Hospital Medicine

Wernicke-Korsakoff syndrome

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Wernicke-Korsakoff syndrome

I. What every physician needs to know.

Wernicke-Korsakoff syndrome (WKS) is a neuro-psychiatric manifestation of thiamine (vitamin B1) deficiency, also known as "wet brain" or alcoholic encephalopathy. It is generally agreed that Wernicke's encephalopathy (WE) and Korsakoff's psychosis are different stages of the same disorder. WE is an acute severe thiamine deficiency with a classic triad of confusion, ataxia, and ophthalmoplegia. Korsakoff's psychosis is a chronic amnestic state that typically--although not always--follows WE.

Thiamine deficiency is associated with excessive alcohol use, poor or unbalanced diet, malabsorption, and increased excretion of the vitamin. The metabolically active thiamine diphosphate is a major cofactor in glucose metabolism. Therefore, in individuals with subclinical thiamine deficiency, a large amount of glucose (given either orally or as dextrose infusion) can trigger WKS. Affected areas of the brain are restricted to regions with high thiamine turnover, including brain stem nuclei of the oculomotor, abducens, acoustic nerves, mammillary bodies, medial thalamus, and cerebellar vermis.

II. Diagnostic Confirmation: Are you sure your patient has Wernicke-Korsakoff syndrome?

The hallmark of WE is the ocular abnormalities, without which it is difficult to make the diagnosis. Complete ophthalmoplegia occurs rarely, and clinicians should be aware of additional eye signs associated with the syndrome. Nystagmus, abducens (cranial nerve VI), nerve palsy, and horizontal or combined horizontal-vertical gaze palsy are the most common findings. In severe disease, there may be a complete loss of ocular movements. Ataxia primarily affects gait; when severe, the patient cannot stand or walk without support.

Abnormal mental status is found in about 90 percent of patients and is characterized by a global confusion and apathy. All features of the triad are documented in fewer than half of the patients. The best aid for a correct diagnosis is a high index of suspicion in any patient with poor nutrition in appropriate clinical settings and at least one component of the classic triad. In many cases, diagnosis is established by response to the treatment with thiamine.

Korsakoff's amnestic state is a mental disorder. Patients exhibit anterograde (defect in learning) and retrograde (loss of memories) amnesias, and confabulation (making up stories). Retentive memory is impaired out of proportion to other cognitive functions in the otherwise alert and responsive patient. In critically ill patients, signs of WE can be overlooked easily, and some patients already have the amnestic state, with no typical ocular or ataxic signs other than residual nystagmus, when they are first seen.

A. History Part I: Pattern Recognition:

WKS can be recognized readily in an alcoholic with the classic triad. A recent systematic review on WE after bariatric surgery indicated that the disease was diagnosed 4-12 weeks postoperatively, mainly in young women with vomiting and concurrent peripheral neuropathy. The onset is acute or subacute. Confusion is the most common presenting symptom, followed by ataxia and visual problems.

Some patients show a disproportionate disorder of retentive memory. History may reveal difficulties with walking and diplopia that precedes cognitive changes by a few days or weeks. Next to nystagmus, the most frequent ocular abnormality is a weakness or paralysis of eye abduction accompanied by double vision and internal strabismus. Eye signs usually occur in combination with other symptoms, rather than alone.

Common signs are confusion, apathy, diplopia, strabismus, nystagmus, weakness or paralysis of eye abduction, ptosis, vestibular dysfunction without hearing loss, and ataxia.

Patients with thiamine deficiency may have symptoms of high-output cardiac failure and gastrointestinal complaints, including nausea, vomiting, and abdominal pain. Concomitant peripheral neuropathy is found in 80 percent of patients with WKS.

Associated signs are postural hypotension, tachycardia, mild hypothermia, peripheral neuropathy, megaloblastic anemia, malnutrition, and tongue redness.

B. History Part 2: Prevalence:

The precise incidence of WKS is unknown. Autopsy reports indicate that prevalence of WKS is approximately 1-2 percent in the general population but much higher in patients at risk (12-14% among alcoholics and 10% in patients with acquired immunodeficiency syndrome [AIDS]). In one post-mortem series, only 20 percent of patients were diagnosed during life. WE affects males slightly more often than females, although, when adjusted to alcohol consumption, women appear to be more susceptible to the disease. Europeans tend to develop Wernicke's encephalopathy more frequently than Asians do.

