wernicke–korsakoff syndrome wernicke–korsakoff syndrome wernicke–korsakoff syndrome (wks) is the combined presence of wernicke encephalopathy (we) and korsakoff syndrome. due to the close relationship between these two disorders, people with either are usually diagnosed with wks as a single syndrome. it mainly causes vision changes, ataxia and impaired memory. wernicke–korsakoff syndromeother nameskorsakoff's psychosis, alcoholic encephalopathy, "wet brain"thiaminespecialtypsychiatry, neurology the cause of the disorder is thiamine (vitamin b1) deficiency. this can occur due to wernicke encephalopathy, eating disorders, malnutrition, and alcohol abuse. these disorders may manifest together or separately. wks is usually secondary to prolonged alcohol abuse. wernicke encephalopathy and wks are most commonly seen in people with an alcohol use disorder. failure in diagnosis of we and thus treatment of the disease leads to death in approximately 20% of cases, while 75% are left with permanent brain damage associated with wks. of those affected, 25% require long-term institutionalization in order to receive effective care. signs and symptoms the syndrome is a combined manifestation of two namesake disorders, wernicke encephalopathy and alcoholic korsakoff syndrome. it involves an acute wernicke-encephalopathy phase, followed by the development of a korsakoff syndrome phase. wernicke encephalopathy we is characterized by the presence of a triad of symptoms: ocular disturbances (ophthalmoplegia) changes in mental state (confusion) unsteady stance and gait (ataxia) this triad of symptoms results from a deficiency in vitamin b1 which is an essential coenzyme. the aforementioned changes in mental state occur in approximately 82% of patients' symptoms of which range from confusion, apathy, inability to concentrate, and a decrease in awareness of the immediate situation they are in. if left untreated, we can lead to coma or death. in about 29% of patients, ocular disturbances consist of nystagmus and paralysis of the lateral rectus muscles or other muscles in the eye. a smaller percentage of patients experience a decrease in reaction time of the pupils to light stimuli and swelling of the optic disc which may be accompanied by retinal hemorrhage. finally, the symptoms involving stance and gait occur in about 23% of patients and result from dysfunction in the cerebellum and vestibular system. other symptoms that have been present in cases of we are stupor, low blood pressure (hypotension), elevated heart rate (tachycardia), as well as hypothermia, epileptic seizures and a progressive loss of hearing. about 19% of patients have none of the symptoms in the classic triad at first diagnosis of we; however, usually one or more of the symptoms develops later as the disease progresses. korsakoff syndrome the dsm-v classifies korsakoff syndrome under substance/medication-induced major or mild neurocognitive disorders, specifically alcohol-induced amnestic confabulatory. the diagnostic criteria defined as necessary for diagnosis includes prominent amnesia, forgetting quickly, and difficulty learning. presence of thiamine deficient encephalopathy can occur in conjunction with these symptoms. despite the assertion that alcoholic korsakoff syndrome must be caused by the use of alcohol, there have been several cases where it has developed from other instances of thiamine deficiency resulting from gross malnutrition due to conditions such as stomach cancer, anorexia nervosa, and gastrectomy. cognitive effects several cases have been documented where wernicke–korsakoff syndrome has been seen on a large scale. in 1947, 52 cases of wks were documented in a prisoner of war hospital in singapore where the prisoners' diets included less than 1 mg of thiamine per day. such cases provide an opportunity to gain an understanding of what effects this syndrome has on cognition. in this particular case, cognitive symptoms included insomnia, anxiety, difficulties in concentration, loss of memory for the immediate past, and gradual degeneration of mental state; consisting of confusion, confabulation, and hallucinations. in other cases of wks, cognitive effects such as severely disrupted speech, giddiness, and heavy-headedness have been documented. in addition to this, it has been noted that some patients displayed an inability to focus, and the inability of others to catch patients' attention. in a study conducted in 2003 by brand et al. on the cognitive effects of wks, the researchers used a neuropsychological test battery which included tests of intelligence, speed of information processing, memory, executive function and cognitive estimation. they found that subjects with wks showed impairments in all aspects of this test battery but most noticeably, on the cognitive estimation tasks. this task required subjects to estimate a physical quality such as size, weight, quantity or time (e.g. what is the average length of a shower?) of a particular item. patients with wks performed worse than normal control participants on all of the tasks in this category. the patients found estimations involving time to be the most difficult, whereas quantity was the easiest estimation to make. additionally, the study included a category for classifying "bizarre" answers, which included any answer that was far outside of the normal range of expected responses. wks patients did give answers that could fall into such a category, such as 15 seconds or 1 hour for the estimated length of a shower, or 4 kg or 15 tonnes as the weight of a car. memory deficits as mentioned previously, the amnesic symptoms of wks include both retrograde and anterograde amnesia. the retrograde deficit has been demonstrated through an inability of wks patients to recall or recognize information for recent public events. the anterograde memory loss is demonstrated through deficits in tasks that involve encoding and then recalling lists of words and faces, as well as semantic learning tasks. wks patients have also demonstrated difficulties in perseveration as evidenced by a deficit in performance on the wisconsin card sorting test. the retrograde amnesia that accompanies wks can extend as far back as twenty to thirty years, and there is generally a temporal gradient seen, where earlier memories are recalled better than more recent memories. it has been widely accepted that the critical structures that lead to the memory impairment in wks are the mammillary bodies, and the thalamic regions. despite the aforementioned memory deficits, non-declarative memory functions appear to be intact in wks patients. this has been demonstrated through measures that assess perceptual priming. other studies have shown deficits in recognition memory and stimulus-reward associative functions in patients with wks. the deficit in stimulus-reward functions was demonstrated by