Wernicke–Korsakoff syndrome

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Wernicke-Korsakoff syndrome
Other namesKorsakoff's psychosis, alcoholic encephalopathy,[1] "wet brain"[2]
Thiamine
SpecialtyPsychiatry, neurology

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.[1]

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.[3] Of those affected, 25% require long-term institutionalization in order to receive effective care.[3][4]

Signs and symptoms

The syndrome is a combined manifestation of two namesake disorders,

Korsakoff syndrome. It involves an acute Wernicke-encephalopathy phase, followed by the development of a Korsakoff syndrome phase.[5]

Wernicke encephalopathy

WE is characterized by the presence of a triad of symptoms:[6]

  1. Ocular disturbances (ophthalmoplegia)
  2. Changes in mental state (confusion)
  3. Unsteady stance and gait (ataxia)

This triad of symptoms results from a deficiency in

epileptic seizures and a progressive loss of hearing.[6]

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.[6]

Korsakoff syndrome

The DSM-5 classifies Korsakoff syndrome under Substance/Medication-Induced Major or Mild Neurocognitive Disorders, specifically alcohol-induced amnestic confabulatory.[7] 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.[7]

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.[8]

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

hallucinations.[3] 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.[9]

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.[10]

Memory deficits

The amnesic symptoms of WKS include both retrograde and anterograde amnesia.

Other studies have shown deficits in recognition memory and stimulus-reward associative functions in patients with WKS.[12] 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.[12]

Confabulation

People with WKS often show confabulation, spontaneous confabulation being seen more frequently than provoked confabulation.[13] 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.[13]

Causes

WKS is usually found in people who have used

sub-clinical thiamine deficiency.[14]

As stated above, Wernicke-Korsakoff syndrome in the United States is usually found in malnourished

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.[15][16][17]

Wernicke-Korsakoff syndrome in people with chronic alcohol use particularly is associated with

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,[18] and the cerebellum.[19]

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.[20]

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.[21] 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.[21]

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.

liver cirrhosis have a higher incidence of both thiamine deficiency and WKS.[22]

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.

Krebs cycle enzymes pyruvate dehydrogenase complex (PDH) and alpha-ketoglutarate dehydrogenase (alpha-KGDH) are impaired.[14] The impaired functioning of the Krebs cycle results in inadequate production of adenosine triphosphate (ATP) or energy for the cells functioning.[14] 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.[14]

Brain atrophy associated with WKS occurs in the following regions of the brain:

  1. the
    mammillary bodies
    ,
  2. the thalamus,
  3. the
    periaqueductal grey
    ,
  4. the walls of the
    3rd ventricle
    ,
  5. the floor of the 4th ventricle,
  6. the cerebellum, and
  7. 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 the direct toxic effects of alcohol as opposed to thiamine deficiency that has been attributed as the underlying cause of Wernicke-Korsakoff Syndrome.[25]

The amnesia that is associated with this syndrome is a result of the atrophy in the structures of the

medial temporal lobe.[26] It has been argued that the memory impairments can occur as a result of damage along any part of the mammillo-thalamic tract, which explains how WKS can develop in patients with damage exclusively to either the thalamus or the mammillary bodies.[25]

Diagnosis

Diagnosis of Wernicke-Korsakoff syndrome is by clinical impression and can sometimes be confirmed by a formal neuropsychological assessment. Wernicke

nystagmus, and Korsakoff's psychosis with anterograde and retrograde amnesia and confabulation upon relevant lines of questioning.[24]

Frequently, secondary to thiamine deficiency and subsequent cytotoxic edema in Wernicke encephalopathy, patients will have marked degeneration of the

mammillary bodies. Thiamine (vitamin B1) is an essential coenzyme in carbohydrate metabolism and is also a regulator of osmotic gradient. Its deficiency may cause swelling of the intracellular space and local disruption of the blood-brain barrier. Brain tissue is very sensitive to changes in electrolytes and pressure and edema can be cytotoxic. In Wernicke this occurs specifically in the mammillary bodies, medial thalami, tectal plate, and periaqueductal areas. People with the condition may also exhibit a dislike for sunlight and so may wish to stay indoors with the lights off. The mechanism of this degeneration is unknown, but it supports the current neurological theory that the mammillary bodies play a role in various "memory circuits" within the brain. An example of a memory circuit is the Papez circuit.[citation needed
]

