Approach Considerations
Wernicke-Korsakoff syndrome (unlike acute Wernicke encephalopathy) is often a long-term condition. It should be treated aggressively as Wernicke encephalopathy in the acute setting, but with the understanding that it is rare for the Korsakoff amnestic state to fully reverse with treatment. After a course of treatment with high-dose parenteral thiamine and reversal of the acute effects of Wernicke encephalopathy, if there is no improvement in the Korsakoff amnestic state or other mental status abnormalities for 7 days, then a strategy of secondary harm prevention should be pursued. This includes maintenance with oral thiamine to prevent further insult, as well as consideration for rehabilitation, treatment of comorbid deficiencies and medical conditions, and consideration of the need for long-term residential care or supportive accommodation.
Dosing
Traditional regimens in the United States have used 100 mg of parental (intravenous or intramuscular) thiamine for 3-7 days (treatment period), followed by oral thiamine indefinitely as long as the patient is consuming alcohol. Because of case reports suggesting that much higher doses are needed (up to 1 g of parental thiamine) to obtain resolution of symptoms, some authorities such as the Royal College of Physicians have suggested 500 mg intravenously 3 times a day for 2-3 days. [47] If no response is noted, discontinue supplementation and assess for supportive care (unless the patient is comatose). If there is a partial response, continue at 250 mg parenterally for 5 days or as long as improvement continues in patients with neuropsychiatric symptoms. [2, 30]
Use of high-dose thiamine (500 mg TID intravenously) may be indicated given the detrimental consequence of untreated or undertreated WKS. A response to high-dose thiamine was reported as last as 30 days after initial recognition and treatment with thiamine at 100mg/day IV. [48] Monitoring of thiamine levels after treatment may be useful in guiding both route of administration and dosing.
After the patient’s response has plateaued, supplement with oral thiamine indefinitely until the patient is no longer at risk (eg, as long as they are drinking alcohol).
Absorption
Most recommendations for the initial use of parental thiamine are based on the poor bioavailability of oral thiamine, which is estimated to be between 3.7% and 5.3%. [49] Studies have suggested that 8.3 mg is the maximum that can be absorbed from a single oral thiamine dose, suggesting an absorption pathway that is easily saturated. [50] This seemed to be confirmed when another study showed very little thiamine is excreted in urine when oral doses greater than 2.5 mg are given. [51]
The most prominent study was in 52 prisoners of war in a report published in 1947. All developed Wernicke-Korsakoff syndrome during a period of starvation and/or nutritional deficiency (eg, living on white rice). Fifteen patients were treated with oral thiamine only and 67% (10 patients) died. Of the 37 who received intramuscular thiamine, 11 died, a mortality rate of 30%. [52]
Recent studies have challenged this and demonstrated that high-dose oral thiamine (500-1500 mg) can achieve correspondingly high blood levels in healthy subjects. [53] However, these studies have generally been in healthy subjects without comorbidities and no measurement has been made of the biological effect or tissues absorption of thiamine, especially in the brain. Until clinical studies have been undertaken on high-dose oral thiamine, the strong recommendation is that parental thiamine be the first line for the initial treatment of Wernicke-Korsakoff syndrome.
Adverse reactions
Allergic/anaphylactic reactions to thiamine do occur, but it does not appear to be at a rate to justify specific concern, despite a case report in the nursing literature that appears to have impacted many hospital protocols for thiamine administration. One paper reported more than 300,000 patients treated with parental thiamine without anaphylaxis. [54]
The Royal College of Physician guidelines recommend that intravenous thiamine be given over 30 minutes. This usually involves adding the thiamine to intravenous rehydration solutions, often with a parenteral multivitamin (banana bag). However, this is an empiric recommendation and is not followed at all institutions.
Other considerations
Administration of intravenous glucose to patients who are severely malnourished can exhaust their supply of thiamine and precipitate Wernicke-Korsakoff syndrome. Thus, good practice demands administration of thiamine prior to or simultaneously with glucose infusion in patients at high risk for Wernicke-Korsakoff syndrome. However, emergency care for life-threatening hypoglycemia should not be withheld for thiamine administration.
Emergency psychiatric hospitalization and evaluation are indicated when the patient is having active psychotic symptoms that pose a danger to himself or herself or to others. Many such patients also meet the criteria of grave disability (ie, inability to provide basic needs, such as food and shelter). In such cases, however, the patient should generally be medically and neurologically stable prior to transfer to a psychiatric facility, where acute medical work-up and monitoring may be available (eg, IV access, neuroimaging, nutritionist, neurology consultation).
