Nystagmus in a child with nephrotic syndrome.

We report a child with steroid-dependent nephrotic syndrome presenting with excessive irritability, double vision and inability to walk for 5 days. On examination, the child was irritable with Glasgow coma sccale (GCS of 12/15, had bilateral convergent squint (R>L), vertical nystagmus, ataxia without any focal neurological deficits and normal fundus. MRI brain with venogram showed bilateral symmetric FLAIR hyperintensity in the medial thalamus and periaqueductal grey matter showing diffuse restriction with normal venogram. A possibility of Wernicke encephalopathy (WE) was considered and the child was started on thiamine supplementation, following which he had significant improvement in his symptoms. His irritability reduced with significant improvement in the range of eye movements and vertical nystagmus. At 3-month follow-up, the child is asymptomatic with normal gait. Although WE is uncommon in children with nephrotic syndrome, the possibility has to be kept in mind when a child presents with atypical neurological symptoms.

Wernicke encephalopathy: limitations in a laboratory and radiological diagnosis.

Wernicke encephalopathy is an emergent neurological disorder caused by vitamin B1 (thiamine) deficiency. Here, we present a case of Wernicke encephalopathy in a male patient in his 70s with normal serum thiamine levels and MRI findings on admission. He had a history of heavy alcohol consumption and a gradual decrease in food intake. On arrival at the hospital, his consciousness was impaired which persisted even after glucose replacement. Moreover, horizontal nystagmus and cerebellar ataxia were observed. Head CT scan and MRI revealed no abnormal findings. Further, his serum thiamine level was within the normal range. The patient was clinically diagnosed with Wernicke encephalopathy, and high-dose thiamine therapy was started. Then, his symptoms improved immediately. Thus, in case of clinical suspicion, treatment for Wernicke encephalopathy must be initiated promptly even in patients with normal serum thiamine levels.

When time is brain: a systematic review about Wernicke encephalopathy as a dramatic consequence of thiamin deficiency in hyperemesis gravidarum.

Nausea and vomiting affect up to 80% of all pregnancies, sometimes so severely that the condition of hyperemesis gravidarum (HG) is established. HG may in addition be a predisposing factor for Wernicke encephalopathy (WE), a severe and life-threatening condition due to vitamin B1 (thiamin) deficiency. If untreated, WE may progress to Korsakoff's syndrome, an irreversible cognitive disorder. We reported a case that recently occurred at our clinic and performed a systematic review of the literature to investigate the clinical presentation, maternal and perinatal outcomes and treatment of WE in women with HG. METHODS: We performed a systematic review of case series and case reports searching the Medline database on Pubmed from inception until December 2021. We used as search terms (Wernicke encephalopathy) OR (Wernicke-Korsakoff syndrome) AND (hyperemesis gravidarum) AND (pregnancy) AND (thiamin deficiency). Articles were considered eligible for inclusion in our review if they described at least one case of WE due to thiamin deficiency in relation to HG. An overall of 82 cases of WE due to HG in pregnancy from 66 manuscripts, including our own, were selected. RESULTS: The maternal mean age was 26.38 ± 5.23 years, while mean gestational week at hospitalization was 14.57 ± 4.12 after a mean of 6.6 ± 3.14 weeks of vomiting duration. WE manifestation occurred at a mean gestational age of 16.54 ± 3.06 weeks. Regarding clinical presentation, ocular signs and symptoms were reported by 77/82 (93.9%) women, 61/82 (74.4%) presented with ataxia and 63/82 (76.8%) with confusion. Dysarthria affected 15/82 women (18,3%), while muscular weakness was present in 36/82 (43.9%) and impaired reflexes in 42/82 (51.2%). Memory impairment involved 25/82 (30.5%) of the study population. Almost all cases reported a thiamin administration treatment, however data regarding the clinical course of the neurological condition and the perinatal outcomes were often missing and showed a great heterogeneity when reported. CONCLUSION: WE is a challenging diagnosis, as its clinical presentation is nonspecific. A high clinical suspicion and the awareness of its possible predisposing conditions such as HG may help clinicians to get a prompt diagnosis and starting treatment, which are vital to prevent possible life-impairing neurological sequelae.

