Wernicke-Korsakoff Syndrome (WKS) classically, but not always, presents with the clinical triad of confusion, ataxia, and nystagmus

DESCRIBE IN DETAIL THE WERNICKE KORSAKOFF SYNDROME ?

A 5 INTRODUCTION

1 Wernicke-Korsakoff Syndrome (WKS) classically, but not always, presents with the clinical triad of confusion, ataxia, and nystagmus.

2 It is best conceptualized as 2 distinct syndromes, with one being characterized by an acute/subacute confusional state and often reversible findings of Wernicke encephalopathy (a type of delirium) and the other by persistent and irreversible findings of Korsakoff dementia.

3 In 1881, Carl Wernicke first described an illness that consisted of paralysis of eye movements, ataxia, and mental confusion, in 3 patients.

A ) The patients, 2 males with alcoholism and a female with persistent vomiting following sulfuric acid ingestion, exhibited these findings, developed coma, and eventually died.

B ) On autopsy, Wernicke detected punctate hemorrhages affecting the gray matter around the third and fourth ventricles and aqueduct of Sylvius. He felt these to be inflammatory and therefore named the disease polioencephalitis hemorrhagica superioris.

C ) Sergei Korsakoff, a Russian psychiatrist, described the disturbance of memory in the course of long-term alcoholism in a series of articles from 1887-1891.

1 He termed this syndrome psychosis polyneuritica, believing that these typical memory deficits, in conjunction with polyneuropathy, represented different facets of the same disease.

D ) In 1897, Murawieff first postulated that a single etiology was responsible for both syndromes.

EPIDEMIOLOGY

The condition affects males slightly more frequently than it affects females.

Age of onset is evenly distributed from 30-70 years.

ETIOLOGY

1 A deficiency of thiamine (vitamin B-1) is responsible for the symptom complex manifested in Wernicke-Korsakoff syndrome, and any condition resulting in a poor nutritional state places patients at risk.

2 The structural lesions associated with Wernicke-Korsakoff syndrome are more likely to manifest in patients with malnutrition. However, it is crucial to recognize that Wernicke-Korsakoff syndrome also appears in patients without exposure to alcohol.

RISK FACTORS

The following are associated with Wernicke-Korsakoff syndrome:

1 Chronic alcoholism

A - There may be a synergistically destructive effect of alcohol and thiamine deficiency that contributes to the Wernicke-Korsakoff syndrome.

B ) Alcohol interferes with active gastrointestinal transport, and chronic liver disease leads to decreased activation of thiamine pyrophosphate from thiamine, as well as decreased capacity of the liver to store thiamine.

C ) Bariatric surgery - Wernicke encephalopathy can present as early as 2 weeks after surgery; recovery typically occurs within 3-6 months of initiation of therapy but may be incomplete if this syndrome is not recognized promptly and treated (the highest risk is in young women with vomiting)

D ) Nutritional deficiency and certain diets

E ) Starvation - Persons with anorexia nervosa, schizophrenia, or terminal cancer prisoners of war
Thiamine-deficient formula

F ) Hyperemesis gravidarum - In a study of 49 cases of Wernicke encephalopathy in pregnancy, pregnancy loss attributable to Wernicke encephalopathy was nearly 48%

G ) Gastric malignancy, inflammatory bowel disease
Intestinal obstruction, including abdominal abscess

H ) Plastic surgery - Panniculectomy

I ) Systemic diseases - Malignancy, disseminated tuberculosis, acquired immunodeficiency syndrome (AIDS), uremia, stem cell transplantation

J ) Iatrogenic - Intravenous hyperalimentation (without thiamine supplementation), refeeding after starvation, chronic hemodialysis

K ) Encephalitic infections or infarctions affecting the mammillary bodies or hippocampus Rare reports - Rare reports

L ) Infants breastfed by mothers with inadequate intake of thiamine

PATHOPHYSIOLOGY

1 Thiamine is absorbed from the duodenum.

2 The body has approximately 18 days of thiamine stores.

3 Thiamine is converted to its active form, thiamine pyrophosphate, in neuronal and glial cells.

4 Thiamine pyrophosphate serves as a cofactor for several enzymes, including transketolase, pyruvate dehydrogenase, and alpha ketoglutarate, that function in glucose use.

5 The main function of these enzymes in the brain is lipid (myelin sheath) and carbohydrate metabolism, production of amino acids, and production of glucose-derived neurotransmitters.

6 Thiamine appears to have a role in axonal conduction, particularly in acetylcholinergic and serotoninergic neurons.

SO , A reduction in the function of these enzymes leads to diffuse impairment in the metabolism of glucose in key regions of the brain, resulting in impaired cellular energy metabolism.

7 Within 2-3 weeks of decreased intake and thiamine depletion, areas of the brain with the highest thiamine content and turnover demonstrate cellular impairment and injury.

