on 21-Feb-2022 (Mon)

Wernicke-Korsakoff syndrome is the best known neurologic complication of thiamine (vitamin B1) deficiency [1]

Wernicke encephalopathy (WE) is an acute syndrome requiring emergent treatment to prevent death and neurologic morbidity. Korsakoff syndrome (KS) refers to a chronic neurologic condition that usually occurs as a consequence of WE.

In 1881, Carl Wernicke described an acute encephalopathy characterized by mental confusion, ophthalmoplegia, and gait ataxia and associated it with autopsy findings of punctate hemorrhages around the third and fourth ventricles and the aqueduct. A few years later, Russian psychiatrist Sergei Korsakoff described a chronic amnestic syndrome in which memory was impaired far out of proportion to other cognitive domains.

While cases of WE in men outnumber those in women, women appear to be more susceptible to developing WE than men. In several series, the female-to-male ratio for WE was higher than the ratio for alcohol dependence [1,7].

Associated conditions — While most often associated with chronic alcoholism, WE occurs also in the setting of poor nutrition caused by malabsorption, poor dietary intake, increased metabolic requirement (eg, during systemic illnesses), or increased loss of the water-soluble vitamin thiamine (eg, in renal dialysis). In one autopsy series, non-alcohol abusers accounted for 12 of 52 cases (23 percent) of WE [8].

Conditions associated with WE include:

● Chronic alcoholism

● Anorexia nervosa or other psychiatric illness leading to poor intake [9,10]

● Hyperemesis of pregnancy [11,12]

● Prolonged intravenous (IV) feeding without proper supplementation [13,14]

● Prolonged fasting or starvation, or unbalanced nutrition, especially with refeeding [15]

● Gastrointestinal disease or surgery (especially bariatric surgery) [10,13,16-21]

● Systemic malignancy [22-24]

● Transplantation [25]

● Hemodialysis or peritoneal dialysis [26-28]

● Acquired immunodeficiency syndrome [29-31]

Thiamine is a cofactor for several key enzymes important in energy metabolism, including transketolase, alpha-ketoglutarate dehydrogenase, and pyruvate dehydrogenase [1]. Thiamine requirements depend on metabolic rate, with the greatest need during periods of high metabolic demand and high glucose intake. This is manifest by the precipitation of WE in susceptible patients by administration of intravenous (IV) glucose before thiamine supplementation [33].

In some cases, low levels of magnesium, an essential cofactor of thiamine into its active diphosphate and triphosphate forms, have been implicated with thiamine deficiency in WE [36].

Because of the role of thiamine in cerebral energy utilization, it has been proposed that its deficiency initiates neuronal injury by inhibiting metabolism in brain regions with high metabolic requirements and high thiamine turnover

Thiamine deficiency in alcohol abusers results from a combination of inadequate dietary intake, reduced gastrointestinal absorption, decreased hepatic storage, and impaired utilization [38].

Neuronal loss is most prominent in the relatively unmyelinated medial thalamus [1,50]. Atrophy of the mamillary bodies is a highly specific finding in chronic WE and Korsakoff syndrome (KS) and is present in up to 80 percent of cases [1,51].

Classic signs — The classic triad of WE includes:

● Encephalopathy

● Oculomotor dysfunction

● Gait ataxia

Large case series, some with neuropathological data, have found that all features of the classic triad are present in only approximately one-third of patients; in most, only one or two elements of the clinical triad were apparent [1,10].

Clinical records documented a high incidence of mental status abnormalities (82 percent), but much lower incidences of ataxia (23 percent), ocular motor abnormalities (29 percent), and polyneuropathy (11 percent).

The symptoms may present more or less simultaneously. Often, however, ataxia precedes other symptoms by a few days or weeks [1].

Encephalopathy – The encephalopathy is characterized by profound disorientation, indifference, and inattentiveness [1]. If these are less severe and permit higher cognitive testing, impaired memory and learning are also evident

Oculomotor dysfunction – Nystagmus, lateral rectus palsy, and conjugate gaze palsies reflect lesions of the oculomotor, abducens, and vestibular nuclei. Ocular abnormalities usually occur in combination rather than alone.

