KORSAKOFF’S SYNDROME

Introduction

The human brain has the ability to store information in the form of memory. This information is stored in the form of synaptic tracts formed inside the brain known as memory tracts. When a person recalls some memory, the same synaptic tracts become activated through which the information traveled for the first time. Recalling the memories makes them more and more consolidated in the brain. However, different disorders can result in memory impairments. One of these disorders is Korsakoff’s syndrome.

Korsakoff’s syndrome is a memory disorder caused by a deficiency of vitamin B1, also known as thiamine. It is most commonly seen in chronic alcoholics. More than 30% of chronic alcoholics are diagnosed with Korsakoff’s syndrome at some stage of life. The disease is characterized by retrograde and anterograde amnesia as well as a state of confusion.

In this article, we will talk about the signs and symptoms of Korsakoff’s syndrome, its biochemical basis, pathophysiology as well as the management of patients.

Signs and Symptoms

Korsakoff’s syndrome is an alcohol-related memory disorder characterized by forgetfulness during the active state of mind. The person often forgets things while engaging in a conversation and goes on repeating the same question again and again. The recent memory of the patient is affected more severely as compared to the remote memory.

The major signs and symptoms of the disease are as follows.

Anterograde Amnesia

It is a type of amnesia characterized by an inability to form new memories. The patients present with a varying degree of forgetfulness. They are unable to keep a record of their daily life activities. They often forget what they have eaten at breakfast or lunch, whether they have taken medicine or not, etc. They may forget about the things that are said by others while engaging in a conversation. They tend to ask the same questions multiple times.

Anterograde amnesia makes life quality much worse for the patients suffering from Korsakoff’s syndrome. This amnesia is caused by damage to the neurons in the medial temporal lobe. Hippocampus is the main organ that is damaged in this disorder.

Korsakoff’s syndrome is one of the major causes of anterograde amnesia seen in patients around the world.

Retrograde Amnesia

In this type of amnesia, the patient is unable to recall the memories formed before the onset of the syndrome. Although anterograde amnesia is more common in Korsakoff’s syndrome, retrograde amnesia up to 30 years prior to the onset of the syndrome is also seen.

Remote memory is only partially lost in Korsakoff’s syndrome. However, in severe cases, complete or partial loss of memory may be present in some patients.

Both anterograde and retrograde amnesia coexist in this syndrome.

Amnesia of Fixation

Amnesia of fixation is characterized by recent memory loss. In this type of amnesia, the patient is unable to keep track of events that occurred a few minutes earlier.

It is a characteristic feature of Korsakoff’s syndrome. This type of amnesia can be manifested when a person engages in some conversation. The repetitive questioning while talking to a person is a feature of fixation amnesia.

Confabulation

Another characteristic feature of Korsakoff’s syndrome is confabulation. This memory disorder is characterized by false and fabricated memories that are believed to be real by the patients. The invented memories range from some minor alterations and beliefs to some strange and bizarre fabrications in the known facts.

The fabricated and invented memories may be related to oneself or about other people in the world. The patients are so firm in their believes that the therapy is very difficult. The application of these false memories can result in some serious circumstances. They can also invent new identities based on confabulation.

Lack of Insight and Apathy

The patients in this syndrome often represent with lack of insight. They are unable to receive different events occurring in their surroundings due to an altered state of mind. They may also not understand the nature of their illness and refuse the available treatment. They have a belief that nothing is wrong with them. It makes the management and treatment of the disease difficult. The patients may also become aggressive sometimes.

Apathy is defined as a loss of interest in different activities. The patients present with a lack of emotions and feelings. They become immune to the changes and do not show a response to sensitive events taking place in their surroundings. The patients suffering from Korsakoff’s syndrome may lack a sense of purpose or meaning of life in the later stages of the disease.

Mental excitation, euphoria, and altered recognition of places and faces may also be seen in this syndrome.

Causes

Chronic alcohol consumption and malnutrition are the two major causes of Korsakoff’s syndrome. Both these conditions cause a decreased supply of thiamine in the body. Alcohol can contribute to thiamine deficiency in the following way.

Decreased Intake of Thiamine

Chronic alcoholism causes an increase in carbohydrate metabolism. As a result, the daily requirements of thiamine are increased. However, chronic alcoholics are unaware of this fact. The poor thiamine diet in these individuals results in thiamine deficiency.

Decreased Thiamine Uptake

Another reason for thiamine deficiency in chronic alcoholics is the reduced uptake of vitamin through the gut walls. Thiamine is absorbed from the intestinal lumen into the cells. Here it is acted upon by thiamine diphosphokinase enzyme to make thiamine diphosphate. This diphosphate form is then transported across the cell into the bloodstream.

Excessive alcohol intake causes inflammation of the gut walls and impairs the uptake of vitamins including thiamine. Also, alcohol consumption limits the activity of the kinase enzyme, further decreasing the thiamine uptake into the blood.

Impaired Utilization

Although chronic alcoholism increases the thiamine requirements of the cells, it also impairs thiamine utilization. Thiamine pyrophosphate acts as a coenzyme in the presence of magnesium. Chronic alcohol consumption often causes a decreased availability of magnesium in the body. In the absence of magnesium ions, TPP requiring enzymes cannot function properly. This results in impaired utilization of thiamine by the cells.

