by David R. Spiegel, MD, and Kheng-Jim Lim, MD
Drs. Spiegel and Lim are from the Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, Virginia.

Innov Clin Neurosci. 2011;8(6):15–19

Funding: The authors had no financial support in the production of this manuscript.

Financial disclosure:
The authors have no conflicts of interest relevant to the content of this article.

Key words: Amnestic disorder, frontal lobe, diencephalic

Abstract: Korsakoff’s Syndrome is an amnestic disorder that involves both anterograde and retrograde amnesia. Traditionally associated with long-standing alcohol misuse, thiamine deficiency has been long posited in its pathogenesis, as has dienecephalic lesions. Yet, through this case report, we highlight similarities (and differences) with medial temporal lobe memory disorders and the role of frontal lobe dysfunction in its retrograde amnesia.


Wernicke’s encephalopathy (WE) and Korsakoff syndrome (KS) are generally viewed as two distinct stages of the same illness called Wernicke-Korsakoff syndrome (WK syndrome). WE, the acute form of the disease, consists of a degenerative brain disorder due to a thiamine deficiency (Vitamin B1), which is the same pathological state that can potentially lead to KS. This disease is typically seen in patients with chronic alcohol abuse, malnutrition, and/or chronic vomiting. This case report will focus exclusively on the alcoholic presentation of this illness. Persons with alcoholism have the following major risk factors in developing WK syndrome: 1) alcohol replaces calories the individual would have received from a balanced, thiamine-rich diet, and 2) alcohol inhibits intestinal ATPases, which are responsible for thiamine absorption.[1] The classic triad of WE symptoms consists of confusion, ophthalmopelegia, and ataxia.[2] KS, on the other hand, is a memory disorder that presents with amnesia, confabulation, attention deficits, and disorientations. The key features in KS include the inability to learn new information or form new memories and the inability to retrieve old memories. Without thiamine supplementation, the deficiency that leads to acute and reversible incidents of WE can eventually lead to the more permanent condition of KS.[3] It is possible for a patient in which both WE and KS symptoms are present to have WE symptoms resolved upon thiamine supplementation. Unfortunately, KS symptoms are generally permanent; thus, early identification and treatment of WE are important.

Case Report

Our patient was a 58-year-old African American man presenting to the emergency department after an unwitnessed fall from a second-story balcony. On admission, the patient had a blood alcohol level of 0.2 percent and a Glasgow coma scale score of 9 (range: 3–15) and he required intubation to protect his airway. After stabilization, a computed tomography (CT) of the head was ordered, which showed a small right frontal subdural hematoma (SDH) without mass effect and diffuse brain atrophy; no neurosurgical intervention was needed.

A psychiatry consult was called due to the patient’s “confusion and agitation.” During our initial evaluation, the patient denied mood disturbance, auditory/visual hallucinations, delusions, or lethality; however, he did confabulate many stories including the death of President Obama and his recent arrival from California that morning. The patient also had symptoms of echolalia and palilalia. Cognitively, he was oriented to “person,” but Confusion Assessment Method4 for delirium screening was negative. Nonetheless, short-term memory was significant, as he was unable to remember three items after a few minutes even with cue recognition. His insight and judgment into his illness were poor, and he scored a 21/30 on mini-Mental State Examination.5 On physical examination, the only pertinent findings were horizontal nystagmus and ataxia. On review of his medical history, it was found that the patient had a history of alcohol dependence. Our working diagnosis was KS, and the patient was immediately started on oral thiamine 100mg daily and folate 1mg daily.

A magnetic resonance imaging (MRI) of his head showed a small residual acute subarachnoid hemorrhage in the right temporal occipital region. Also, many subdural hematomas of varying ages were found in the right frontal, the left hemispheric, and the right temporal occipital regions of the brain. There was also a minimal midline shift to the right of approximately 2.2mm. Moderate generalized volume loss in addition to scarring from microvascular disease was also noted. Of note, was the visualization of severely atrophic mammillary bodies. At this point, the patient with started on donepezil 5mg every night at bedtime or QHS.

During his hospital course, he did show some minor improvement, including reduced severity of his horizontal nystagmus, possibly due to his treatment with thiamine. Also after one week of tolerating donepezil without any adverse effects, his dose was increased to 10mg QHS.