Nystagmus is the most common finding and is typically evoked by horizontal gaze to both sides [1]. Vertical nystagmus can also occur, usually an upbeat nystagmus at initial presentation, though it may convert later to a downbeat nystagmus [54]

Lateral rectus palsy is virtually always bilateral. Vertical gaze palsies are less common than conjugate gaze palsies, and isolated vertical gaze palsy, internuclear ophthalmoplegia, and complete ophthalmoplegia are rare

Pupillary abnormalities, usually sluggish or unequal pupils, may be present. A light-near dissociation is sometimes seen.

Ataxia primarily involves stance and gait and is likely due to a combination of polyneuropathy, cerebellar involvement, and vestibular dysfunction [1,55]. When severe, walking is impossible. Less affected patients walk with a wide-based gait and slow, short-spaced steps. Gait abnormalities are appreciated only on tandem gait in some patients.

Cerebellar pathology is generally restricted to the anterior and superior vermis; thus, ataxia of the legs or arms and dysarthria or scanning speech are uncommon [1].

Vestibular dysfunction may be the major cause of acute gait ataxia in WE, also explaining the dissociation between gait and limb abnormalities [ 1,55,56]. These findings contrast with those reported in patients with alcoholic cerebellar degeneration, in whom lower extremity ataxia is common [57].

Other signs — In addition to the classic triad, stupor or coma, hypotension, and hypothermia were prominent findings in unsuspected cases [52].

Peripheral neuropathy is common and typically involves just the lower extremities [1]. Patients complain of the gradual onset of weakness, paresthesias, and pain affecting the distal lower extremities. In many patients there are no symptoms of neuropathy, but examination reveals diminished or absent ankle jerks and distal sensory loss.

Lesions in the posterior and posterolateral hypothalamus were noted in two patients with WE and hypothermia in one report [62]. This location is consistent with the known thermoregulatory functions of the hypothalamus. Other signs of autonomic involvement may include hypotension and syncope. In one autopsy series, hypotension and hypothermia were prevalent in unsuspected cases of WE [52].

While overt beriberi heart disease is rare in WE, other cardiovascular signs and symptoms are common and include tachycardia, exertional dyspnea, elevated cardiac output, and electrocardiogram (EKG) abnormalities [1]. These reverse with thiamine administration.

Differential diagnosis — WE should be considered in the differential diagnosis of all patients presenting with acute delirium or acute ataxia. It follows that other causes of delirium are considered in the diagnosis of a patient presenting with WE (table 1).

Also, structural diseases in the medial thalami, hippocampi, or inferior medial temporal lobes should be considered because of the neuroanatomic overlap with WE. These include top-of-the-basilar stroke, hypoxic-ischemic encephalopathy after cardiac arrest, herpes simplex encephalitis, and third ventricular tumors [66,67].

Suggested criteria for the diagnosis of WE and Korsakoff syndrome (KS) in chronic alcohol abusers are based upon clinical-neuropathological correlation [3,68]. WE is diagnosed in patients with two of the following four Caine criteria:

● Dietary deficiency

● Oculomotor abnormalities

● Cerebellar dysfunction

● Either altered mental status or mild memory impairment

In one study of 106 autopsied alcohol abusers, the Caine criteria increased the diagnostic sensitivity for WE from 22 percent, using the classic triad, to 85 percent [68]. The Caine criteria are clearly more sensitive than the classic triad, but given the high morbidity and mortality associated with the disorder, they are not sensitive enough. Specificity is low, and these criteria were not intended to apply to nonalcoholics in whom the diagnosis is further impeded by a lower index of suspicion.

The sensitivity and specificity of these blood tests in symptomatic patients are unclear, as blood level may not accurately reflect brain thiamine level. A normal blood level does not exclude the possibility of WE [72].

Laboratory testing — There are no laboratory studies that are diagnostic of WE. Thiamine deficiency can be most reliably detected by measurement of erythrocyte thiamine transketolase activity (ETKA) before and after the addition of thiamine pyrophosphate (TPP).

Fortunately, intravenous (IV) administration of thiamine is safe, simple, inexpensive, and effective [3,96]. Adverse reactions, including anaphylaxis and bronchospasm, are reported but are extremely rare; in the United Kingdom, there were four reported cases for every five million intramuscular (IM) doses used and one report for every one million IV doses used [97-100].

Patients with suspected WE require immediate parenteral administration of thiamine. A recommended regimen is 500 mg of thiamine IV infused over 30 minutes three times daily for two consecutive days and 250 mg IV or IM once daily for an additional five days, in combination with other B vitamins [98].