oscar-berman and pulaski who presented patients with reinforcements for certain stimuli but not others, and then required the patients to distinguish the rewarded stimuli from the non-rewarded stimuli. wks patients displayed significant deficits in this task. the researchers were also successful in displaying a deficit in recognition memory by having patients make a yes/no decision as to whether a stimulus was familiar (previously seen) or novel (not previously seen). the patients in this study also showed a significant deficit in their ability to perform this task. confabulation people with wks often show confabulation, spontaneous confabulation being seen more frequently than provoked confabulation. spontaneous confabulations refer to incorrect memories that the patient holds to be true, and may act on, arising spontaneously without any provocation. provoked confabulations can occur when a patient is cued to give a response, this may occur in test settings. the spontaneous confabulations viewed in wks are thought to be produced by an impairment in source memory, where they are unable to remember the spatial and contextual information for an event, and thus may use irrelevant or old memory traces to fill in for the information that they cannot access. it has also been suggested that this behaviour may be due to executive dysfunction where they are unable to inhibit incorrect memories or because they are unable to shift their attention away from an incorrect response. causes wks is usually found in people who have used alcohol chronically. wernicke–korsakoff syndrome results from thiamine deficiency. it is generally agreed that wernicke encephalopathy results from severe acute deficiency of thiamine (vitamin b1), whilst korsakoff's psychosis is a chronic neurologic sequela of wernicke encephalopathy. the metabolically active form of thiamine is thiamine pyrophosphate, which plays a major role as a cofactor or coenzyme in glucose metabolism. the enzymes that are dependent on thiamine pyrophosphate are associated with the citric acid cycle (also known as the krebs cycle), and catalyze the oxidation of pyruvate, α-ketoglutarate and branched chain amino acids. thus, anything that encourages glucose metabolism will exacerbate an existing clinical or sub-clinical thiamine deficiency. as stated above, wernicke–korsakoff syndrome in the united states is usually found in malnourished chronic alcoholics, though it is also found in patients who undergo prolonged intravenous (iv) therapy without vitamin b1 supplementation, gastric stapling, intensive care unit (icu) stays, hunger strikes, or people with eating disorders. in some regions, physicians have observed thiamine deficiency brought about by severe malnutrition, particularly in diets consisting mainly of polished rice, which is thiamine-deficient. the resulting nervous system ailment is called beriberi. in individuals with sub-clinical thiamine deficiency, a large dose of glucose (either as sweet food, etc. or glucose infusion) can precipitate the onset of overt encephalopathy. wernicke–korsakoff syndrome in people with chronic alcohol use particularly is associated with atrophy/infarction of specific regions of the brain, especially the mammillary bodies. other regions include the anterior region of the thalamus (accounting for amnesic symptoms), the medial dorsal thalamus, the basal forebrain, the median and dorsal raphe nuclei, and the cerebellum. one as-yet-unreplicated study has associated susceptibility to this syndrome with a hereditary deficiency of transketolase, an enzyme that requires thiamine as a coenzyme. post-gastrectomy the fact that gastrointestinal surgery can lead to the development of wks was demonstrated in a study that was completed on three patients who recently undergone a gastrectomy. these patients had developed wks but were not alcoholics and had never suffered from dietary deprivation. wks developed between 2 and 20 years after the surgery. there were small dietary changes that contributed to the development of wks but overall the lack of absorption of thiamine from the gastrointestinal tract was the cause. therefore, it must be ensured that patients who have undergone gastrectomy have a proper education on dietary habits, and carefully monitor their thiamine intake. additionally, an early diagnosis of wks, should it develop, is very important. alcohol–thiamine interactions strong evidence suggests that ethanol interferes directly with thiamine uptake in the gastrointestinal tract. ethanol also disrupts thiamine storage in the liver and the transformation of thiamine into its active form. the role of alcohol consumption in the development of wks has been experimentally confirmed through studies in which rats were subjected to alcohol exposure and lower levels of thiamine through a low-thiamine diet. in particular, studies have demonstrated that clinical signs of the neurological problems that result from thiamine deficiency develop faster in rats that have received alcohol and were also deficient in thiamine than rats who did not receive alcohol. in another study, it was found that rats that were chronically fed alcohol had significantly lower liver thiamine stores than control rats. this provides an explanation for why alcoholics with liver cirrhosis have a higher incidence of both thiamine deficiency and wks. pathophysiology the vitamin thiamine, also referred to as vitamin b1, is required by three different enzymes to allow for conversion of ingested nutrients into energy. thiamine can not be produced in the body and must be obtained through diet and supplementation. the duodenum is responsible for absorbing thiamine. the liver can store thiamine for 18 days. prolonged and frequent consumption of alcohol causes a decreased ability to absorb thiamine in the duodenum. thiamine deficiency is also related to malnutrition from poor diet, impaired use of thiamine by the cells and impaired storage in the liver. without thiamine the kreb's cycle enzymes pyruvate dehydrogenase complex (pdh) and alpha-ketoglutarate dehydrogenase (alpha-kgdh) are impaired. the impaired functioning of the kreb's cycle results in inadequate production of adenosine triphosphate (atp) or energy for the cells functioning. energy is required by the brain for proper functioning and use of its neurotransmitters. injury to the brain occurs when neurons that require high amounts of energy from thiamine dependent enzymes are not supplied with enough energy and die. brain atrophy associated with wks occurs in the following regions of the brain: the mammillary bodies, the thalamus, the periaqueductal grey, the walls of the 3rd ventricle, the floor of the 4th ventricle, the cerebellum, and the frontal lobe. in addition to the damage seen in these areas there have been reports of damage to cortex, although it was noted that this may be due to