8 The earliest biochemical change is the decrease in α-ketoglutarate-dehydrogenase activity in astrocytes.

9 Acute thiamine deficiency leads to mitochondrial dysfunction and therefore oxidative toxicity in areas of the brain starting with areas with the highest metabolic activity. The exact mechanism of neuronal cell death remains to be elucidated.

10 Additional findings include increased astrocyte lactate and edema, increased extracellular glutamate concentrations, increased nitric oxide from endothelial cell dysfunction, deoxyribonucleic acid (DNA) fragmentation in neurons, free radical production and increase in cytokines, and breakdown of the blood-brain barrier.

11 Thiamine appears to have a role in acetylcholinergic and serotoninergic synaptic transmission and axonal conduction.

12 Symptoms of Wernicke-Korsakoff syndrome are attributed to these focal areas of damage.

13 Ocular motor signs are attributable to lesions in the brainstem affecting the abducens nuclei and eye movement centers in the pons and midbrain.

A ) These lesions are characterized by a lack of significant destruction to nerve cells, which accounts for the rapid improvement and degree of recovery observed with thiamine repletion.

B ) Ataxia is a manifestation of damage to the cerebellum, particularly the superior vermis.

C ) The cerebellar changes consist of a degeneration of all layers of the cortex, particularly the Purkinje cells.

D ) The loss of neurons leads to persistent ataxia of gait and stance.

E ) In addition to cerebellar dysfunction, the vestibular apparatus is also affected.

F ) In addition, chronic alcohol consumption results in a 35% decrease in transketolase activity within the cerebellum, which is likely due to thiamine deficiency.

G ) Vestibular paresis, confirmed by abnormal results on caloric testing, is observed in the early stages of disease and generally improves with treatment.

H ) The amnestic component is related to damage in the diencephalon, including the medial thalamus, and connections with the medial temporal lobes and amygdala.

I ) The slow and incomplete recovery of memory deficits suggests that amnesia is related to irreversible structural damage.

J ) McEntee and colleagues demonstrated decreased levels of a metabolite of norepinephrine (3-methoxy-4-hydroxyphenolglycol, or MHPG) in the cerebrospinal fluid (CSF) of some patients with Wernicke-Korsakoff syndrome.

1 They pointed out that the diencephalic lesions are located within monoamine-containing pathways.

2 Clonidine, an alpha-noradrenergic agonist, seemed to improve the memory disorder of their patients.

A ) They postulated that damage to these pathways may be the basis for the amnestic features of Wernicke-Korsakoff syndrome.

B ) Patients with permanent Korsakoff psychosis are not routinely treated with clonidine.

K ) Variants in the gene coding for the high-affinity thiamine transporter protein SLC19A2 in neurons may also contribute to the susceptibility of Wernicke-Korsakoff syndrome.

L ) Patients with a functional impairment in the ability to effectively transport thiamine may have impaired ability to cope with thiamine deficiency or respond to thiamine replacement.

M ) Vertical nystagmus may persist for months. Fine horizontal nystagmus may persist indefinitely in as many as 60% of patients, but patients completely recover from sixth nerve palsies, ptosis, and vertical-gaze palsies.

DIAGNOSIS

1 ACCORDING TO CAINE CRITERIA -

These criteria suggest that a diagnosis of Wernicke encephalopathy can be made if 2 of the following are present in a patient with chronic alcoholism:

1 Eye signs (ocular abnormalities as described above)

2 Cerebellar signs (ataxia as described above)

3 Mild memory impairment of confusion without another etiology

4 Signs of malnutrition on physical or laboratory exam

2 ACCORDING TO BRITISH ROYAL COLLEGE OF PHYSICIAN CRITERIA

are similar; they suggest treating everyone who has evidence of alcohol abuse and any one of the following:

1 Acute confusion

2 Decreased consciousness

3 Ataxia

4 Ophthalmoplegia

5 Memory disturbances

6 Hypothermia

7 hypotension

DIFFERENTIAL DIAGNOSIS - MAIN

1 Temporal lobe epilepsy

2 Temporal lobe infarction

3 Concussive head injury

4 Dementia with Lewy bodies

5 Transient global amnesia

6 Anoxic encephalopathy

7 Alzheimer disease

8 Third ventricle tumor

9 Herpes simplex virus

DIFFERENTIAL DIAGNOSIS - OTHERS

1 Alcohol-Related Psychosis

2 Alcoholism

3 Anorexia Nervosa

4 Delirium

5 Delirium Tremens (DTs)

6 Delusional Disorder

7 Hepatic Encephalopathy

8 Hypoglycemia

9 Hyponatremia

10 Postconcussive Syndrome Psychiatric Care

WORK UP / INVESTIGATIONS

1 Electrolytes - To rule out an acute metabolic derangement causing mental confusion
Lactic acidosis may occur as a result of thiamine deficiency and is often under-recognized. Supplementation with thiamine often leads to resolution of lactic acidosis

2 Magnesium level as it may explain impaired thiamine utilization

3 Complete blood count (CBC) - To rule out an acute infectious process, thrombocytosis, or erythrocytosis predisposing to thrombosis and infarction

4 Coagulation panel - To evaluate for a potential bleeding diathesis

5 Arterial blood gas - To evaluate for hypoxemia, hypercarbia, acidosis, or alkalosis

6 Serum/urine toxic drug screen - To rule out acute toxic ingestion; this is most helpful if results are available rapidly

7 Liver-associated enzymes - May provide evidence of alcohol abuse or liver dysfunction

8 Serum thiamine levels

1 Serum thiamine levels have been used in case reports to confirm Wernicke-Korsakoff syndrome. However, studies have not directly examined the correlation between a critical serum thiamine level and the development of neurologic symptoms and Wernicke-Korsakoff syndrome itself.