Because gastrointestinal absorption of thiamine is erratic in alcoholic and malnourished patients, oral administration of thiamine is an unreliable initial treatment for WE [ 38]. High-dose parenteral thiamine therapy is justified based on the failure of lower doses to produce clinical improvement in some patients with WE; however, there are no randomized studies to support a particular dosing regimen [97,98,100-102].

Administration of glucose without thiamine can precipitate or worsen WE; thus, thiamine should be administered before glucose.

Daily oral administration of 100 mg of thiamine should be continued after the completion of parenteral treatment and after discharge from the hospital until patients are no longer considered at risk. Magnesium and other vitamins are replaced as well, along with other nutritional deficits if present.

or practical purposes, all at-risk patients with undiagnosed altered mental status, oculomotor disorders, or ataxia should receive parenteral thiamine.

Prompt administration of thiamine leads to improvement in ocular signs within hours to days [1]. If ocular palsies fail to respond, other diagnoses should be considered. In one report, recovery of vestibular function began during the second week after thiamine treatment; improvement in gait ataxia coincided with recovery of vestibular function [55]. Confusion subsides over days and weeks. Signal abnormality on magnetic resonance imaging (MRI) resolves with clinical improvement [90,104]. This early therapeutic response likely represents the recovery from a biochemical rather than a structural lesion.

As an example, patients admitted for alcohol withdrawal should receive thiamine 100 to 250 mg daily, depending on their nutritional status and perceived risk of WE.

Many of the vitamin deficiency diseases, such as scurvy (vitamin C), beriberi (thiamine), and pellagra (niacin), have been almost completely eliminated in resource-rich countries except in occasional patients with underlying medical disorders or highly restricted diets.

Thiamine (also written as thiamin, and also known as vitamin B1) serves as a catalyst (coenzyme required for the catalysis) in the conversion of pyruvate to acetyl coenzyme A (CoA) and is involved in many other cellular metabolic activities, including the tricarboxylic acid (TCA) cycle [3]. In addition, it participates in initiation of nerve impulse propagation.

Thiamine deficiency causes clinical phenotypes of beriberi and Wernicke-Korsakoff syndrome.

Thiamine is primarily found in foods such as yeast, legumes, pork, brown rice, and cereals made from whole grains. However, thiamine is very low in white ("polished" rice) or milled white cereals including wheat flour because the processing removes thiamine [4].

The thiamine molecule is denatured at high pH and high temperatures. Hence, cooking, baking, and canning of some foods as well as pasteurization can destroy thiamine. Milk products, fruits, and vegetables are poor sources of thiamine.

Thiamine deficiency is most commonly reported in populations in which the diet consists mainly of polished rice or milled white cereals, including some refugee populations [ 5].

Thiamine is absorbed in the small intestine via both active transport and passive diffusion. The maximal absorption of thiamine is in the jejunum and ileum [3].

The highest concentrations are found in the skeletal muscles, the liver, the heart, the kidneys, and the brain. Thiamine's biologic half-life is approximately 10 to 20 days; due to limited tissue storage, continuous intake is required to maintain normal markers for thiamine sufficiency [6-9].

Thiamine has an unidentified role in the initiation of nerve impulse propagation that is independent of its coenzyme functions. Accordingly, thiamine deficiency is associated with neuropathy, known as beriberi neuropathy, or dry beriberi. There are several proposed mechanisms. Thiamine has an important role in synthesis of glutamate and γ-aminobutyric acid as well as myelin sheath maintenance [14]. Thiamine also appears to promote cholinergic and serotonergic nerve conduction and synaptic axonal transmission [15,16]. Mechanism of thiamine deficiency-induced neuropathy is likely in part related to impairment of these processes.

Most laboratories now measure blood thiamine concentration directly, in preference to the erythrocyte thiamine transketolase activity (ETKA) method described below [17]. However, this has limited sensitivity and specificity in severe acute conditions because it may be falsely reduced during systemic inflammation [18]. The normal range for blood thiamine concentration varies somewhat among laboratories but is approximately 70 to 180 nmol/L (3.0 to 7.7 mcg/dL) [19,20]. Interpretation of thiamine levels may be further confounded in the presence of hypoalbuminemia. This has not been well studied.

