Continuing Education Activity

Korsakoff syndrome is a chronic neuropsychiatric syndrome that is caused by the deficiency of thiamine, also known as vitamin B1. This deficiency leads to damage to multiple areas of the brain, which in turn cause amnesia and confusion. Korsakoff syndrome is most commonly seen in the context of chronic alcohol abuse and thought to be on the spectrum with Wernicke encephalopathy, however, Wernicke encephalopathy is acute and often reversible while Korsakoff syndrome is chronic and may be irreversible. This activity describes the evaluation and management of patients with Korsakoff syndrome and highlights the role of the interprofessional team in improving care for affected patients.

Objectives:

• Describe the pathophysiology of Korsakoff syndrome.
• Review the presentation of a patient with Korsakoff syndrome.
• Summarize the treatment options for Korsakoff syndrome.
• Outline the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by korsakoff syndrome.

Introduction

While there is no consensus for the actual definition of Korsakoff syndrome, it is generally agreed to be a chronic neuropsychiatric syndrome due to thiamine (vitamin B1) deficiency.[1] Damage to multiple areas on the brain leads to amnesia and confusion. While classically associated with chronic alcohol use, Korsakoff syndrome can be the result of other processes that ultimately lead to thiamine deficiency. Korsakoff syndrome is most often seen in the context of chronic alcohol abuse and thought to be on the spectrum with Wernicke encephalopathy. Wernicke encephalopathy is acute and often reversible while Korsakoff syndrome is chronic and may be irreversible.[2] When Wernicke encephalopathy accompanies Korsakoff syndrome, it is referred to as Wernicke-Korsakoff syndrome, and due to the considerable overlap of the two diseases, this article will refer to the both of them when evaluating and treating a patient.

Etiology

Any condition leading to chronic thiamine deficiency can lead to Wernicke’s encephalopathy and if untreated, to Korsakoff syndrome.[3]  The most common cause of Korsakoff syndrome is chronic alcohol abuse. Alcohol interferes with GI tract absorption of thiamine as well as interfering with the liver's ability to store thiamine. Additionally, accompanying malnutrition often compounds the effects of alcoholism leading to further thiamin deficiency. Other causes of Korsakoff syndrome include eating disorders, chronic vomiting (including hyperemesis gravidarum), psychiatric disorders, chemotherapy, and cancer.[4][5]

Epidemiology

The worldwide prevalence of Wernicke-Korsakoff syndrome is thought to be between 0 and 2%.  Those at higher risk include the homeless, elderly and psychiatric patients. Because Korsakoff syndrome is grossly underdiagnosed and there is disagreement regarding precise diagnostic criteria, there is little data on the incidence and prevalence.[1]

Pathophysiology

Thiamine is an essential cofactor for multiple enzymes involved in brain cell metabolism.[6] Without these enzymes, there is a reduction in metabolism of multiple cell components and ATP. Thiamine mediates pyruvate metabolism, and its deficiency can lead to elevated lactate, which can lead to edema, loss of neurons, and reactive gliosis throughout the brain. The cognitive deficits seen in Korsakoff syndrome are thought to be primarily due to damage to the following areas- the anterior nucleus of the thalamus, mammillary bodies, and corpus callosum.[7] There is also evidence of decreased glucose metabolism in the cerebral cortex.[8] Cerebellar degeneration is also common among alcoholics and can lead to the ataxia and oculomotor deficits seen in Wernicke-Korsakoff syndrome.

Histopathology

The most common histologic findings for Wernicke-Korsakoff syndrome include gliosis and microhemorrhages in the following areas: periaqueductal and paraventricular grey matter, atrophy in the mamillary bodies and thalamus, volume deficits in the hippocampus, cerebellar hemispheres, pons, and anterior superior vermis.

History and Physical

As mentioned above, Wernicke encephalopathy and Korsakoff syndrome are often thought to be on a spectrum with one another as they are both due to thiamine deficiency. Thus, clinicians should screen for them together. Wernicke encephalopathy classically presents with the triad of altered mental status, ophthalmoplegia, and ataxia. In reality, less than 20% of patients will present with all three of these findings.[3] The following signs and symptoms should cause suspicion for Wernicke-Korsakoff syndrome[3]:

• Altered mental status (up to 82% of patients) - amnesia, disorientation, confabulations
• Oculomotor findings - most often horizontal nystagmus, retinal hemorrhage, ophthalmoplegia, cranial nerve IV palsy, conjugate gaze
• Ataxia - wide-based gait

The cognitive impairments specific to Korsakoff syndrome vs. Wernicke encephalopathy include anterograde amnesia, profoundly limiting one's learning capacity, retrograde amnesia, as well as executive deficits, resulting in decreased inhibition and difficulties with judgment, planning and problem-solving.[7] Anterograde amnesia can result in the classic symptom of confabulations, replacing one's gap in memory with untrue information.[9]

The Caine criteria have been described to have a sensitivity or 85% and specificity of 100% for Wernicke encephalopathy, in the alcoholic population.[3] Because of the strong overlap, this can be used to help screen for Korsakoff syndrome as well.

