohol-induced cognitive dysfunction in rats. Male Wistar rats were given ethanol (10g/kg; oral gavage) for 10 weeks, and treated with alpha-tocopherol and tocotrienol for the same duration. The learning and memory behavior was assessed using Morris water maze and elevated plus maze test. The rats were sacrificed at the end of 10th week and cytoplasmic fractions of cerebral cortex and hippocampus were prepared for the quantification of acetylcholinesterase activity, oxidative-nitrosative stress parameters, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). From the 6th week onwards, ethanol-treated rats showed significant increase in transfer latency in both the behavioral paradigms which was coupled with enhanced acetylcholinesterase activity, increased oxidative-nitrosative stress, TNF-alpha and IL-1beta levels in different brain regions of ethanol-treated rats. Co-administration of alpha-tocopherol as well as tocotrienol significantly and dose-dependently prevented these behavioral, biochemical and molecular changes in the brains of ethanol-treated rats. However, the effects were more pronounced with tocotrienol. The current study thus demonstrates the possible involvement of oxidative-nitrosative stress mediated activation of inflammatory cascade in chronic alcohol-induced cognitive dysfunction and also suggests the effectiveness of vitamin E isoforms, of which tocotrienol being more potent, in preventing the cognitive deficits associated with chronic alcohol consumption.

The effect of 12-week open-label memantine treatment on cognitive function improvement in patients with alcohol-related dementia.

There is compelling evidence that alcohol-induced neurotoxicity is related to glutamate excitotoxicity. It was hypothesized that the low-affinity NMDA receptor antagonist memantine would improve the cognitive function of patients with alcoholic dementia. The aim of this study was to test this hypothesis and to evaluate the effect of memantine on the cognitive improvement of patients with alcohol-related dementia (ARD). The study was designed as a 12-wk open-label study investigating the efficacy of 20 mg memantine, a low-affinity NMDA receptor antagonist, as a treatment for cognitive and behavioural problems in 19 patients with probable ARD according to the criteria for ARD proposed by Oslin and colleagues. The CERAD-K (Consortium to Establish a Registry for Alzheimer's Disease - Korean version) and several clinical assessment scales were completed before and after the 12-wk memantine treatment period. Significant improvements in the mean scores from baseline to final assessment were observed in the Global Deterioration Scale (p<0.05), Brief Psychiatric Rating Scale (p<0.01), Geriatric Quality of Life - Dementia scale (p<0.01) and Neuropsychiatric Inventory (p<0.01) at the end of week 12. The CERAD-K subscales of word list recall (p<0.05), word list recognition (p<0.05), time orientation (p<0.01), drawing an interlocking pentagon (p<0.05), and the total MMSE-K (Mini Mental State Examination - Korean version) scores (p<0.01) of the patients all showed significant improvement following the memantine trial. In this open-label study, patients with ARD treated with 20 mg/d memantine for 12 wk showed improvement on global cognition, quality of life and behavioural symptoms. The result of this study suggests the possible usefulness of memantine for the treatment of ARD. As this was an open-label study, the possibility that participants improved cognitively on their own due to protracted abstinence from alcohol cannot be discounted.

Influence of reboxetine on salivary MHPG concentration and cognitive symptoms among patients with alcohol-related Korsakoff's syndrome.

This study is based on the hypothesis of a paraventricular cerebral noradrenaline deficit in alcoholic Korsakoff's syndrome. In a randomized open study the effects of a 4-week treatment with the selective noradrenaline reuptake inhibitor reboxetine on (1) the salivary concentration of the noradrenaline metabolite MHPG and (2) changes in cognitive performance measured by the Mini Mental Status Test were examined. The study group consisted of 105 patients diagnosed with alcohol-related Korsakoff's syndrome (ICD-10: F10.6). Korsakoff's patients showed a reduced concentration of salivary MHPG compared to healthy controls; this reduction did not correlate with the results of the Mini Mental Status Test. An increase in salivary MHPG was found together with an improvement in the Mini Mental Status Test both in the verum group treated with reboxetine and in the control group upon completion of the 4-week study. However, a subgroup with a shorter duration of disease (<1 year) was found to profit significantly from reboxetine treatment, as shown by improvements in cognitive performance.