Because the body's thiamine reserves are sufficient for approximately 10-20 days, any condition of unbalanced nutrition that lasts more than three weeks may lead to the syndrome. High-calorie and high-carbohydrate diets increase the demand for thiamine. White polished rice is highly deficient in thiamine because milling removes the husk, which is rich in thiamine, so diets that consist predominantly of polished rice put individuals at risk. Diet restrictions in place for socio-economic reasons, hunger strike, psychogenic food refusal, slimming diets, and neglect in old age can all lead to thiamine deficiency.

Alcohol is known to decrease thiamine absorption by 40 percent and to result in decreased hepatic storage of the vitamin. Heavy drinkers may have a genetic predisposition to developing WKS. Genetic changes in the effectiveness of the thiamine transport system may lead to diminished thiamine transport into brain cells and contribute to impaired ability to respond to therapy. Decreased transketolase activity and variation in the X-linked transketolase-like 1 (TKTL1) and SLC19A2 genes may contribute to genetic susceptibility to WKS.

In the United States, WKS is usually found in malnourished alcoholics. However, the Wernicke's encephalopathy has been recognized more frequently in a variety of clinical settings recently, particularly after bariatric procedures.

Conditions that predispose to WKS include chronic alcohol use, starvation that is due to treatment of obesity, unbalanced diet, refeeding syndrome, AIDS, anorexia nervosa, persistent nausea and vomiting, total parenteral nutrition without thiamine supplementation, long-term hemodialysis, systemic cancer and chemotherapy, medications (intravenous [IV] high-dose nitroglycerin, tolazamide, phenytoin), gastrectomy and partial or subtotal colectomy, magnesium depletion, chronic diuretic use, thyrotoxicosis, and hyperemesis gravidarum.

C. History Part 3: Competing diagnoses that can mimic Wernicke-Korsakoff syndrome.

WE should be considered in any patient who presents with acute delirium or ataxia. Basilar stroke, hippocampal damage after cardiac arrest, third ventricular tumors, and herpes simplex encephalitis should all be considered in the differential diagnosis. Bilateral oculomotor abnormalities occur with bacterial or carcinomatosis meningitis, myasthenia gravis, and botulism. An equivalent type of memory loss may also follow frontal lobe lesion, temporal lobe epilepsy, and concussive head injury. Alcoholic cerebellar degeneration causes similar ataxia. However, these disorders can usually be differentiated from WKS on the basis of history and appropriate testing. Symptoms usually remain more or less unchanged and will not improve with thiamine therapy.

Korsakoff's amnestic state must be distinguished from the other forms of dementia. Gait disturbances and horizontal nystagmus provide a means of identifying the cause of dementia as alcoholic or nutritional in origin.

D. Physical Examination Findings.

In Wernicke's encephalopathy, changes in mental status range from apathy, inability to concentrate, and drowsiness to a global confusional state. Loss of consciousness is distinctly rare. Patients demonstrate misidentification of those nearby, profound inattentiveness, and inability to understand the immediate situation. Remarks are irrational and show no consistency from one moment to the next. Spontaneous speech is minimal, and many questions go unanswered. The confusion recedes gradually, and as it does, the defect in the retentive memory and learning stands out more clearly.

Nystagmus (usually horizontal) is the most common ocular finding. Prominent nystagmus in the abducting eye is characteristic of internuclear ophthalmoplegia. Cranial nerve VI (abducens) palsy causes weakness of the lateral rectus muscle and results in medial deviation of the eye, decreased abduction, and horizontal diplopia. Abducens palsy is usually bilateral but not necessarily symmetrical. With complete abducens paralysis, nystagmus is absent but it becomes evident as the weakness improves with treatment.

Cranial nerve III (oculomotor) palsy causes deviation of the eye laterally (unopposed lateral rectus) and downward (unopposed superior oblique). The eye is "down and out" and fails to adduct on lateral gaze. Another finding is conjugate gaze palsies (usually horizontal). Ptosis can be present. Pupils are ordinarily spared; however, mild anisocoria or sluggish reaction to light is occasionally seen). Each of the eye abnormalities may be present alone, but a constellation of signs is usually found.

The ataxia affects gait predominantly. The patient has a wide-based gait and slow, short-spaced steps, and in severe cases the patient cannot stand or walk without support. In some patients gait abnormalities are better appreciated in tandem walking. Abnormal limb movements are uncommon, as is dysarthria. In many patients with no symptoms of peripheral neuropathy, examination may reveal diminished or absent ankle jerks and patchy distal sensory loss.

