Korsakoff Syndrome

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 the metabolism of multiple cell components and ATP. Thiamine mediates pyruvate metabolism, and its deficiency can lead to elevated lactate, 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. 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:

• 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[3] 

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 confabulation, replacing one's gap in memory with untrue information.[9] The Caine criteria have been described to have a sensitivity of 85% and specificity of 100% for Wernicke encephalopathy in the alcoholic population.[3] Because of the strong overlap, this can also be used to help screen for Korsakoff syndrome. Caine criteria for the diagnosis of Wernicke encephalopathy in chronic alcoholics. Two of the following 4 signs are necessary to diagnose Wernicke encephalopathy clinically:

• 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. However, 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 also need glucose replacement, 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 correcting hypoglycemia.[10] Some suggestions are prolonged and not an acute replacement of glucose without thiamine supplementation and increased 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](B3)

Differential Diagnosis

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

Prognosis

High suspicion of Wernicke’s encephalopathy is key to improving patient prognosis. Classically, the thinking was that once Korsakoff syndrome had set in, amnesia was generally irreversible. 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 been shown to correlate with a worse prognosis.[3]