[Thiamine treatment today]. / Tiaminbehandling i dag.

This article reviews some of the established data on thiamin and the most common symptoms of deficiency. Guidelines for appropriate therapy are offered. Thiamin or vitamin B1 was among the first vitamins to be discovered. Beriberi was the first disease to be associated with thiamin deficiency, and Wernicke's encephalopathy was shown to respond to thiamin treatment a few years later. However, thiamin treatment remains inadequate or delayed. Treatment is efficient in the early stages, but delays often causes permanent damage. It is important that all physicians are aware of what patients are susceptible to develop thiamin deficiency and that they recognize the symptoms as early as possible.

[Clinical and neuropathological aspects of Wernicke-Korsakoff syndrome]. / Aspectos clínicos e neuropatológicos da síndrome de Wernicke-Korsakoff.

Alcohol abuse is one of most serious problems in public health and the Wernicke-Korsakoff syndrome one of the gravest consequences of alcoholism. The pathology is often undiagnosed in its less evident presentations, therefore an accurate diagnostic approach is a critical step in planning treatment. Besides new pharmacological proposals, treatment is based on the restoration of thiamine, although this is insufficient to prevent the psychological decline of a great number of patients. The cognitive impact of the pathology is derived from the interaction of alcoholic neurotoxicity, thiamine deficiency and personal susceptibility. In this article the history, epidemiology, clinical and neuropathological features of the Wernicke-Korsakoff syndrome, as well as some aspects of its treatment and prognosis, are described.

The performance of amnesic subjects on tests of delayed matching-to-sample and delayed matching-to-position.

Forced-choice tests of recognition have become the favoured behavioural method for the assessment of models of amnesia in nonhuman primates, yet the profile of deficits shown by human amnesic subjects remains uncertain. The present study explored the performance of 12 amnesic subjects on two delayed matching-to-sample tasks. Experiment 1, which used retention delays of between 2 and 60 sec, confirmed that amnesia impairs such tasks, even when there is only one item to be remembered. The results also highlighted the need to match levels of performance before the effects of delay can be interpreted. In Experiment 2 care was taken to eliminate ceiling effects and to match the subjects at the shortest delay (3 sec). This was achieved by giving the control subjects harder versions of the same task. The amnesic subjects still showed a faster rate of forgetting for abstract patterns, indicating that this is a genuine feature of amnesia. In contrast, the amnesic subjects' performance on a spatial matching-to-sample task was not differentially affected by delays of up to 40 sec. There was no evidence that the amnesic subjects were disproportionately impaired on this spatial task, nor could the different aetiological groups be distinguished by their patterns of DMS performance.

Fluvoxamine treatment of alcoholic amnestic disorder.

The serotonin uptake inhibitor fluvoxamine was assessed in treatment of alcohol-induced Korsakoff's syndrome (KS) using fixed (4 weeks, 200 mg/day) or individualized (6 weeks, plasma concentration > or = 400 ng/ml) dosing in randomized placebo-controlled double-blind crossover studies. Cognitive functions and concentrations of the major cerebrospinal fluid (CSF) metabolites of serotonin (5-HIAA), norepinephrine (MHPG), and dopamine (HVA) were determined in abstinent, nondepressed KS patients (aged 45-75), at baseline and placebo (3-4 weeks), and after 3-4 (n = 10) or 6 (n = 4) weeks of fluvoxamine administration. Fluvoxamine decreased CSF 5-HIAA compared to placebo (P < 0.003) without consistent changes in HVA or MHPG. Reductions in 5-HIAA correlated with improvements on the Wechsler Memory Scale Memory Quotient (P < 0.05), independent of effects on attention/vigilance or Beck Depression Inventory scores. Reductions in 5-HIAA correlated with plasma fluvoxamine (P < 0.03) only for fluvoxamine concentrations below 450 ng/ml. These findings suggest improvement of memory consolidation and/or retrieval in patients with Korsakoff's syndrome by fluvoxamine via serotonergic mechanisms.

Effects of fluvoxamine treatment on cognitive functioning in the alcoholic Korsakoff syndrome.