Other causes

Besides alcohol consumption and malnutrition, other causes that can contribute to Korsakoff’s syndrome are eating disorder, vomiting, and chemotherapy.

Prolonged vomiting causes a washout of contents in the digestive tract. Essential nutrients along with vitamins are lost. This can be a potential cause of thiamine deficiency.

Eating disorders in some individuals may also result in thiamine deficiency leading to Korsakoff’s syndrome.

It can also be a consequence of chemotherapy in certain cancers.

Biochemical Basis

Thiamine deficiency is the reason for the neurological manifestation of the disease. Thiamine is an essential nutrient that is to be obtained via diet. After absorption through the duodenum of the small intestine, thiamine is transported via the blood to all the cells of the body. Within the cytoplasm, thiamine is esterified with a phosphate group to form thiamine pyrophosphate (TPP). This coenzyme is needed for several biochemical reactions taking place in the neurons as well as other cells. Some of these reactions involve;

  • Synthesis of acetyl CoA from pyruvate during carbohydrate metabolism
  • Reactions of the citric acid cycle
  • Transketolase reactions of the hexose monophosphate pathway
  • Amino acid metabolism
  • Synthesis of acetylcholine, necessary for nerve transmission in the CNS

Korsakoff’s syndrome is seen in chronic alcoholics or patients with malnutrition due to thiamine deficiency. Decreased thiamine levels in the body limit the functioning of neurons. Recall that neurons in the brain get most of the energy for cellular processes via glucose metabolism. Thiamine pyrophosphate is an essential enzyme required for carbohydrate metabolism. In the decreased supply of thiamine, carbohydrate metabolism is severely affected in the neurons present in different areas of the brain. As a result, the neurological symptoms of Korsakoff’s start appearing.

Besides, thiamine is needed for the synthesis of glucose-derived neurotransmitters like acetylcholine. Acetylcholine is the major neurotransmitter in the synapses of the CNS. The decreased supply of acetylcholine due to thiamine deficiency severely affects the nerve impulse transmission across the neurons of the CNS.

Pathophysiology

The pathophysiology of Korsakoff’s syndrome is based on thiamine depletion. It can cause neuronal damage in the following ways.

Mitochondrial Damage and Cell Death

Thiamine depletion causes reduced availability of thiamine pyrophosphate, a coenzyme needed for reactions in the citric acid cycle. Recall that the citric acid cycle takes place in the mitochondria of the cell. The defective citric acid cycle causes accumulation of the substrates in mitochondria that can cause mitochondrial damage. Mitochondrial damage can cause leakage of mitochondrial proteins and can activate apoptosis pathways and can cause cell death

Most of the energy needed by the cell is provided by mitochondria. The decreased supply of ATP due to mitochondrial damage can cause cell death in several ways;

  • Decreased ATP in the cell causes decreases functioning of the sodium-potassium pump. The resulting ionic imbalance causes cellular swelling and membrane blebbing. This leads to necrosis and cell death.
  • In the absence of ATP, cells shift to anaerobic glycolysis. The build-up of lactic acid decreases the pH inside the cells causing clumping of different proteins. This also causes cell death via necrosis.
  • ATP depletion also causes detachment of the ribosome from the RER. Decreased protein production then results in cell death.

Apoptosis due to Thiamine Deficiency

In addition to the mitochondrial pathway, thiamine deficiency can result in apoptosis of neurons and the associated cells in other ways. It has been suggested that thiamine deficiency causes loss of JNK1, a mitogen-activated kinase involved in cellular protection. The decreased protective function of JNK1 in thiamine deficiency can cause apoptosis of cells in the CNS.

Oxidative Stress causing Cell death

Abnormal carbohydrate metabolism in thiamine deficiency causes an excessive build-up of free radicals in the neurons. These free radicals can cause damage to the cells in several ways. In normal cells, the free radicals are removed by certain antioxidant compounds like glutathione.

In thiamine deficiency, oxidative stress is more than what can be handled by neurons. It causes cell death via necrotic pathways.

Changes in the Brain

The changes in the brain can be seen 2 to 3 weeks after thiamine depletion. Cellular impairment and injury can be seen in the areas of the brain that contain higher thiamine levels. Decreased metabolism can be visualized via PET scan of the brain.

Additional pathological findings include the following.

  • Astrocytes lactate and edema
  • Endothelial cell damage causing the release of nitric oxide
  • DNA fragmentation in the neurons
  • Increased glutamate concentration in the extracellular fluid of the brain
  • Increased cytokines production
  • Breakdown of the blood-brain barrier

Neuron injury and lesions can be seen in different areas of the brain. The sensitivity of different areas for thiamine deficiency is also different.

The cerebellum is by far the most sensitive region to thiamine deficiency. Ataxia is the common manifestation of cerebellar damage in Korsakoff’s syndrome. All the layers of the cerebellum undergo damage. Purkinje cells are the ones that bear more damage and injury due to thiamine deficiency. The cerebellar injury is responsible for ataxia and gait problems seen in Korsakoff’s syndrome.