The importance of thiamine (vitamin B1) in humans.

Thiamine (thiamin, B1) is a vitamin necessary for proper cell function. It exists in a free form as a thiamine, or as a mono-, di- or triphosphate. Thiamine plays a special role in the body as a coenzyme necessary for the metabolism of carbohydrates, fats and proteins. In addition, it participates in the cellular respiration and oxidation of fatty acids: in malnourished people, high doses of glucose result in acute thiamine deficiency. It also participates in energy production in the mitochondria and protein synthesis. In addition, it is also needed to ensure the proper functioning of the central and peripheral nervous system, where it is involved in neurotransmitter synthesis. Its deficiency leads to mitochondrial dysfunction, lactate and pyruvate accumulation, and consequently to focal thalamic degeneration, manifested as Wernicke's encephalopathy or Wernicke-Korsakoff syndrome. It can also lead to severe or even fatal neurologic and cardiovascular complications, including heart failure, neuropathy leading to ataxia and paralysis, confusion, or delirium. The most common risk factor for thiamine deficiency is alcohol abuse. This paper presents current knowledge of the biological functions of thiamine, its antioxidant properties, and the effects of its deficiency in the body.

Can thiamine substitution restore cognitive function in alcohol use disorder?

AIMS: While clinical consequences of thiamine deficiency in alcohol use disorder (AUD) are severe, evidence-based recommendations on dosage, type of administration and duration of thiamine substitution (TS), and its' target levels remain sparse. This study aimed to compare the effect of two best practice TS regimens on thiamine blood levels (i.e. thiamine pyrophosphate, TPP) and cognitive function. METHODS: In 50 patients undergoing in-patient alcohol-withdrawal treatment, TPP levels were determined at baseline and end of weeks 1, 2 and 8 following administration of oral TS (3 × 100 mg/day for 7 days followed by 1 × 100 mg/day thereafter) either with or without preceding intravenous TS (3 × 100 mg/day for 5 days). An extensive psychiatric assessment was conducted at baseline, including an evaluation of AUD severity and depressive symptoms. Additionally, cognitive function and depressive symptoms were repeatedly evaluated. RESULTS: Relevant increases (mean increase by 100.2 nmol/l [CI 76.5-123.8], P < 0.001) in peripheral blood TPP levels were observed in all patients at the end of weeks 1 and 2. Furthermore, no relevant difference between the intravenous and the oral group was found (average difference between increases: 2.3 nmol/l, P = 0.912). Importantly, an association between the 'extent of the response' to TS and the performance in a memory task was revealed in secondary analyses. CONCLUSION: TS was associated with improving cognitive function in patients with AUD, independently of the substitution regime. Thus, in clinical practice, oral TS might be a sufficient but obligatory medication to prevent cognitive decline in AUD in the absence of Wernicke-Korsakoff Syndrome.

Fetal demise and Wernicke-Korsakoff syndrome in a patient with hyperemesis gravidarum: a case report.

BACKGROUND: Wernicke-Korsakoff syndrome is a neuropsychiatric disorder caused by thiamine deficiency composed of two related disorders accounting for an acute presentation and chronic progression. Hyperemesis gravidarum presents a significant risk factor for Wernicke-Korsakoff syndrome as symptoms may rapidly progress in the setting of pregnancy. We present the first-reported case of hyperemesis-gravidarum-associated Wernicke encephalopathy in a patient in the first half of pregnancy in which a missed diagnosis led to septic shock, fetal demise, and eventual profound Korsakoff syndrome. CASE PRESENTATION: We present the case of a 33-year-old primigravid African American woman at 15 weeks gestational age who initially presented at a community emergency department with nausea and vomiting that ultimately progressed to severe hyperemesis-gravidarum-associated Wernicke-Korsakoff syndrome, fetal demise, and septic shock. The patient received a total of 6 weeks of high-dose parenteral thiamine. Magnetic resonance imaging of the head and formal neuropsychological assessment following treatment plateau confirmed the diagnosis of Wernicke-Korsakoff syndrome. CONCLUSIONS: The multisystem complications seen in severe thiamine deficiency can delay timely administration of high-dose thiamine, particularly in pregnancy, in which the classic triad of Wernicke-Korsakoff syndrome may not raise clinical suspicion due to rapid progression of neurological sequelae in this population. We advise a low threshold for parenteral thiamine repletion in pregnant women with persistent vomiting as hyperemesis gravidarum-induced severe thiamine deficiency can result in Wernicke-Korsakoff syndrome, sepsis, and fetal demise.