Prior to discharge, the patient was administered the Repeatable Battery for the Assessment of Neuropsychological Status (R-BANS).[6] Please see Table 1 for complete evaluation. Overall, the patient evidenced significant difficulties in short-term immediate and short-term delayed memory, with some difficulties in visuospatial construction also noted. More well-learned memories for common objects and semantic fluency remained grossly intact.


The prevalence of WK syndrome is often underdiagnosed as it was found that only 20 percent of patients with WE are diagnosed prior to their death.[3] Diagnosing a patient with WE is essential to prevent damage to the diencephalic regions of the brain, particularly the mammillary bodies,[7-10] and the development of KS, when it is often too late for pharmacological intervention, as there is no optimal treatment for KS.[3] It has been found that 80 percent of patients who do develop KS will leave the hospital with a permanent memory disorder.[11] Even when WE is properly treated with thiamine, not all symptoms fully subside, as some patients will continue to have a mild ataxia indicating permanent neurological damage, even in this early stage of the disease.[12]

One reason for missed diagnosis of WE is that the classic triad of symptoms, eye signs, ataxia, and confusion, are not always present together in patients. Various pathological studies indicate that only 10 percent of patients present with the classical triad of symptoms. Many patients present with only one symptom, the most common being mental change.[13] The incidence of WE in the general population is around 1 to 2 percent, but in individuals with chronic alcoholism the prevalence is around 12 to 14 percent.[3] Patients who are at high risk of thiamine deficiency need appropriate evaluation and treatment.[13]

A literature review for potential treatments for KS provided a limited evidence base, as there was either only small studies that lacked sufficient power or case reports. Several case reports have suggested the potential benefit of an acetylcholinesterase (AChE) inhibitor on improving memory in WK syndrome.[14,15] However, there was also some contradictory literature stating that AChE inhibitors were no better than placebo in memory improvement.[16] A small descriptive study in individuals who developed nonalcoholic KS after a hunger strike demonstrated that the use of donepezil did not result in any improvement of memory.[17] With this limited and contradictory literature regarding pharmacological treatment of KS, larger placebo-controlled studies seem warranted.

The clinical hallmark of KS is temporally graded retrograde amnesia (RA) and anterograde amnesia (AA). It is now understood that damage to either the medial temporal lobe (MTL) or diencephalon impairs declarative memory (conscious knowledge about facts and events) while sparing nondeclarative memory and other cognitive functions. Damage to the MTL (as in dementia of the Alzheimer’s type [DAT]) or diencephalic damage (as in KS) exhibit a similar phenotype of amnesia with markedly impaired declarative memory (anterograde and retrograde). AA may best be explained by the fact that these diencephalic nuclei and tracts are anatomically related to the MTL through the ventroamygdalofugal pathway. The latter connects perirhinal cortex and the amygdala to the medial dorsal nucleus of the thalamus, via the inferior thalamic peduncle. Furthermore, the hippocampal formation originates projections via the fornix to the mammillary nuclei, which, in turn, project to the anterior thalamic nuclei via the mammillothalamic tract. These connections may explain why diencephalic lesions and MTL lesions can cause a similar memory impairment, as discussed previously.[18] Findings from functional magnetic resonance imaging (fMRI) also point to an extended anatomical system supporting new learning that includes the MTL, the diencephalon (i.e., a hippocampal-thalamic axis),9 and ventrolateral prefrontal cortex.[18] Some,[20,21] but not all studies,[19] support a relationship between mammillary body size and AA. Interestingly, our patient’s structural scan brain pathology was remarkable for atrophic mammillary bodies with clinical signs of AA.

