Identifying, Assessing, and Treating Korsakoff Syndrome Patients: Updated Perspectives.

ABSTRACT: Objectives consist of updating published reports on the recognition, assessment, and care of patients with Wernicke-Korsakoff syndrome (WKS). Methods included defining relevant terms, describing core clinical phenomena, conducting meaningful reviews for latter-day WKS publications, and selecting instructive case examples. Findings covered epidemiology, precipitants, neuroimaging studies, alternate learning strategies in WKS, adjunctive treatments, and promising research. In conclusion, patients, their family members, clinicians, and public health experts should benefit from this updated knowledge. Countries with substantial alcohol consumption should consider emulating Holland in designating WKS research centers, founding regional clinical facilities, and funding multidisciplinary expert teams.

Hyperemesis-induced Wernicke-Korsakoff Syndrome due to Hypergastrinemia during Long-term Treatment with Proton Pump Inhibitors.

We herein report a patient with Wernicke-Korsakoff syndrome (WKS) who had neither a history of alcoholism or of history of gastric surgery. A 56-year-old woman was transferred to our hospital because of the loss of consciousness and she was diagnosed to have Wernicke encephalopathy. She showed proton pump inhibitor-induced refractory hypergastrinemia with the subsequent development of hyperemesis and a vitamin B1 deficiency.

Wernicke-Korsakoff Syndrome: A Case Series in Liaison Psychiatry.

Wernicke-Korsakoff syndrome (WKS) is a life-threatening and underdiagnosed neuropsychiatric condition caused by thiamine deficiency that comprises Wernicke encephalopathy and Korsakoff syndrome. Although mainly associated with chronic alcoholism, WKS can arise from other circumstances. This report describes a series of cases of WKS that were clinically evaluated by liaison psychiatrists on a nonpsychiatric inpatient unit. The cases illustrate a deficit in the recognition and adequate treatment of WKS, demonstrating its clinical complexity and the need to improve physicians' knowledge.

Prevalence and Improvement of Caine-Positive Wernicke-Korsakoff Syndrome in Psychiatric Inpatient Admissions.

BACKGROUND: Wernicke-Korsakoff Syndrome (WKS) resulting from thiamine deficiency is classically defined as including encephalopathy, ataxia, and ophthalmoplegia. Only 16% of autopsy-confirmed patients with WKS exhibit all three signs. Caine-positive WKS criteria include two or more of the following: nutritional deficiency, delirium or mild memory impairment, cerebellar dysfunction/ataxia, and oculomotor abnormalities. OBJECTIVE: We describe Caine-positive WKS prevalence among psychiatric inpatients and compare pretreatment-versus-posttreatment neurocognitive improvement to an unaffected group. METHODS: This 6-month quality-improvement evaluation included two-stage screening for Caine-positive WKS, administering high-dose intravenous thiamine (day 1: 1200 mg; days 2-4: 200 mg) with reexamination on day 5. We used descriptive statistics and fitted random effects models to examine rate-of-change differences in pre-/posttreatment Montreal Cognitive Assessment (MoCA), delayed 5-item recall, and gait/coordination scores between treated Caine-positive patients with WKS and untreated Caine-negative patients. RESULTS: Of 262 patients, 32 (12%) had Caine-positive WKS; 17 (53%) used alcohol currently. Treated Caine-positive WKS (n = 26) versus Caine-negative comparison (n = 34) before and after treatment observed a mean change (standard deviation) in the MoCA score of 3.6 (2.5) versus 1.8 (2.5) (P < 0.01); 5-item recall: 1.8 (1.4) versus 0.5 (1.4) (P < 0.001); gait/coordination scores: -0.6 (1.2) versus -0.1 (0.6) (P < 0.001). Oculomotor abnormalities were infrequent (n = 4 in Caine-positive WKS, n = 2 in Caine-negative comparison groups). CONCLUSIONS: Caine-positive WKS prevalence among psychiatric inpatients was 12%; only half used alcohol. Patients treated with high-dose thiamine demonstrated clinically significant neurocognitive improvement.

Seeing life through rose-colored spectacles: Autobiographical memory as experienced in Korsakoff's syndrome.