Caine criteria for the diagnosis of Wernicke encephalopathy in chronic alcoholics. Two of the following four signs are necessary to diagnose Wernicke encephalopathy[3] clinically[3]:

• Dietary deficiency
• Oculomotor abnormalities
• Cerebellar dysfunction
• Either altered mental status or mild memory impairment

Evaluation

Korsakoff syndrome is, for the most part, a clinical diagnosis. It should be diagnosed when the signs and symptoms described above are present in a patient with risk factors for thiamine deficiency. Thiamine blood tests often take days to result and should not delay empiric treatment. Regarding neuroimaging, CT and MRI of the brain are not often indicated for emergent diagnosis of Korsakoff syndrome, although they may be warranted to rule out other causes of the patient’s symptoms. Non-emergent MRI can reveal specific findings of Wernicke-Korsakoff syndrome including changes in the mamillary bodies, thalami, tectal plate, and periaqueductal areas but sensitivity is only 53%.

Treatment / Management

The mainstay of treatment in an acute presentation is thiamine replacement. There is little evidence on the amount of thiamine to replace, but typical regimens include high dose thiamine at 500 mg- 1500 mg, IV, three times daily for at least 3 days.[3] Electrolyte abnormalities should be corrected and fluids replaced. In particular, magnesium requires replacement, as thiamine-dependent enzymes cannot operate in a magnesium-deficient state. Many patients will present needing glucose replacement as well, and traditionally it was thought that replacing glucose before thiamine could exacerbate the patient’s symptoms. Following a review of 19 papers, it has been recommended not to delay in correcting hypoglycemia.[10] There are suggestions that prolonged and not acute replacement of glucose without thiamine supplementation increased the risk of Wernicke encephalopathy. After the acute phase of vitamin and electrolyte replacement, there is mounting evidence that memory rehabilitation is beneficial in Korsakoff syndrome. Declarative memory ("knowing what") seems to be most affected in Korsakoff syndrome, leading to many patients requiring lifelong care. Because procedural learning ("knowing how") seems to remain somewhat maintained in Korsakoff syndrome, memory rehabilitation focussed in this area has shown promising outcomes. There has been some success in small Korsakoff syndrome patient populations in learning procedures and improving their autonomy.[7]

Differential Diagnosis

Differential diagnosis will vary based on the patient’s presentation but may include infection, seizure, intoxication, metabolic disorders, medications, stroke, head trauma, brain mass, multiple sclerosis, migraines, vertigo, ethanol neurotoxicity, schizophrenia.[3]

Prognosis

High suspicion for Wernicke’s encephalopathy is key to improving patient prognosis. Classically, the thinking was that once Korsakoff syndrome has set in, amnesia was generally irreversible. As noted above, more recent research has shown promise in memory rehabilitation including memory compensation techniques and error-less learning strategies.[1]

Regarding neuroimaging, associations with cortical lesions have shown to correlate with a worse prognosis.[3]

Consultations

Consultations with dietary, social work, neurology, and neuropsychiatry can be beneficial in the treatment of Wernicke-Korsakoff syndrome.

Deterrence and Patient Education

Wernicke-Korsakoff syndrome is vastly underdiagnosed. [3] Patient often do not present themselves due to substance abuse, and it is not until they are brought in by family members that there is an evaluation. Alcohol withdrawal and intoxication can interfere with diagnosis as well. Even once presenting to the physician, it is often misdiagnosed, with one study estimating Wernicke encephalopathy is missed in 68% of alcoholic patients and 94% of nonalcoholic patients.[3] There are also gaps in research of Wernicke-Korsakoff syndrome due to a lack of a formal definition for Korsakoff syndrome, which makes it difficult to accumulate data, especially regarding epidemiology, diagnosis, and prognosis.

Patients who are unable or unwilling to quit alcohol may benefit from proper nutrition and thiamine supplementation.

Pearls and Other Issues

Korsakoff syndrome is a neuropsychiatric condition causing damage to multiple areas of the brain that results in cognitive impairment and amnesia.

Korsakoff syndrome can result from any condition leading to thiamine deficiency but most often seen in chronic alcohol abuse.

Wernicke-Korsakoff syndrome is a clinical diagnosis, and Wernicke encephalopathy should be suspected in anyone at risk for thiamine deficiency who presents with oculomotor findings, ataxia or confusion. Once amnesia and executive deficits are present, Korsakoff syndrome should be suspected.

The key to good outcomes is catching Wernicke encephalopathy early and treating with thiamine.

Enhancing Healthcare Team Outcomes

Providing quality care for patient’s with Korsakoff syndrome requires a large number of resources and coordination between a variety of healthcare professionals. In the early stages, triage nurses, visiting nurses and EMS providers can help identify patients who may be presenting for other complaints or would otherwise not seek care. Effective screening tools in the emergency department or outpatient clinic could help identify alcohol abuse, the major risk factor for Wernicke-Korsakoff syndrome. In the acute setting, identifying the disease (preferably early on or before the onset of Korsakoff Syndrome) and treating requires interprofessional work between the emergency physicians, neurologists, and dieticians to rule out other causes and treat. Long term care of these patients may require the attention of neuropsychiatrists, neurologists, psychiatrists, dieticians, social workers, and the patient’s primary care provider to ensure sobriety, continued nutrition, and memory rehabilitation.