"Ten dollars today or 50 dollars after one month?" Temporal discounting in Korsakoff syndrome.

OBJECTIVE: Little research has investigated decision making in patients with Korsakoff syndrome (KS). Specifically, to our knowledge, there is a lack of research investigating whether patients with KS may tend to prefer immediate over future rewards (i.e., temporal discounting). Further, we investigated the relationship between temporal discounting and inhibition. METHODS: We, for the first time, invited patients with KS and control participants to perform a temporal discounting task, in which they answered questions probing preferences between an immediate, but smaller amount of money, and a delayed, but larger amount of money (e.g., "would you prefer 10 dollars today or 50 dollars after one month?"). Furthermore, inhibition was measured using the Stroop Colour Word Test. RESULTS: Analysis demonstrated higher temporal discounting in patients with KS than in control participants. Temporal discounting in both populations was significantly correlated with inhibition. CONCLUSIONS: Patients with KS may have difficulties to suppress the temptation of smaller, but immediate, rewards.

Wernicke encephalopathy and beriberi disease presenting as STEMI-equivalent.

Thiamine deficiency is commonly associated with malnutrition, alcoholism and bariatric surgery. Thiamine deficiency can manifest in different ways, especially in developing countries: as peripheric neuropathy, as Wernicke encephalopathy or as beriberi disease. The authors present the case of a 72-year-old male, with a hiatal hernia that led to thiamine deficiency due to malnutrition. The initial clinical manifestation was an ST-elevation myocardial infarct equivalent, an ECG with a shark-fin pattern that evolved to a Wellens type B pattern. The patient evolved with severe altered mental status. A Wernicke encephalopathy diagnosis was confirmed by MRI; the patient was medicated with high-dose thiamine, with quick recovery, both neurologic and cardiac. The clinical history and response to treatment confirm the diagnosis of Wernicke encephalopathy and beriberi disease.

Protocatechuic Acid Prevents Some of the Memory-Related Behavioural and Neurotransmitter Changes in a Pyrithiamine-Induced Thiamine Deficiency Model of Wernicke-Korsakoff Syndrome in Rats.

The purpose of this research was to investigate the effects of protocatechuic acid (PCA) at doses of 50 and 100 mg/kg on the development of unfavourable changes in cognitive processes in a pyrithiamine-induced thiamine deficiency (PTD) model of the Wernicke-Korsakoff syndrome (WKS) in rats. The effects of PCA were assessed at the behavioural and biochemical levels. Behavioural analysis was conducted using the Foot Fault test (FF), Bar test, Open Field test, Novel Object Recognition test (NOR), Hole-Board test and Morris Water Maze test (MWM). Biochemical analysis consisting of determination of concentration and turnover of neurotransmitters in selected structures of the rat CNS was carried out using high-performance liquid chromatography. PTD caused catalepsy (Bar test) and significantly impaired motor functions, leading to increased ladder crossing time and multiplied errors due to foot misplacement (FF). Rats with experimentally induced WKS showed impaired consolidation and recall of spatial reference memory in the MWM test, while episodic memory related to object recognition in the NOR was unimpaired. Compared to the control group, rats with WKS showed reduced serotonin levels in the prefrontal cortex and changes in dopamine and/or norepinephrine metabolites in the prefrontal cortex, medulla oblongata and spinal cord. PTD was also found to affect alanine, serine, glutamate, and threonine levels in certain areas of the rat brain. PCA alleviated PTD-induced cataleptic symptoms in rats, also improving their performance in the Foot Fault test. In the MWM, PCA at 50 and 100 mg/kg b.w. improved memory consolidation and the ability to retrieve acquired information in rats, thereby preventing unfavourable changes caused by PTD. PCA at both tested doses was also shown to have a beneficial effect on normalising PTD-disrupted alanine and glutamate concentrations in the medulla oblongata. These findings demonstrate that certain cognitive deficits in spatial memory and abnormalities in neurotransmitter levels persist in rats that have experienced an acute episode of PTD, despite restoration of thiamine supply and long-term recovery. PCA supplementation largely had a preventive effect on the development of these deficits, to some extent also normalising neurotransmitter concentrations in the brain.