We investigated whether patients with Korsakjoff's Sybdrome (KS) would demonstrate a discrepancy between (low) autobiographical specificity and (high) sense of reliving. We invited 20 KS patients and 24 controls to retrieve personal memories. After memory retrieval, they were invited to rate subjective characteristics of their recall (e.g., reliving, travel in time, remembering, realness). Besides this rating, we analyzed memories objectively with regard to specificity. Analysis demonstrated poorer sense of reliving and memory specificity in KS patients than in controls. Critically, a discrepancy (i.e., higher level of sense of reliving than of specificity) was observed in KS participants but not in controls. We propose a hypothesis of "genuine consciousness experience" in which the discrepancy between sense of reliving and specificity mirrors how KS patients can benefit from an authentic experience of the past despite compromise in their autobiographical recall.

Phenomenological characteristics of autobiographical memory in Korsakoff's syndrome.

A body of research suggests compromise of autobiographical memory in Korsakoff's syndrome (KS). The present paper extends this literature by investigating the subjective experience of autobiographical recall in the syndrome. Patients with KS and controls were asked to retrieve autobiographical memories. After memory retrieval, participants were asked to rate phenomenological characteristics of their memories (i.e., reliving, back in time, remembering, realness, visual imagery, auditory imagery, language, emotion, rehearsal, importance, spatial recall and temporal recall). Analysis showed lower "Mean Phenomenological Experience" in the Korsakoff patients than in controls. However, the Korsakoff patients attributed relatively high emotional value and importance to their memories. Although our findings suggest compromised phenomenological reliving of autobiographical memory in patients with KS, affective characteristics such as emotion and importance are likely to play a main role in the subjective experience of the past in these patients.

Source monitoring in Korsakoff's syndrome: "Did I touch the toothbrush or did I imagine doing so?"

There is a body of research suggesting compromised ability to distinguish between different external sources of information (i.e., external monitoring) in Korsakoff's syndrome. Here we replicate and extend this literature by assessing the ability of patients with Korsakoff's syndrome to distinguish between different external sources of information (i.e., external monitoring), between internal and external sources of information (i.e., reality monitoring), and between different internal sources of information (i.e., internal monitoring). On the external monitoring assessment, patients with Korsakoff's syndrome and controls watched the experimenter place objects (e.g., a toothbrush) in either a black or white box; afterward, they were asked to remember where the objects had been placed. On the reality monitoring assessment, participants had to either place objects or watch the experimenter place objects in a black box; afterward, they were asked to remember whether the objects had been placed in the box by themselves or by the experimenter. On the internal monitoring assessment, participants had to either place objects or imagine themselves placing objects in a black box; afterward, they were asked to remember whether they had previously placed the objects in the box or imagined doing so. Analyses demonstrated lower external and internal monitoring in patients with Korsakoff's syndrome than in controls, but no significant difference was observed between the two populations on the reality monitoring condition. Our data provide preliminary evidence that the ability to recognize oneself as the author of one's own actions may be relatively preserved in Korsakoff's syndrome.

What does extinction have to do with confabulation?

Behaviourally spontaneous confabulation denotes a distinct syndrome consisting of confabulations that patients act upon, disorientation, and amnesia. It corresponds to the stable form of the original Korsakoff syndrome. While the syndrome may also occur in confusional states and degenerative dementia, this article is about the syndrome as it occurs after acute and focal brain damage. The patients act according to ideas and obligations that can mostly be traced back to real experiences in their past, but which are not currently valid guides of thinking and behaviour. This inability to abandon behavioural guides (anticipations) that are currently not valid corresponds to a failure of behavioural extinction and to the inability to abandon a previously rewarded choice in reversal learning when the expected reward (outcome) fails to occur, that is, following extinction trials. This article describes evidence from human and animal experiments showing that the posterior medial orbitofrontal cortex (OFC), which is typically damaged in these patients, and connected structures of the reward system contain the neural apparatus to signal the non-occurrence of anticipated outcomes, thereby presumably synchronizing thought and behaviour with current reality. Failure of this function, which we call orbitofrontal reality filtering, is associated with behaviourally spontaneous confabulation and disorientation after acute and focal brain damage, but not with other forms of confabulation, and not with reality confusion in degenerative dementia. Potential links with psychosis and decision making will be discussed.

Olmesartan-induced Enteropathy Manifesting as Wernicke-Korsakoff Syndrome.