Korsakoff's amnestic state. As a rule, the patient has no insight into his or her illness, lacks initiative, and is indifferent to everything and everyone around him. The defect in learning can be remarkably severe: despite countless attempts, the patient cannot remember the simplest of facts; the patient understands what is wanted of him or her but easily forgets. Retrograde amnesia is usually severe and covers a period prior to the onset of illness. Anterograde and retrograde amnesia are always coupled. Language, computation, and all habitual actions are preserved.

Confabulation can be associated with both phases of WKS. The implication that confabulation is a deliberate attempt to hide the memory defect is probably incorrect since, as the patient improves, the tendency to confabulate diminishes.

E. What diagnostic tests should be performed?

WKS remains a clinical diagnosis. The Mini-Mental State Examination helps to screen for global confusion and confirms disorientation in time and place. Supplemental memory questions about recent news, sporting, cultural, or personal events should also be asked.

Testing of extraocular movements and gaze in all nine directions reveals nystagmus evoked by gaze and decreased abduction. During testing, the patient may experience diplopia when two images appear side by side. With oculomotor palsy, the eye is unable to adduct. Conjugate gaze is abnormal. Ophthalmoscopical exam may demonstrate retinal hemorrhage and papilledema.

Observation of gait demonstrates truncal ataxia and unsteadiness. In severe cases standing and walking is impossible.

Diagnostic confirmation of Korsakoff's amnestic state usually requires detailed neuro-psychiatric and neuro-psychological evaluation by a psychiatrist.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There are no specific routine laboratory tests available.

Serum thiamine levels and urinary thiamine excretion may be decreased but do not accurately reflect tissue concentration and are not reliable indicators of thiamine deficiency. A normal thiamine level does not exclude WE. The assay of erythrocyte transketolase activity and measurement of blood pyruvate levels are associated with technical difficulties; it takes several days to get the results.

Lactic acidosis that is due to pyruvate accumulation may occur with or without Wernicke's encephalopathy in thiamine deficiency. The cerebrospinal fluid (CSF), when available, is usually normal or shows only mild elevation of protein. Electroencephalogram (EEG) shows diffuse mild to moderately slow activity.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Obtaining a brain magnetic resonance imaging (MRI) is often unnecessary, although it may be useful in patients with coma, when ocular and ataxic signs are otherwise nonexistent. The acute WE changes are most apparent on the fluid-attenuated inversion recovery (FLAIR) and T2-weighted images and typically demonstrate hyperintense signals in the periaqueductal region of the midbrain, mammilary bodies, and thalamus. The reported sensitivity of MRI and specificity are 53 percent and 93 percent, respectively. MRI of patients with Korsakoff's amnestic state finds absent or severely atrophic mammilary bodies. Radiographic studies may be normal in patients with WKS (Figure 1).

Figure 1.

Axial plane image with T2 FLAIR shows hyperintense density of the mammilary bodies. Courtesy of Dr. Dublin AB, UC Davis MC.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Serum thiamine level, erythrocyte transketolase activity, and blood pyruvate levels.

III. Default Management.

There are no randomized trials to support a particular treatment regimen or dosing of the thiamine.

The standard dose of thiamine (100 milligrams [mg] once daily) may not be sufficient to revise the manifestation of WKS. Because of the short half-life of the vitamin, multiple daily administrations are needed to correct deficiency. Authors have hypothesized that higher doses of thiamine are necessary for optimal crossing of the blood-brain barrier and prevention of permanent cognitive and neurologic impairment. Thomson et al. stated that 500 mg or higher of thiamine are necessary to correct a thiamine deficiency in alcoholics and nutritionally deprived patients.

A commonly used thiamine regimen is 100 mg intravenously every eight hours (Foster et al.). European guidelines recommend administration of 500 mg of thiamine intravenously three times daily for two consecutive days. Where there is no response, treatment may be discontinued after two or three days. Where an effective response is observed, 250 mg of thiamine should be given intravenously or intramuscularly once daily for an additional three to five days or until clinical improvement ceases. Donnino et al. recommended increasing the thiamine dose to 500 mg intravenously if the patient "fails" the 100 mg regimen. Nonetheless, since the data is insufficient to make a definite dosage recommendations, clinical judgment should be exercised in all cases.