Wernicke-Korsakoff Syndrome associated with hyperemesis gravidarum and fetal death: Case report and literature review / Síndrome de Wernicke-Korsakoff associado a hiperêmese gravídica e morte fetal: Relato de caso e revisão de literatura

We describe a clinical case of a pregnant patient with hyperemesis gravidarum who progressed to abortion, Wernicke's encephalopathy, and Korsakoff's psychosis, all related to thiamine deficiency. The patient presented symptoms of disorientation, nonspecific limb movements, and fever, initially treated with metronidazole and ceftriaxone for suspected infected abortion. Subsequently, the patient was diagnosed with retained and infected abortion, and thiamine replacement therapy was initiated with an intravenous loading dose of 900 mg/day. During hospitalization, the patient presented with tetraparesis, nystagmus, decreased level of consciousness, anterograde and retrograde amnesia, confabulation, and aphasia. Magnetic resonance imaging showed lesions in the pons, typical of Wernicke's encephalopathy. The patient was empirically treated with acyclovir and ampicillin and showed clinical improvement. The text also provides a brief narrative review of the literature on the topic.

Descrevemos um caso clínico de uma paciente grávida com hiperêmese gravídica que evoluiu para aborto, Encefalopatia de Wernicke e Psicose de Korsakoff, ambas relacionadas à deficiência de tiamina. A paciente apresentou sintomas de desorientação, movimentos inespecíficos dos membros e febre, sendo, inicialmente, tratada com metronidazol e ceftriaxona por suspeita de aborto infectado. Posteriormente, a paciente foi diagnosticada com aborto retido e infectado e iniciou-se a reposição de tiamina com dose endovenosa de ataque de 900 mg/dia. Durante o internamento, a paciente apresentou tetraparesia, nistagmo, rebaixamento do nível de consciência, amnésia anterógrada e retrógrada, confabulação e afasia. A ressonância magnética mostrou lesões na ponte, típicas da Encefalopatia de Wernicke. A paciente foi tratada com aciclovir e ampicilina empiricamente e apresentou melhoras no quadro clínico. O texto também faz uma breve revisão narrativa da literatura sobre o tema.

Korsakoff syndrome and altered pain perception: a search of underlying neural mechanisms.

OBJECTIVES: Patients with Korsakoff syndrome (KS) may have a diminished pain perception. Information on KS and pain is scarce and limited to case descriptions. The present study is the first to investigate the underlying neural mechanisms of altered pain perception in patients with KS more systematically. METHODS: We conducted a literature search on neural correlates of pain perception in other neurocognitive disorders in which extensive research was done. RESULTS: The brain areas that are affected in KS showed considerable overlap with the neural correlates of pain perception in other neurocognitive disorders. We discussed which different aspects of disturbed pain perception could play a role within KS, based on distinct neural damage and brain areas involved in pain perception. CONCLUSIONS: Combining current knowledge, we hypothesize that diminished pain perception in KS may be related to lesioned neural connections between cerebral cortical networks and relays of mainly the thalamus, the periaqueductal gray, and possibly lower brain stem regions projecting to the cerebellum. Based on these neural correlates of altered pain perception, we assume that increased pain thresholds, inhibition of pain signals, and disturbed input to cerebral and cerebellar cortical areas involved in pain processing, all are candidate mechanisms in cases of diminished pain perception in KS. We recommend that clinicians need to be alert for somatic morbidity in patients with KS. Due to altered neural processing of nociceptive input the clinical symptoms of somatic morbidity may present differently (i.e. limited pain responses) and therefore are at risk of being missed.