Cases of sprue-like enteropathy associated with olmesartan have sporadically been encountered since it was first reported in 2012, and their most characteristic manifestation is severe diarrhea. We herein report the first case of sprue-like enteropathy manifesting as Wernicke-Korsakoff syndrome due to vitamin B1 malabsorption with only minimally increased bowel movements. When patients are receiving olmesartan and they complain of nonspecific chronic gastrointestinal symptoms, it is important to consider changing the drugs before any serious malabsorption syndrome develops.

Wernicke-Korsakoff syndrome in patients with cancer: a systematic review.

Wernicke-Korsakoff syndrome in patients with cancer is understudied. Much of what is known-that significant under-recognition and delays in treatment exist-comes from studies of alcohol misuse disorders or non-alcohol-related Wernicke-Korsakoff syndrome in patients. We investigated the frequency and associated features of cancer-related Wernicke-Korsakoff syndrome in the published literature. We included 90 articles reporting on 129 patients. Only 38 (30%) of 128 patients with data available exhibited the entire triad of classic features of Wernicke-Korsakoff syndrome: confusion, ataxia, and ophthalmoplegia or nystagmus. Diagnosis during life was missed altogether in 22 (17%) of 128 patients. The operational diagnostic criteria (at least two of the following: nutritional deficiency, ocular signs, cerebellar signs, and either altered mental status or mild memory impairment), which are considered more reliable than the classical triad, were used in only nine (7%) cases, yet 120 (94%) met the operational criteria for diagnosis at the time of presentation when applied retroactively. Complete recovery was reported in only 47 (36%) cases. Given that oncologists or haematologists accounted for only 17 (19%) first authors among the articles included, it is important that oncologists are aware of the risk factors for cancer-related Wernicke-Korsakoff syndrome, and that they are vigilant about diagnosing and treating the disease especially in the absence of alcohol misuse disorders.

The neurobiology of thalamic amnesia: Contributions of medial thalamus and prefrontal cortex to delayed conditional discrimination.

Although medial thalamus is well established as a site of pathology associated with global amnesia, there is uncertainty about which structures are critical and how they affect memory function. Evidence from human and animal research suggests that damage to the mammillothalamic tract and the anterior, mediodorsal (MD), midline (M), and intralaminar (IL) nuclei contribute to different signs of thalamic amnesia. Here we focus on MD and the adjacent M and IL nuclei, structures identified in animal studies as critical nodes in prefrontal cortex (PFC)-related pathways that are necessary for delayed conditional discrimination. Recordings of PFC neurons in rats performing a dynamic delayed non-matching-to position (DNMTP) task revealed discrete populations encoding information related to planning, execution, and outcome of DNMTP-related actions and delay-related activity signaling previous reinforcement. Parallel studies recording the activity of MD and IL neurons and examining the effects of unilateral thalamic inactivation on the responses of PFC neurons demonstrated a close coupling of central thalamic and PFC neurons responding to diverse aspects of DNMTP and provide evidence that thalamus interacts with PFC neurons to give rise to complex goal-directed behavior exemplified by the DNMTP task.

The role of ventral midline thalamus in cholinergic-based recovery in the amnestic rat.

The thalamus is a critical node for several pathways involved in learning and memory. Damage to the thalamus by trauma, disease or malnourishment can impact the effectiveness of the prefrontal cortex (PFC) and hippocampus (HPC) and lead to a profound amnesia state. Using the pyrithiamine-induced thiamine deficiency (PTD) rat model of human Wernicke-Korsakoff syndrome, we tested the hypothesis that co-infusion of the acetylcholinesterase inhibitor physostigmine across the PFC and HPC would recover spatial alternation performance in PTD rats. When cholinergic tone was increased by dual injections across the PFC-HPC, spontaneous alternation performance in PTD rats was recovered. In addition, we tested a second hypothesis that two ventral midline thalamic nuclei, the rhomboid nucleus and nucleus reuniens (Rh-Re), form a critical node needed for the recovery of function observed when cholinergic tone was increased across the PFC and HPC. By using the GABAA agonist muscimol to temporarily deactivate the Rh-Re the recovery of alternation behavior obtained in the PTD model by cholinergic stimulation across the PFC-HPC was blocked. In control pair-fed (PF) rats, inactivation of the Rh-Re impaired spontaneous alternation. However, when inactivation of the Rh-Re co-occurred with physostigmine infusions across the PFC-HPC, PF rats had normal performance. These results further demonstrate that the Rh-Re is critical in facilitating interactions between the HPC and PFC, but other redundant pathways also exist.