In most cases, patients with psychotic symptoms may require inpatient medical hospitalization and psychiatric consultation. Once medically stabilized, patients may need continued psychiatric care if severe psychotic symptoms persist.
In patients with comorbid acute alcohol withdrawal, treatment with IV/IM thiamine occurs concurrently with the indicated alcohol withdrawal procedures.
Other deficiencies
Supplementation of electrolytes, particularly magnesium and potassium (often low in people with alcoholism), may be required in addition to thiamine. Magnesium acts as a cofactor for many enzymes (eg, transketolase for the conversion of thiamine to thiamine pyrophosphate), and, therefore, its deficiency may lead to a refractory response to thiamine supplementation. [4] In patients who are chronically malnourished, the remainder of the B vitamins also should be supplemented with an intravenous or oral multivitamin supplement. In patients with clinical evidence of Wernicke-Korsakoff syndrome, vitamin B-12 levels should be measured.
Further inpatient care
Evaluation for progression or recovery from Wernicke-Korsakoff syndrome symptom complex is the primary reason for further inpatient care. Patients also require monitoring for alcohol withdrawal and the potential cardiac manifestations of Wernicke-Korsakoff syndrome (eg, congestive heart failure). Owing to the acuity of the confessional state and continued neuronal damage, inpatient treatment may be needed to ensure sufficient thiamine supplementation via either oral and parenteral routes.
Diet and Activity
A balanced diet should be resumed as early as possible. Vitamin and electrolyte supplementation should be adhered to in addition to a well-balanced diet initially. Supplementation can be tapered as the patient resumes normal intake and demonstrates symptomatic improvement.
Due to gait abnormalities, unassisted ambulation is discouraged during the initial phase of treatment. Patients may require physical therapy evaluation for gait assistance. Gait abnormalities may be permanent, depending on the severity at initial presentation and the timeliness of therapy.
Referral and Follow-Up Care
Long-term alcohol use is the most common etiology for Wernicke-Korsakoff syndrome, and abstinence provides the best chance for recovery. Referral to an alcohol recovery program should be part of the treatment regimen. Inpatient treatment versus outpatient rehabilitation depends on the needs of the individual and risks of relapse.
Recovering patients will require outpatient follow-up care to evaluate for continued progress or relapse. Patients with long-term alcoholism may benefit from further inpatient or outpatient rehabilitation, depending on the likelihood of compliance.
Patients should continue taking thiamine supplementation, as well as other vitamins and electrolytes, until a well-balanced diet can be maintained. Long-term supplementation may be required in patients who cannot maintain adequate nutritional intake, whether from noncompliance or the underlying disorder.
Deterrence and Prevention
Long-term alcohol use is the most common etiology for the development of Wernicke-Korsakoff syndrome. Abstinence from alcohol, in conjunction with thiamine replacement, provides the best chance for recovery. Refer patients for alcohol abuse counseling, community alcohol abuse treatment programs (eg, Alcoholics Anonymous and other consumer support programs), and couples/family therapy on an individual basis to deter future alcohol use and prevent future episodes of Wernicke-Korsakoff syndrome.
In patients at risk for malnutrition (eg, after gastric bypass surgery), appropriate thiamine and other B-vitamin supplementation should be taken in accordance with a nutritionist’s advice.
In emergency management of patients with acute confusion and concurrent risk factors (eg, alcohol dependence and malnutrition), thiamine administration should be strongly considered, especially prior to glucose administration. [55] Generally, high-carbohydrate diets increase the demand for thiamine. [2] Immediate intravenous thiamine supplementation is the standard of care in ER patients with alcohol use disorders and withdrawal, and should be strongly considered in anyone with malnutrition.
In a large, prospective study, the introduction of thiamine-enriched bread flour was shown to reduce the prevalence of Wernicke-Korsakoff syndrome in Australia. [56] However, whether thiamine fortification in general or additional supplementation in alcoholic beverages could reduce Wernicke-Korsakoff syndrome has not been systematically studied.
Neuropsychological Testing and Rehabilitation
After the acute clinical symptoms stabilize and adequate thiamine supplementation is established, persistent cognitive symptoms will likely stabilize and plateau. Neuropsychological testing should be considered in patients with persistent cognitive symptoms to delineate the various cognitive domains that are impaired. Most commonly, declarative memory, immediate recall, attention and concentration, and executive function are impaired. [57] Procedural learning and memory rehabilitation can be employed to help the patient compensate for certain cognitive deficits to improve quality of life and overall functional improvement. [58]