Wernicke-Korsakoff Syndrome in a Young Adult on Dialysis Who Showed Bilateral Ganglia Lesions.

A 30-year-old man admitted with renal dysfunction (serum creatinine, 8.19 mg/dL) was diagnosed with immunoglobulin A nephritis through a renal biopsy. He was treated with intravenous methylprednisolone pulse therapy and urgent hemodialysis, and eventually, he underwent maintenance hemodialysis. On day 108, he developed amnesia. Magnetic resonance imaging revealed bilateral basal ganglia lesions. Wernicke encephalopathy (WE) was diagnosed based on decreased serum thiamine concentration (12.8 µg/dL; reference range, 24-66 µg/dL). Thiamine replacement therapy was initiated, but the Wernicke-Korsakoff syndrome persisted. Careful monitoring of thiamine is required in patients undergoing dialysis. In addition, patients with WE may exhibit bilateral basal ganglia lesions.

Structural brain substrates of the deficits observed on the BEARNI test in alcohol use disorder and Korsakoff's syndrome.

Chronic and excessive alcohol consumption can result in alcohol use disorder (AUD) without neurological complications and in Korsakoff's syndrome (KS) when combined with thiamine deficiency. These two clinical forms are accompanied by widespread structural brain damage in both the fronto-cerebellar (FCC) and Papez circuits (PC) as well as in the parietal cortex, resulting in cognitive and motor deficits. BEARNI is a screening tool especially designed to detect neuropsychological impairments in AUD. However, the sensitivity of this tool to the structural brain damage of AUD and KS patients remains unknown. Eighteen KS patients, 47 AUD patients and 27 healthy controls (HC) underwent the BEARNI test and a 3 T-MRI examination. Multiple regression analyses conducted between GM density and performance on each BEARNI subtest revealed correlations with regions included in the FCC, PC, thalamus and posterior cortex (precuneus and calcarine regions). All these brain regions were altered in KS compared to HC, in agreement with the cognitive deficits observed in the corresponding BEARNI subtests. The comparison between KS and AUD regarding the GM density in the several nodes of the FCC and calcarine regions revealed that they were atrophied to the same extent, suggesting that BEARNI is sensitive to the severity of alcohol-related GM abnormalities. Within the PC, the density of the cingulate cortex and thalamus, which correlated with the memory and fluency subscores, was smaller in KS than in AUD, suggesting that BEARNI is sensitive to specific brain abnormalities occurring in KS.

The era of our lives: The memory of Korsakoff patients for the first Covid-19 pandemic lockdown in the Netherlands.

Memories for worldwide and emotional events (such as 9/11) are more vividly relived and recalled than memories for everyday events. Previous studies have shown that flashbulb memories of a single event enhanced the memory strength in severe amnesia. It is currently unknown whether macro-events that stretch out over longer periods of time (weeks, months) strengthen memory even further. Our aim was therefore to investigate to what extent patients with severe amnesia, due to Korsakoff's syndrome (KS), were able to relive the first Covid-19 lockdown in the Netherlands, and whether experienced emotions enhanced reliving of the participants. We included 22 KS patients and 24 age-, education-, and gender-matched healthy controls. Covid-19 related memories were assessed by measures of autobiographical memory specificity, phenomenological reliving, emotional intensity and semantic-and episodic knowledge about the first lockdown in March 2020 - May 2020 in the Netherlands. Although amnesia patients remembered significantly fewer autobiographical details regarding the Covid-19 lockdown than healthy controls, one fourth of the KS patients recalled specific events. Amnesia patients reported levels of emotional intensity equivalent to those in the control group. Stronger autobiographical reliving was associated with higher emotional intensity. Both amnesia patients and healthy controls had higher recall of episodic than semantic lockdown related information. In conclusion, results demonstrate that information for macro-events can still be memorized and relived, most specifically when emotional valence is high, even by highly amnestic patients.