Neural Correlate of Anterograde Amnesia in Wernicke-Korsakoff Syndrome.

The neural correlate of anterograde amnesia in Wernicke-Korsakoff syndrome (WKS) is still debated. While the capacity to learn new information has been associated with integrity of the medial temporal lobe (MTL), previous studies indicated that the WKS is associated with diencephalic lesions, mainly in the mammillary bodies and anterior or dorsomedial thalamic nuclei. The present study tested the hypothesis that amnesia in WKS is associated with a disrupted neural circuit between diencephalic and hippocampal structures. High-density evoked potentials were recorded in four severely amnesic patients with chronic WKS, in five patients with chronic alcoholism without WKS, and in ten age matched controls. Participants performed a continuous recognition task of pictures previously shown to induce a left medial temporal lobe dependent positive potential between 250 and 350 ms. In addition, the integrity of the fornix was assessed using diffusion tensor imaging (DTI). WKS, but not alcoholic patients without WKS, showed absence of the early, left MTL dependent positive potential following immediate picture repetitions. DTI indicated disruption of the fornix, which connects diencephalic and hippocampal structures. The findings support an interpretation of anterograde amnesia in WKS as a consequence of a disconnection between diencephalic and MTL structures with deficient contribution of the MTL to rapid consolidation.

A single-system model predicts recognition memory and repetition priming in amnesia.

We challenge the claim that there are distinct neural systems for explicit and implicit memory by demonstrating that a formal single-system model predicts the pattern of recognition memory (explicit) and repetition priming (implicit) in amnesia. In the current investigation, human participants with amnesia categorized pictures of objects at study and then, at test, identified fragmented versions of studied (old) and nonstudied (new) objects (providing a measure of priming), and made a recognition memory judgment (old vs new) for each object. Numerous results in the amnesic patients were predicted in advance by the single-system model, as follows: (1) deficits in recognition memory and priming were evident relative to a control group; (2) items judged as old were identified at greater levels of fragmentation than items judged new, regardless of whether the items were actually old or new; and (3) the magnitude of the priming effect (the identification advantage for old vs new items) overall was greater than that of items judged new. Model evidence measures also favored the single-system model over two formal multiple-systems models. The findings support the single-system model, which explains the pattern of recognition and priming in amnesia primarily as a reduction in the strength of a single dimension of memory strength, rather than a selective explicit memory system deficit.

Biomarkers of delirium as a clue to diagnosis and pathogenesis of Wernicke-Korsakoff syndrome.

BACKGROUND AND PURPOSE: Wernicke's encephalopathy (WE) and Korsakoff's syndrome are considered to be different stages of the same disorder due to thiamine deficiency, which is called Wernicke-Korsakoff syndrome (WKS). The earliest biochemical change is the decrease of α-ketoglutarate-dehydrogenase activity in astrocytes. According to autopsy-based series, mental status changes are present in 82% of WE cases. The objective of the present review is to identify possible underlying mechanisms relating the occurrence of delirium to WKS. METHODS: Studies involving delirium in WKS, however, are rare. Therefore, first, a search was done for candidate biomarkers of delirium irrespective of the clinical setting. Secondly, the results were focused on identification of these biomarkers in reports on WKS. RESULTS: In various settings, 10 biochemical and/or genetic biomarkers showed strong associations with the occurrence of delirium. For WKS three of these candidate biomarkers were identified, namely brain tissue cell counts of CD68 positive cells as a marker of microglial activation, high cerebrospinal fluid lactate levels, and MHPG, a metabolite of norepinephrine. Based on current literature, markers of microglial activation may present an interesting patho-etiological relationship between thiamine deficiency and delirium in WKS. CONCLUSIONS: In WKS cases, changes in astroglia and microglial proliferation were reported. The possible loss-of-function mechanisms following thiamine deficiency in WKS are proposed to come from microglial activation, resulting in a delirium in the initial phase of WKS.

Wernicke-Korsakoff-syndrome: under-recognized and under-treated.

