This review is based on material known to the authors or identified through searches of PubMed (up to March 2007) for original articles or previous reviews of the subject, using a combination of the following terms: “Wernicke's encephalopathy”, “thiamine deficiency”, “diagnosis”, “pathophysiology”, “genetics”, and “treatment”. Selection of material for inclusion was based on originality, quality, and relevance to the topic.
ReviewWernicke's encephalopathy: new clinical settings and recent advances in diagnosis and management
Introduction
Wernicke's encephalopathy is an acute, neuropsychiatric syndrome that is common relative to other neurological disorders. It is characterised by nystagmus and ophthalmoplegia, mental-status changes, and unsteadiness of stance and gait—although this triad is seen in only 16% of patients.1, 2 The disorder results from a deficiency in vitamin B1 (thiamine), which in its biologically active form, thiamine pyrophosphate, is an essential coenzyme in several biochemical pathways in the brain.3 Carl Wernicke described this distinctive entity in 1881 as acute superior haemorrhagic polioencephalitis in two alcohol-misusing men and a young woman who developed persistent vomiting due to pyloric stenosis after the ingestion of sulphuric acid.4 The classic triad and fundoscopic changes, consisting of swelling of the optic disks and retinal haemorrhages, were present in these patients.4 All of them died within 2 weeks of onset of neurological manifestations.
Campbell and Russell in the 1940s stressed the nutritional association of the encephalopathy and suggested thiamine deficiency as a causative factor.5 Thiamine requirement is directly related to both total caloric intake and the proportion of calories provided as carbohydrates.6 Thus, high caloric and high carbohydrate diets increase the demand for thiamine. The recommended dose of thiamine for an average, healthy adult is 1·4 mg per day or 0·5 mg of thiamine per 1000 kcal consumed. This dose is higher in children, in critically ill conditions, and during pregnancy and lactation.7 Because thiamine is absorbed in the duodenum by a rate-limited process, in healthy individuals, the calculated maximum amount of thiamine that can be absorbed from a single oral dose is about 4·5 mg.8 At the blood–brain barrier, transport occurs by both passive and active mechanisms,8 which allows a rapid correction of brain thiamine deficiency, mainly by passive diffusion, if a steep concentration gradient between plasma and the brain is established, as happens after parenteral administration of the vitamin.8
Although in recent years there has been an increase in the number of clinical settings in which Wernicke's encephalopathy is encountered, this potentially fatal disease is still greatly underdiagnosed in both adults and children. However, major advances have been made in our understanding of the pathophysiology, genetics, prophylaxis, and management of Wernicke's encephalopathy. In this review, we provide an update on these advances, emphasising the predisposing factors, including clinical settings, in which Wernicke's encephalopathy is encountered and offer some new insights into diagnostic and management procedures.
Section snippets
Epidemiology
In adults, autopsy studies have revealed a higher prevalence of Wernicke's encephalopathy lesions (0·8–2·8%) than is predicted by clinical studies (0·04–0·13%).2, 9, 10 Similar data have been reported in children.10 In particular, in adult patients who misused alcohol2 and those with AIDS,11 Wernicke's encephalopathy confirmed at autopsy had been missed by routine clinical examination in 75–80% of cases. In children, about 58% of cases have been missed at routine clinical examination.10
Genetics
In the late 1970s, a biochemical study showed that, in fibroblasts from patients with Wernicke-Korsakoff syndrome (WKS), transketolase had decreased affinity for thiamine pyrophosphate.25 The abnormality persisted through several generations of culture medium in the presence of excess thiamine and absence of ethanol.25 Thus, the occurrence of this enzyme variant may put individuals at risk for Wernicke's encephalopathy when on a diet marginal or deficient in thiamine. This finding is consistent
Pathophysiology
Thiamine deficiency leads to brain lesions—usually restricted to selective, vulnerable regions, with high thiamine content and turnover—within 2–3 weeks.38 This timescale is related to the time necessary to deplete the body's stores of thiamine, which are only sufficient for up to 18 days.39 After about 3 weeks of thiamine deficiency, the blood levels of thiamine also fall,40 leading to impaired function of enzymes requiring thiamine pyrophosphate as a coenzyme.38, 39 Thiamine is absorbed in
Neuropathology
Macroscopic and microscopic features depend on the stage and the severity of Wernicke's encephalopathy.54 About 50% of patients have symmetrical, greyish discolouration, congestion, and fresh pinpoint haemorrhages, mainly in the periaqueductal grey matter, the mamillary bodies, and medial thalamus.9 Typical histopathological changes affect specific areas of the brain,9 such as the medial dorsal thalamic nucleus bilaterally, in 100% of patients.9 The superior vermis of the cerebellum is involved
Clinical spectrum of thiamine deficiency
In an individual, the symptoms or signs of thiamine deficiency may vary greatly according to the clinical setting and patient's age and genetic susceptibility. Neurological or cardiovascular disturbances are present and may coexist in one patient. The involvement of the cardiovascular system may take two forms: a common, high-output state characterised by heart failure, orthopnea, and pulmonary and peripheral oedema, and a rare, low-output state, characterised by severe hypotension, lactic
Clinical features
Early detection of subclinical thiamine deficiency is a difficult task, as symptoms may be vague and non-specific, such as frequent headaches, fatigue, irritability, abdominal discomfort, and decline in the growth rate of children.39 Definite thiamine deficiency presents with Wernicke's encephalopathy, which has an acute onset and is characterised by mental status changes, ocular abnormalities, and motor problems, such as gait incoordination and ataxia. About 82% of patients have mental status
Predisposing factors and clinical settings
In recent years, there has been an increase in the number of clinical settings in which Wernicke's encephalopathy is observed. Those more commonly encountered in clinical practice are discussed below (panel 2).
Korsakoff's syndrome
Korsakoff's syndrome is defined as a disproportionate impairment in memory, relative to other features of cognitive function, resulting from nutritional (thiamine) deficiency.134 In particular, the syndrome is characterised by a chronic striking loss of working memory with relatively little loss of reference memory.135, 136, 137 Korsakoff's syndrome usually follows or accompanies Wernicke's encephalopathy, with the typical clinical pattern emerging when the acute global confusional state of the
Diagnosis
The high rate of incorrect diagnosis for Wernicke's encephalopathy might be caused by either a relatively non-specific clinical presentation of the disease in some cases or poorly recognised clinical presentation and neurological signs. In particular, the possibility of an incorrect diagnosis is high in alcohol-dependent patients presenting to accident and emergency departments.8 The common signs of Wernicke's encephalopathy are difficult, if not impossible, to differentiate from drunkenness,
Management
Wernicke's encephalopathy is a medical emergency, and in patients in whom the disorder is suspected thiamine should be initiated immediately, either intravenously or intramuscularly, to ensure adequate absorption.75 Because thiamine hydrochloride can be inactivated by heat, its solutions should be fresh. A recent Cochrane review indicates that there is insufficient evidence from randomised controlled trials to guide the clinician as to the optimum dose, frequency, route, or duration of thiamine
Conclusions
Any condition of unbalanced nutrition that lasts for 2–3 weeks can lead to thiamine depletion and Wernicke's encephalopathy with damage in selective diencephalic and brainstem areas. Post-mortem findings indicate that prevalence is higher than appreciated. The disorder may occur in people with chronic alcoholism and in a myriad of clinical settings that include gastrointestinal surgery procedures, gastrointestinal disorders associated with recurrent vomiting or chronic diarrhoea, cancer, and
Search strategy and selection criteria
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