"Cinderella was attacked by the big bad wolf, but the police saved her": intrusions and confabulations on story recall in Korsakoff's syndrome and alcohol-related cognitive impairments.

BACKGROUND: The relation between confabulations and intrusions in patients with Korsakoff's syndrome (KS) and patients with alcohol-related cognitive impairments (ARCI) remains under debate. This study examines (1) differences in the production of confabulations and intrusions between patients with KS and ARCI, (2) whether an altered fairy tale induces more intrusions, and (3) whether different types of intrusions were significantly related to confabulations. METHODS: Twenty-three patients with KS and twenty-two patients with ARCI recalled three different types of stories: a novel story, a fairy tale, and a modified fairy tale. Different types of intrusions were correlated with confabulation measures. RESULTS: Patients with KS produced more intrusions in the modified fairy tale condition than patients with ARCI, but these were unrelated to confabulations. Only unrelated intrusions were related to provoked confabulations. CONCLUSIONS: The results of this study indicate that researchers and clinicians must be aware that in general, intrusions on memory tests should not be interpreted as confabulations. Especially spontaneous confabulations appear to be something completely different from intrusions on any type of story recall. When measuring confabulations it is crucial to use validated instruments.

Is there a time window for MRI in Wernicke encephalopathy - a decade of experience from a tertiary hospital.

OBJECTIVE: Wernicke encephalopathy (WE) is a neuropsychiatric syndrome caused by thiamine deficiency. Despite its low sensitivity, brain magnetic resonance imaging (MRI) is the most useful diagnostic technique. Our aim was to investigate whether the timing of the imaging study, and thiamine replacement can influence brain MRI findings in these patients. METHODS: Retrospective observational study of hospitalized patients between January/2008 and December/2020 with a clinical diagnosis of WE. Data from clinical presentation, diagnostic features, therapeutic approach, and outcomes were collected. RESULTS: We identified 41 patients (55 ± 13.3 years) with WE. Brain MRI was performed in 36 patients, and one third had T2/FLAIR hyperintensities suggestive of WE. We found an association between a history of poor diet and periventricular hyperintensities (p = 0.023), especially on the ventral surface of the thalamus and the periaqueductal region. It was found that the odds of having a typical imaging of WE decreased by 5.3% for each additional unit (100 mg) of thiamine administered (p = 0.046) (95% CI [0.89, 0.99]). On the other hand, the number of days from clinical presentation was not found to be a viable predictor (p = 0.254) (95% CI [0.88, 1.03]) Recovery was positively correlated with the total dose of thiamine received until discharge (p = 0.020). CONCLUSIONS: MRI hyperintensities seem to be dependent on the timing of thiamine correction and, particularly, on the thiamine dosage prescribed at admission. Nevertheless, thiamine replacement should not be delayed, as its timely prescription is associated with a better prognosis at discharge.

A case report of Wernicke Korsakoff syndrome in a patient with cholangiocellular carcinoma: An underestimated cause of encephalopathy in cancer patients.