  • Axial MRI FLAIR image showing hyperintense signal in the mesial dorsal thalami, a common finding in Wernicke encephalopathy. This patient was nearly in coma when IV thiamine was started, he responded moderately well but was left with some Korsakoff type deficits.
    Axial MRI FLAIR image showing hyperintense signal in the mesial dorsal thalami, a common finding in Wernicke encephalopathy. This patient was nearly in coma when IV thiamine was started, he responded moderately well but was left with some Korsakoff type deficits.
  • Axial MRI B=1000 DWI image showing hyperintense signal indicative of restricted diffusion in the mesial dorsal thalami
    Axial MRI B=1000 DWI image showing hyperintense signal indicative of restricted diffusion in the mesial dorsal thalami
  • Axial MRI FLAIR image showing hyperintense signal in the periaqueductal gray matter and tectum of the dorsal midbrain
    Axial MRI FLAIR image showing hyperintense signal in the periaqueductal gray matter and tectum of the dorsal midbrain

Prevention

As described, Korsakoff syndrome usually follows or accompanies Wernicke encephalopathy. If treated quickly, it may be possible to prevent the development of WKS with thiamine treatments. This treatment is not guaranteed to be effective and the thiamine needs to be administered adequately in both dose and duration. A study on Wernicke-Korsakoff syndrome showed that with consistent thiamine treatment there were noticeable improvements in mental status after only 2–3 weeks of therapy.[6] Thus, there is hope that with treatment Wernicke encephalopathy will not necessarily progress to WKS.[vague]

In order to reduce the risk of developing WKS it is important to limit the intake of alcohol in order to ensure that proper nutrition needs are met. A healthy diet is imperative for proper nutrition which, in combination with thiamine supplements, may reduce the chance of developing WKS. This prevention method may specifically help heavy drinkers who refuse to or are unable to quit.[1]

A number of proposals have been put forth to fortify alcoholic beverages with thiamine to reduce the incidence of WKS among those heavily abusing alcohol. To date, no such proposals have been enacted.[27][28][29][30][31][excessive citations]

Daily recommendations of thiamine requirements are 0.66 mg per 8,400 kilojoules (2,000 kilocalories) of food energy intake—approximately equivalent to 1.2 mg for men and 1.1 mg for women.[14]

Treatment

The onset of Wernicke encephalopathy is considered a medical emergency, and thus thiamine administration should be initiated immediately when the disease is suspected.

intravenous fluids containing vitamins and minerals, is one means of treatment.[33][34]

Epidemiology

WKS occurs more frequently in men than women and has the highest prevalence in the ages 55–65. Approximately 71% are unmarried.[4]

Internationally, the prevalence rates of WKS are relatively standard, being anywhere between zero and two percent. Despite this, specific sub-populations seem to have higher prevalence rates including people who are homeless, older individuals (especially those living alone or in isolation), and psychiatric inpatients.[35] Additionally, studies show that prevalence is not connected to alcohol consumption per capita. For example, in France, a country that is well known for its consumption and production of wine, prevalence was only 0.4% in 1994, while Australia had a prevalence of 2.8%.[36]

History

Wernicke encephalopathy

gray matter around the third and fourth ventricles and the cerebral aqueduct. Brain atrophy was only found upon post-mortem autopsy. Wernicke believed these hemorrhages were due to inflammation and thus the disease was named polioencephalitis haemorrhagica superior. Later, it was found that Wernicke encephalopathy and alcoholic Korsakoff syndrome are products of the same cause.[35]

Korsakoff syndrome

Sergei Korsakoff was a Russian physician after whom the disease "Korsakoff's syndrome" was named. In the late 1800s Korsakoff was studying long-term alcoholic patients and began to notice a decline in their memory function.[35] At the 13th International Medical Congress in Moscow in 1897, Korsakoff presented a report called: "On a special form of mental illness combined with degenerative polyneuritis". After the presentation of this report the term "Korsakoff's syndrome" was coined.[25]

Although WE and AKS were discovered separately, these two syndromes are usually referred to under one name, Wernicke-Korsakoff syndrome, due to the fact that they are part of the same cause and because the onset of AKS usually follows WE if left untreated.[citation needed]

Society and culture

The British neurologist Oliver Sacks describes case histories of some of his patients with the syndrome in the book The Man Who Mistook His Wife for a Hat (1985).[citation needed]

Frontman and lead vocalist of the hard rock band Breaking Benjamin, Benjamin Burnley, is well known to be living with Wernicke-Korsakoff syndrome due to his past alcoholism. He has written multiple songs about addiction and his experiences with alcohol, with many of such songs being found on the band's 2009 album Dear Agony as it was the first album Burnley had written and recorded completely sober.[citation needed]

See also

References

External links