Eight patients suffering from the alcoholic Korsakoff syndrome (AKS) were entered in a double-blind cross-over trial of fluvoxamine 200 mg per day for 4 weeks versus matched placebo for 4 weeks. At the end of each phase, patients were assessed using a detailed neuropsychological test battery. Verbal fluency performance was significantly impaired following fluvoxamine treatment. No significant differences emerged on any of the other cognitive test measures when fluvoxamine was compared with placebo. However, two of the patients developed a major depressive episode while receiving fluvoxamine.

Alcohol, thiamin deficiency, and neuropsychological disorders.

In this paper, two of the major themes in contemporary neuropsychological research are reviewed. These are the nature of cognitive impairment observed in alcohol related brain injury, and the cause or causes of alcohol related brain injury. Two experiments are briefly reported which address these issues. The first experiment concerns the nature of abilities which are involved in a test of memory (delayed matching to sample), which is fundamental to current experimental models of human amnesia. The second experiment involves preliminary data from a randomised, double-blind, multi-dose trial of intra-muscular thiamin for the treatment of alcohol related brain injury, in alcohol dependent subjects who do not show any overt signs of Wernicke-Korsakoff syndrome.

Korsakoff's syndrome, cognition and clonidine.

Eighteen patients suffering from Alcoholic Korsakoff's Syndrome participated in a placebo-controlled double-blind cross-over trial of clonidine 0.3 mg b.d. for two weeks versus matched placebo for two weeks. A detailed neuropsychological assessment was carried out at the end of each treatment phase and staff ratings of behaviour were also obtained. Clonidine treatment resulted in no significant improvement over placebo on any of the cognitive measures employed. The results contradict previous smaller studies which had suggested that chronic treatment with clonidine had a memory-enhancing effect in Korsakoff's syndrome.

Pathophysiology of cerebellar dysfunction in the Wernicke-Korsakoff syndrome.

Cerebellar ataxia is a common presenting sign in the Wernicke-Korsakoff syndrome (WKS). Recovery from ataxia following thiamine treatment is rarely complete, suggesting the existence of both a reversible ("biochemical") lesion as well as irreversible, neuropathological damage. Cerebellar pathology in WKS includes severe loss of Purkinje cells in superior cerebellar vermis as well as neuronal loss from the granular layer. In addition, damage to inferior olivary nucleus could result in loss of climbing fibre input to cerebellum in this condition. Experiments using an animal model of WKS, the pyrithiamine-treated rat, reveal selective reversible decreases of alpha-ketoglutarate dehydrogenase (alpha KGDH) in cerebellum. Decreased enzyme activities are associated with decreased cerebellar content of GABA and aspartate. Thiamine reversal of neurological symptoms results in normalization of cerebellar enzyme activities and GABA content suggesting that reduced activities of alpha KGDH constitute "the biochemical lesion" in these animals. Possible mechanisms implicated in neuronal cell death in cerebellum include impaired cellular energy metabolism, focal lactic acidosis and excitotoxic damage resulting from excess glutamate release mediated by N-methyl-D-aspartate (NMDA) receptors. Similar mechanisms could be involved in the reversible and irreversible neurological symptoms of WKS in humans.

Treating organic abulia with bromocriptine and lisuride: four case studies.

Abulia refers to an impairment of will, or the inability to initiate behaviour and action. There are reports of successful treatment of akinetic mutism, the most severe form of abulia, with bromocriptine. Four case studies are presented describing the successful treatment of abulia at a lesser severity than akinetic mutism with bromocriptine. Abulia was caused by brain damage due to alcohol in two cases, Wilson's disease and basal ganglia infarct in one each. Maximum bromocriptine dose varied from 25-70 mg. All improved considerably. Withdrawal or reduction of medication in three produced deterioration. The prescription of a neuroleptic drug had a similar effect in the fourth. One patient with a previous history developed a depressive relapse and so the drug was withdrawn and lisuride introduced. This produced a similar improvement. These cases highlight the value of identifying the syndrome of organic abulia and suggest that dopamine agonists may have a place in its treatment, though controlled studies are needed.