Current theories indicate RA in KS may be due to frontal lobe dysfunction, which is thought to play a role in semantic retrieval of memories, maintenance of short-term memory, and suppression of irrelevant associations as well as interference.[22] The memory deficits seen in KS are also similar to other MTL dementias, especially, DAT (Table 2). A study done in 1991 by Kopelman compared the frontal functioning of patients with DAT and KS. One of the experiments measured frontal function by several assessments (FAS verbal fluency, FAS with Miller’s correction, alternating birds and colors assessment, Modified Weigl Test, card-sorting categories, card-sorting perseverations, cognitive estimates, and picture arrangement errors) and found that DAT patients tended to be more severely impaired than KS patients.[22] Additionally, the study looked at the correlation between frontal lobe dysfunction and retrograde/anterograde memory loss. It was noted that the Alzheimer’s group showed a consistent degree of impairment in both retrograde and anterograde memory loss. However, the KS group was found to have an impairment in anterograde memory loss with a relative sparing of retrograde memory.[22] It has been suggested that RA in KS patients may be associated with frontal atrophy on CT scan and poorer performance on “frontal lobe” neuropsychological testing as compared to KS patients with minimal frontal atrophy.[22]

While most accounts of diencephalic amnesia emphasize the functional importance of the hippocampal projections to the mammillary bodies, other forms of mammilary body atrophy and mesencephalic contributions to amnesia have been proposed. For instance, one study[23] demonstrated the importance of the other major input to the mammillary bodies, the projections from the ventral tegmental nucleus of Gudden (VTNg). The VTNg is reciprocally connected with the medial mammillary nucleus and uses gamma aminobutyric acid (GABA), (possibly) to form inhibitory synapses that act as an inhibitory feedback loop that controls the transfer of information from the hippocampus to the anterior thalamic nuclei.[23]

Selective, excitotoxic lesions of the VTNg impaired the performance of rats on spatial memory tasks that are all sensitive to mammillary body and mammillothalamic tract lesions as well as to lesions of the anterior thalamic nuclei and hippocampus. The implication is that the loss of the reciprocal connections between VTNg and the medial mammillary nucleus may account for this learning deficit. Additionally, there appears to be a close relationship between brain regions that result in spatial memory impairments when damaged in animals and those that result in AA/episodic memory impairments in humans. This relationship suggests that the VTNg contributes to episodic memory and new learning in humans as well as spatial memory and consequently indicates that extending the diencephalic-hippocampal models of memory to incorporate the limbic midbrain should be considered.[23]

Goldberg et al[24] described a patient with severe RA and AA due to head trauma who subsequently had his AA improve; however, he continued to have profound RA. A CT completed after the resolution of his AA showed density changes in the region of his ventral tegmental nucleus, components of medial forebrain bundles, and projection from the locus cereleus with no abnormalities of the dorsomedial or anterior thalamic nuclei, mammillary bodies, or the temporal stem. With these structural findings, it was hypothesized that the ascending reticular projections into the hippocampi and mammillary bodies were severed with sparing of the projections to the thalamus and neocortex. The severed ascending reticular projections to the hippocampi and mammillary bodies were thought to be the cause of the RA. The Goldberg et al case[24] demonstrates the importance of selective mesencephalic reticular activation of the hippocampi and mammillary bodies as key elements in long-term memory retrieval.

In summary, while the AA seen in KS is thought to be due to diencephalic lesions,[4] RA may be due to frontal neuronal loss.[22] Interestingly, frontal neuronal loss and diencephalic lesions individually typically cause minimal and no effect on RA, respectively. Yet, the combination of the two lesions seems to cause extensive RA.[22] Additionally, the confabulation often seen in KS patients may be a result of cognitive disinhibition by orbitofrontal lesions, a frontal-subcortical pathway that, when lesioned, has been postulated to result in behavioral disinhibition[25,26]

Limitations about the patient’s cognitive performance and overall level of functioning need to consider certain premorbid factors, including low educational level, poor occupational attainment, and possible head trauma and cerebrovascular insults that can occur in patients with chronic alcohol misuse and associated KS.[27] This case highlights the potential complexities in evaluating and treating patients with KS.

Undoubtedly, more work is necessary to positively identify the neurological pathology of KS. Current literature supports the theory that AA in KS is due to diencephalic pathology (thalamus and mammillary bodies), classically, as a result of neurotoxicity due to chronic alcohol abuse and/or its role in thiamine deficiency. The current theory behind RA and confabulation seem to favor a frontal lobe dysfunction. Ultimately, despite severely impaired memory, studies suggest that patients with WK syndrome are capable of learning simple repetitive actions that involve procedural memory.[11]


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