ETKA – This is a functional test and results are influenced by the hemoglobin concentration. In patients with subclinical thiamine deficiency, ETKA levels are low and increase by 10 to 25 percent when stimulated in vitro with TPP [3,7].

Beriberi in infants becomes clinically apparent between the ages of two and three months and mainly affects infants who are breastfed by women with a thiamine-deficient diet [5]. The clinical features are variable and may include a fulminant cardiac syndrome with cardiomegaly, tachycardia, a loud piercing cry, cyanosis, dyspnea, vomiting and pulmonary hypertension [22-24]. Older infants may have neurologic symptoms resembling aseptic meningitis, including agitation, an aphonic (soundless) cry, vomiting, nystagmus, purposeless movements, altered consciousness, and seizure, with no abnormalities on cerebrospinal fluid analysis [18,25,26].

Adult beriberi — Beriberi in adults has two clinical phenotypes, described as "dry" or "wet." Dry beriberi is the development of a symmetrical peripheral neuropathy characterized by both sensory and motor impairments, mostly of the distal extremities. Wet beriberi includes signs of cardiac involvement with cardiomegaly, cardiomyopathy, heart failure, peripheral edema, and tachycardia, in addition to neuropathy [4].

A number of studies have suggested that subclinical thiamine deficiency is common among hospitalized patients with heart failure, especially if they are treated with loop diuretics; some of these studies also report improvement in left ventricular function after thiamine supplementation [34-38]. However, this remains controversial because of subsequent studies suggesting lower frequencies of subnormal thiamine levels among stable patients with heart failure [39,40] as well as questions involving assay validity [41].

Treatment for beriberi in adults typically starts with parenteral administration of thiamine if the patient is critically ill (5 to 30 mg/dose, three times daily for several days), followed by oral thiamine, 5 to 30 mg/day. Higher doses of thiamine (similar to those used for Wernicke-Korsakoff syndrome) may be used and are safe but do not appear to provide additional benefit.

Toxicity — No syndrome of excess thiamine has been identified. It is believed that toxic levels are unlikely because the kidneys can rapidly clear almost all excess thiamine and because (like most water-soluble vitamins) thiamine is not stored [2]. The biologic half-life of thiamine in humans is approximately 10 to 20 days [6].

VITAMIN B3 (NIACIN) — Niacin (nicotinic acid and nicotinamide) is an essential nutrient involved in the synthesis and metabolism of carbohydrates, fatty acids, and proteins.

Niacin deficiency causes pellagra, which is characterized by a photosensitive pigmented dermatitis (typically located in sun-exposed areas), diarrhea, and dementia, and may progress to death; the "4 Ds" serves as a mnemonic for the manifestations of niacin deficiency [ 68,69].

Niacin is widely distributed in plant and animal foods. Good sources include yeast, meats (especially liver), grains, legumes, corn treated with alkali (as in corn used in tortillas), and seeds [3]

It is possible to maintain adequate niacin status on a high-protein diet (eg, protein intake of 100 g/day) since tryptophan can be converted to a niacin derivative in the liver. However, it requires approximately 60 mg of tryptophan to produce 1 mg of niacin, and this process requires vitamin B6 (pyridoxine), with significant individual variation [3,70].

Niacytin is the primary form of niacin found in mature grains, and it is nutritionally unavailable because it is bound in a complex with hemicellulose. The niacin can be released from the grain by soaking and cooking in an alkaline solution, known as nixtamalization [71].

Through a passive process, niacin is rapidly taken up by the liver, kidneys, and erythrocytes. Additionally, a portion of dietary tryptophan can be converted into nicotinamide in the liver. This conversion, which is widely variable in humans, provides a significant portion of niacin needs [70,73]. Interruptions in this conversion, such as medications, may cause overt pellagra (see 'Deficiency (pellagra)' below).

Pellagra (meaning "raw skin") is characterized by a photosensitive pigmented dermatitis (typically located in sun-exposed areas), diarrhea, and dementia

In the United States and other resource-rich countries, pellagra tends to occur in alcoholics and has been reported as a complication of bariatric surgery, anorexia nervosa, or malabsorptive disease [ 77,78].

Pellagra due to dietary deficiency can still be seen in resource-limited countries where the bulk of the local diet consists of untreated corn or sorghum. This is because niacin bioavailability, and therefore its absorption, is poor unless corn is treated with alkali, as in the process of preparing tortillas (nixtamalization) (see 'Sources' above). These diet characteristics are found in India, parts of China, and Africa. In Central America and Mexico, where treated corn in the form of tortillas is a staple of the local diet, pellagra is rare.