For patients in whom there is low suspicion of WE or for those who require prophylaxis, 100 mg of thiamine per day should be administered intravenously. Prophylactic treatment with thiamine is recommended for all high-risk patients.

After discharge, oral thiamine supplementation of 100 mg daily should be continued for several months.

A. Immediate management.

WE is a medical emergency that requires immediate administration of IV thiamine. Current guidelines promote high-dose regimens.

B. Physical Examination Tips to Guide Management.

Most patients respond in a predictable manner to the administration of thiamine; a patient's failure to do so raises doubts about the diagnosis. Ocular signs tend to improve within hours; horizontal nystagmus may disappear in minutes; abducens palsy, ptosis, and vertical gaze palsies recover within a week; ataxia begins to improve within a week; and the state of global confusion typically improves within hours or days.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

None

D. Long-term management.

Long-term management of WKS involves a balanced diet and supplementation with B vitamins, as the patient is usually deficient in more than thiamine alone.

E. Common Pitfalls and Side-Effects of Management

The initial dose of thiamine is always given before or simultaneously with infusion of dextrose. Most patients will present to the emergency department, and this approach should not be forgotten in patients with hypoglycemia.

Thiamine is usually dissolved in 100 milliliters of normal saline or 5 percent glucose and infused over a period of thirty minutes. The overall safety profile is excellent, although Wrenn et al. reported prurtius and transient local irritation. Anaphylactoid reaction is extremely rare.

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

Give prophylactic thiamine supplementation.

G. Immunosuppression (HIV, chronic steroids, etc).

Give prophylactic thiamine supplementation.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

Thiamine storage is impaired in patients who abuse alcohol, who have malabsorption or persistent vomiting, and after gastrointestinal (GI) surgeries. Parenteral administration of thiamine may be necessary. Give prophylactic thiamine supplementation.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

Give prophylactic thiamine supplementation.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Monitor for resolution of confusion and ocular signs in response to thiamine administration.

B. Anticipated Length of Stay.

Length of stay depends on response to therapy--ideally, less than one week.

C. When is the Patient Ready for Discharge.

The patient is ready for discharge when he or she is able to ambulate and care for himself or herself or when appropriate home support or placement has been arranged.

D. Arranging for Clinic Follow-up

Patients should follow up with primary care physician in one or two weeks. The need for additional clinic follow-up is dictated by ocular, neurological, or mental impairment.

1. When should clinic follow up be arranged and with whom.

The patient should follow up with neurology, ophthalmology, primary care, and psychiatry.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

None.

E. Placement Considerations.

At least 25 percent of patients with Korsakoff's amnestic state require long-term institutionalization. Consultations with physical therapy, a social worker, and a dietitian are warranted prior to discharge.

F. Prognosis and Patient Counseling.

Prospective studies (mainly on alcoholics) have estimated that WE leads to Korsakoff's psychosis in 80-85 percent of patients. Approximately half of the patients with ataxia recover incompletely. In 60 percent of cases, a fine horizontal nystagmus remains as a permanent sequela. Full resolution of WKS occurs in only 14-49 percent of cases. Recovery from Korsakoff's amnestic state occurs in less than 20 percent of patients.

Patients should be counseled on quitting drinking.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

None.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients with alcoholism and hepatic encephalopathy have a high risk of WE. When admitted, they might benefit from two to three days of treatment with parenteral thiamine to replete storage.

VI. What's the Evidence?

Donnino, MW, Vega, J, Miller, J, Walsh, M. "Myths and misconceptions of Wernicke's encephalopathy: what every emergency physician should know". Ann of Emer Med. vol. 50. 2007. pp. 715-721.

Kumar, N. "Neurologic presentations of nutritional deficiencies". Neurol Clin. vol. 28. 2010. pp. 107-170.

Latt, N., Dore, G.. "Thiamine in the treatment of Wernicke encephalopathy in patients with alcohol use disorders". Int medicine Journal. vol. 44. 2014. pp. 911-915.

Sechi, GP, Serra, A. "Wernicke's encephalopathy: new clinical settings and recent advances in diagnosis and management". Lancet Neurol. vol. 6. 2007. pp. 442-455.

Singh, S, Kumar, A. "Wernicke encephalopathy after obesity surgery". Neurology. vol. 68. 2007. pp. 807-811.

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