INTRODUCTION: Wernicke's encephalopathy, a disorder caused by thiamin deficiency, is characterized by a classical triad of encephalopathy, ataxia, and ophthalmoplegia. Although alcoholism is the most common predisposing factor, it can also be associated with nonalcoholic states (hyperemesis gravidarum, intestinal obstruction, bariatric surgery, and others). This work presents a case of nonalcoholic Wernicke-Korsakoff syndrome diagnosed in a cholangiocellular carcinoma patient and literature review. CASE REPORT: A 65-year-old male patient with a history of cholangiocellular carcinoma (Klatskin tumor) was treated with radiotherapy at the operation site after Roux-en-Y hepaticojejunostomy. During follow-up, the patient developed gastric outlet obstruction and was diagnosed with peritoneal carcinomatosis after a palliative gastrojejunostomy. As the patient could not tolerate oral nutrition during hospitalization, total parenteral nutrition was administered. After 10 days of admission, the patient showed decreased response to verbal stimuli as well as bilateral horizontal nystagmus, lethargy, and disorientation. Furthermore, the patient displayed confabulation. Clinical and imaging findings were consistent with Wernicke's encephalopathy. Therefore, treatment with intravenous thiamin replacement was initiated. The patient's encephalopathy regressed on the second day after treatment, and he recovered the place-person-time orientation. In the following month, the abnormal imaging findings were almost entirely resolved. CONCLUSION: In order to prevent irreversible brain damage induced by chronic thiamin deficiency, thiamin replacement therapy with parenteral nutrition solutions should be included as a treatment for hospitalized cancer patients unable to receive enteral nutrition for a long time.

"Remember to take your medication": Prospective memory in Korsakoff's syndrome.

BACKGROUND: While event-based prospective memory refers to enacting intending action in response to a specific event or cue ("e.g., When I tell you there are 10 minutes left, please give me this stopwatch"), time-based prospective memory refers to enacting intending action in relation to a specific time ("In 10 minutes time, please ask me for a pencil"). Relative to event-based prospective memory, little is known about time-based prospective memory in Korsakoff's syndrome (KS). METHOD: We used behavioral tasks to investigate event- and time-based prospective memory as well as episodic memory and executive function in patients with KS and control participants. RESULTS: Analysis demonstrated lower event- and time-based prospective memory in patients with KS than in control participants. Interestingly, we found lower time-based than event-based prospective memory in patients with KS. Further, significant correlations were observed between prospective memory and episodic memory and executive function in the patients. CONCLUSIONS: Prospective memory is important for everyday life tasks, and failures of prospective memory can endanger patients' safety. One clinical implication of our findings is the importance of including an evaluation of prospective memory in cognitive evaluation of KS.

SLC19A1 Genetic Variation Leads to Altered Thiamine Diphosphate Transport: Implications for the Risk of Developing Wernicke-Korsakoff's Syndrome.

AIMS: Wernicke-Korsakoff syndrome (WKS) is commonly associated with chronic alcohol misuse, a condition known to have multiple detrimental effects on thiamine metabolism. This study was conducted to identify genetic variants that may contribute to the development of WKS in individuals with alcohol dependence syndrome through alteration of thiamine transport into cells. METHODS: Exome sequencing data from a panel of genes related to alcohol metabolism and thiamine pathways were analysed in a discovery cohort of 29 individuals with WKS to identify possible genetic risk variants associated with its development. Variant frequencies in this discovery cohort were compared with European frequencies in the Genome Aggregation Database browser, and those present at significantly higher frequencies were genotyped in an additional cohort of 87 alcohol-dependent cases with WKS and 197 alcohol-dependent cognitively intact controls. RESULTS: Thirty non-synonymous variants were identified in the discovery cohort and, after filtering, 23 were taken forward and genotyped in the case-control cohort. Of these SLC19A1:rs1051266:G was nominally associated with WKS. SLC19A1 encodes the reduced folate carrier, a major transporter for physiological folate in plasma; rs1051266 is reported to impact folate transport. Thiamine pyrophosphate (TPP) efflux was significantly decreased in HEK293 cells, stably transfected with rs1051266:G, under thiamine deficient conditions when compared with the efflux from cells transfected with rs1051266:A (P = 5.7 × 10-11). CONCLUSION: This study provides evidence for the role of genetic variation in the SLC19A1 gene, which may contribute to the development of WKS in vivo through modulation of TPP transport in cells.