2 One small study did show that the serum thiamine level correlated well with cerebellar vermal atrophy.

3 For now, the role of serum thiamine levels remains uncertain, although it may eventually play a part in confirming the diagnosis of Wernicke-Korsakoff syndrome and/or monitoring adequacy of treatment.

9 Lumbar puncture/CSF analysis

A ) Seriously consider this procedure for any confused patient with fever and/or headache, particularly elderly patients, to rule out an infectious etiology.

B ) Patients with Wernicke-Korsakoff syndrome have a protein content that is within the reference range or mildly elevated without pleocytosis on CSF analysis.

10 Imaging Studies

A ) CT brain scan (noncontrast)

Computed tomography (CT) scanning can help in the rapid assessment for hemorrhage, mass effect, edema, and large, subacute stroke.

B ) MRI of the brain with contrast

1 MRI can be a useful confirmatory in cases in which there is a clinical suspicion or a diagnostic procedure in patients presenting with a suggestive history and stupor or coma, in whom ataxia and ophthalmoplegia are not detectable.

2 The possible diagnosis of Wernicke-Korsakoff syndrome should be communicated to the radiologists prior to ordering the scan to confirm that protocols suitable for the highest-yield imaging of the mammillary bodies, hippocampus, medial thalami, periaqueductal region, and the tectum of the midbrain are used.

3 While specificity of MRI findings is high, the sensitivity is not; one study reported 53%.

4 Nevertheless, early diagnosis of WKS using MRI (T2 and FLAIR hyperintensities) in typical locations (thalami, mammillary bodies, tectal plate, and peraqueductal area) and atypical locations (cerebellum, cranial nerve nuclei, and cerebral cortex) has been proposed.

5 As opposed to structural lesions and necrosis of the mammillary bodies, another study compared 9 patients with chronic Wernicke encephalopathy to 7 patients with Alzheimer disease and 37 controls.

6 They found that 78% of the chronic Wernicke patients had smaller mammillary bodies than 36 of 37 controls and 7 of 7 Alzheimer patients.

7 The decrease was not related to age or ventricular size and is consistent with previous reports of autopsy findings.

MANAGEMENT

1 PATIENT EDUCATION -

A ) In alcohol-related Wernicke-Korsakoff syndrome, abstinence from alcohol and maintenance of a balanced diet offer the best chance for recovery and prevention of future episodes.

B ) Patients who have undergone gastric bypass surgery are recommended to adhere to a balanced diet and continue vitamin supplementation.

2 FAMILY EDUCATION -

A ) Family education and support is an important component of taking care of anyone with a dementia illness, including Wernicke-Korsakoff syndrome.

B ) Patients with persistent dementia usually require 24-hour supervision, because they usually have poor insight into their illness and significant functional impairments in activities of daily living.

C ) Some patients with alcohol dependence may continue to prefer alcohol use, despite their cognitive deficits.

D ) In severe cases, private or public guardianships (or conservatorships) may need to be sought from the courts.

3 Dosing

1 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.

2 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.

3 If no response is noted, discontinue supplementation and assess for supportive care (unless the patient is comatose).

4 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.

5 Use of high-dose thiamine (500 mg TID intravenously) may be indicated given the detrimental consequence of untreated or undertreated WKS.

6 A response to high-dose thiamine was reported as last as 30 days after initial recognition and treatment with thiamine at 100mg/day IV.

7 Monitoring of thiamine levels after treatment may be useful in guiding both route of administration and dosing.

8 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).

9 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%.

A ) 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.

B ) 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.

C ) The most prominent study was in 52 prisoners of war in a report published in 1947.

D ) All developed Wernicke-Korsakoff syndrome during a period of starvation and/or nutritional deficiency (eg, living on white rice).

E ) 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%.

F ) Recent studies have challenged this and demonstrated that high-dose oral thiamine (500-1500 mg) can achieve correspondingly high blood levels in healthy subjects.

G ) 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.

H ) 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

1 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.

2 One paper reported more than 300,000 patients treated with parental thiamine without anaphylaxis.

3 The Royal College of Physician guidelines recommend that intravenous thiamine be given over 30 minutes.

4 This usually involves adding the thiamine to intravenous rehydration solutions, often with a parenteral multivitamin (banana bag).

5 However, this is an empiric recommendation and is not followed at all institutions.