The amnesia related symptoms seen in Korsakoff’s syndrome are due to damage to the diencephalon. Medial areas of the thalamus are more severely affected including the connections with the medial temporal lobe and amygdala. Incomplete recovery from amnesia suggests that neurons in these areas have undergone permanent structural damage that cannot be repaired.

Diagnosis

The diagnosis of the disease is mainly clinical. A history of alcohol abuse and altered mental status are the diagnostic features of Korsakoff’s syndrome. Although lab tests and imaging studies are not necessary, they may be done for research purposes. Thiamine levels in the body of patients can be checked via different diagnostic techniques. Imaging techniques such as PET scan can be used to demonstrate the metabolic changes in the brain of patients.

Treatment

The main goal in the treatment of Korsakoff’s syndrome is to correct the thiamine deficiency of patients. For this purpose, IV or IM thiamine supplements are given to patients. They are advised to maintain proper thiamine rich diet and hydration.

Brain damage and amnesia may not recover after using thiamine supplements. Drug therapy is also available for such patients. They are prescribed to take oral thiamine for 3 to 12 months. Clonidine drug has been found to reverse the memory impairment in some patients.

In severely malnourished patients, an intravenous dose of glucose along with thiamine has been proved to be a good treatment in immediate cases.

For memory impairments, certain learning therapies have been advised for the rehabilitation of patients. The patients need full-time care during rehabilitation. Patient education is also needed for alcohol abstinence and maintenance of proper diet during the rehabilitation process.

Risk Factors

Different risk factors can expose a person to the disease. These include the following;

  • Age: people between 30 to 70 years of age are at greater risk of getting the disease
  • Sex: Males are more frequently affected than females
  • Alcoholism: Korsakoff’s syndrome is much more common in alcoholics as compared to non-alcoholic persons
  • Diet: People with thiamine poor diet are at greater risk of developing the disease in their middle age

Prevention

Korsakoff’s syndrome is a preventable disease if proper care is taken. It is mainly associated with chronic alcohol abuse or extreme dieting habits. One can prevent the disease by limiting alcohol abuse and taking proper diet to avoid thiamine deficiency. Vitamin B complex supplements may also be used for the prevention of the disease.

Summary

Korsakoff’s syndrome is a memory disorder seen in alcoholics. The pathology behind the disease is thiamine deficiency caused by alcohol consumption.

Patients with Korsakoff’s syndrome present with anterograde as well as retrograde amnesia. Amnesia of fixation represented by recent memory loss is also seen in the syndrome.

Confabulation is a characteristic symptom of Korsakoff’s syndrome in which patients develop some false and fabricated memories and believe them to be true. The patients often do not have an insight into the syndrome.

Alcohol and malnutrition are the major causes of the disease. Alcohol can cause thiamine deficiency by;

  • Decreasing thiamine uptake by damaging the gut wall and inactivating enzymes
  • Decreasing thiamine utilization due to magnesium deficiency
  • Increasing the cellular requirements of thiamine

Persistent vomiting, chemotherapy, and extreme eating habits may also cause Korsakoff’s syndrome.

Thiamine is necessary for carbohydrate metabolism and synthesis of certain neurotransmitters like acetylcholine. The deficiency of this essential nutrient can cause neuronal damage.

Thiamine deficiency can cause cell death due to mitochondrial damage via apoptosis. It can also cause necrosis of neurons due to decreased availability of ATP. Increased oxidative stress may also be a cause of injury to neurons seen in this disease.

Certain changes can be seen in the brain after a few weeks of thiamine deficiency. Cerebellum and thalamus are the most severely affected areas of the brain causing ataxia and memory impairment.

The diagnosis of the disease is mainly based on clinical examination.

Thiamine replacement therapy is the most effective treatment in Korsakoff’s syndrome. Rehabilitation care should also be provided to patients.

Certain risk factors can contribute to the development of this syndrome. It can be prevented by taking precautionary measures.

References

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  3. Nyssen R. (1957). “[Experimental contribution to the study of fixation amnesia in Korsakoff’s syndrome of alcoholic origin]”. Acta Neurologica et Psychiatrica Belgica (in French). 57 (8): 839–66. PMID 13478443.
  4. C. W. M. Whitty; O. L. Zangwill (22 October 2013). Amnesia: Clinical, Psychological and Medicolegal Aspects. Elsevier Science. p. 76. ISBN 978-1-4831-6514-1.
  5. Benon R., LeHuché R. (1920). “Cranial Injuries and Korsakoff’s Psychosis” [Traumatismes crâniens et psychose de Korsakoff]. Archives Suisses de Neurologie, Neurochirurgie et Psychiatrie (in French): 319.
  6. Kolb, Bryan; Whishaw, Ian Q. (2003). Fundamentals of human neuropsychology. New York: Worth Publishers. p. 473. ISBN 978-0-7167-5300-1OCLC 55617319.

Image source

  1. https://pixabay.com/illustrations/brain-thought-mind-idea-psychology-4314636/
  2. https://commons.wikimedia.org/wiki/File:MRI_FLAIR_sequence_Wernicke_Encephalopathy.jpg