BACKGROUND: Wernicke-Korsakoff syndrome (WKS) is a well described syndrome of neurological and cognitive problems that comprises both Wernicke's encephalopathy (WE) and Korsakoff syndrome (KS). WE is an acute neuropsychiatric disorder caused by thiamine deficiency. KS is a chronic consequence of thiamine deficiency with prominent impairment in memory formation. METHOD: The authors review the literature on the pathophysiology, presentation, and treatment of WKS, focusing on the acute identification and treatment of WE. RESULTS: Most cases of WE are missed by clinicians, likely because patients do not present with the classic signs associated with the condition. Attaining high serum levels of thiamine during treatment may be important to restore cognitive function as quickly as possible, though the exact dosing and route needed for effective treatment is unknown. Data indicates that the administration of intravenous (IV) thiamine has little risk. CONCLUSION: In order to prevent this potentially devastating disease, physicians should have a high index of suspicion for WKS and dose thiamine accordingly.

Quality of life of patients with Korsakoff's syndrome and patients with dementia: a cross-sectional study.

OBJECTIVES: Korsakoff's syndrome (KS) is a chronic disorder caused by thiamine (vitamin B1) deficiency and alcoholism. The disorder is characterized by severe amnesia and often compared with dementia. The purpose of this study was to compare the quality of life between patients with KS and patients with dementia from the same nursing homes. DESIGN: Cross-sectional study design. SETTING: Three nursing homes in the Netherlands. PARTICIPANTS: Participants were 72 patients diagnosed with KS and 75 patients diagnosed with dementia through extensive neuropsychological evaluation and multidisciplinary diagnostics. MEASUREMENTS: Quality of life (QoL) was scored with the QUALIDEM scale. Multivariate linear regression analysis was used to compare QoL between patients with KS and patients with dementia, applying the covariates "age," "gender," and "nursing home." RESULTS: Of the 147 included patients, 72 (48.9%) were diagnosed with KS. Overall QoL was higher in KS. Patients with KS scored better than patients with dementia on the QUALIDEM subscales "Restless tense behavior," "Social relations," and "Having something to do." A trend toward a better score was found for the subscale "Positive affect"; a trend toward a lower score was found for "Feeling at home." CONCLUSIONS: KS is associated with profound differences in QoL compared with dementia. Patients with KS tend to have more social relationships and more positive emotions than patients with dementia. Furthermore, patients with dementia show more restless behavior than patients with KS; however, patients with KS tend to feel less at home in a nursing home than patients with dementia. Results suggest that both patients with dementia and patients with KS are in need of specialized nursing homes and care programs to accomplish their specific needs.

Implicit memory in Korsakoff's syndrome: a review of procedural learning and priming studies.

Korsakoff's syndrome (KS) is characterized by dense anterograde amnesia resulting from damage to the diencephalon region, typically resulting from chronic alcohol abuse and thiamine deficiency. This review assesses the integrity of the implicit memory system in KS, focusing on studies of procedural learning and priming. KS patients are impaired on several measures of procedural memory, most likely due to impairment in cognitive functions associated with alcohol-related neural damage outside of the diencephalon. The pattern of performance on tasks of implicit priming suggests reliance on a residual, non-flexible memory operating more or less in an automatic fashion. Our review concludes that whether measures of implicit memory reveal intact or impaired performance in individuals with KS depends heavily on specific task parameters and demands, including timing between stimuli, the specific nature of the stimuli used in a task, and the integrity of supportive cognitive functions necessary for performance.

Context memory in Korsakoff's syndrome.

Memory for contextual information and target-context integration are crucial for successful episodic memory formation and are impaired in patients with Korsakoff's syndrome. In this paper we review the evidence for the notion that a context memory deficit makes an important contribution to the amnesia in these patients. First, we focus on anterograde memory for contextual (spatial and temporal) information. Next, the use of contextual cues in memory retrieval is examined and their role in retrograde amnesia and confabulation. Evidence on the role of contextual cues and associations in working memory is discussed in relation to the underlying neurocognitive mechanisms and their dissociation from long-term encoding. Finally, we focus on implicit learning of contextual information in Korsakoff patients. It can be concluded that Korsakoff patients are impaired in the explicit processing of contextual information and in target-context binding, both in long-term (retrograde and anterograde) memory and in working memory. These results extend the context memory deficit hypothesis. In contrast, implicit contextual learning is relatively preserved in these patients. These findings are discussed in relation to evidence of dysfunction of the extended diencephalic-hippocampal memory circuit in Korsakoff's syndrome.