The most characteristic finding of pellagra is the presence of a symmetric hyperpigmented rash, similar in color and distribution to a sunburn, which is present in the exposed areas of skin. Dermatitis in the sun-exposed area of the neck gives a characteristic appearance that has been called "Casal necklace" (picture 2) [79]. Other clinical findings are a red tongue and many nonspecific symptoms, such as diarrhea and vomiting. Neurologic symptoms include insomnia, anxiety, disorientation, delusions, dementia, and encephalopathy (table 3).

Niacin deficiency can also be seen in three other settings:

● Carcinoid syndrome, in which metabolism of tryptophan is to 5-OH tryptophan and serotonin rather than to nicotinic acid. This leads to the deficiency of active forms of niacin and the development of pellagra. (See "Clinical features of carcinoid syndrome".)

● Prolonged use of isoniazid since isoniazid depletes stores of pyridoxal phosphate, which enhances the metabolism of tryptophan into niacin. Several other drugs induce niacin deficiency by inhibiting the conversion of tryptophan to niacin, including fluorouracil, pyrazinamide, 6-mercaptopurine, hydantoin, ethionamide, phenobarbital, azathioprine, and chloramphenicol [80].

● Hartnup disease (MIM #234500)

Toxicity — The best established side effect of niacin is the flushing reaction associated with the crystalline nicotinic acid and not nicotinamide [83]. Symptoms are dose-dependent yet variable from person to person. The flushing can be experienced in a mild form while taking doses as small as 10 mg/day [84]. Despite the inconvenience and the undesirability of the reactions, there are no serious sequelae from flushing [83].

In pharmacologic doses (eg, 1000 to 3000 mg/day), common side effects of niacin are flushing, nausea, vomiting, pruritus, hives, elevation in serum aminotransferases [85], and constipation.

Caution should be used in patients with a history of gout since niacin is also known to elevate serum uric acid concentration.

The above side effects are most common and severe when niacin is administered in doses of 2000 to 6000 mg/day [84]. At such high doses, the hepatic metabolism becomes saturated and side effects of this drug can be more frequently encountered. A niacin-induced myopathy has also been described in a patient taking doses of 3000 mg/day [88]. Liver dysfunction and fulminant hepatitis also have been reported [2,87,89,90].

Vitamin B6 consists of pyridoxine, pyridoxamine, pyridoxal, and the phosphorylated derivative of each of these compounds. Overt deficiency of vitamin B6 is probably rare, and the primary manifestations are dermatitis, glossitis, and microcytic anemia. Vitamin B6 toxicity manifests with a peripheral neuropathy, dermatoses, photosensitivity, dizziness, and nausea.

Sources — Pyridoxine and pyridoxamine are predominantly found in plant foods; pyridoxal is most commonly derived from animal foods. Meats, whole grains, vegetables, and nuts are the best sources. Cooking, food processing, and storage can reduce vitamin B6 availability by 10 to 50 percent [105,106].

Actions – Pyridoxal phosphate is used for Schiff base formation during the transamination of amino acids, a key step in gluconeogenesis. Pyridoxal phosphate is also involved in decarboxylation of amino acids, a key reaction in the conversion of tryptophan to niacin, heme synthesis, sphingolipid biosynthesis, neurotransmitter synthesis, immune function [107], and steroid hormone modulation.

Deficiency — Overt deficiencies of vitamin B6 are probably rare. Marginal deficiencies may be more common, manifested as nonspecific stomatitis, glossitis, cheilosis, irritability, confusion, and depression, and possibly peripheral neuropathy (table 3) [3,110]. Severe deficiency is associated with seborrheic dermatitis, microcytic anemia, and seizures [3].

Certain drugs are associated with vitamin B6 insufficiency because they interfere with pyridoxine metabolism, including isoniazid, penicillamine, hydralazine, and levodopa/carbidopa [110,112].

Cystathionine synthase is a PLP-dependent enzyme, which produces cystathionine from serine and homocysteine. As a result, vitamin B6 insufficiency can lead to elevations in plasma homocysteine concentrations, a risk factor for the development of atherosclerosis and venous thromboembolism [ 113]. (See "Overview of homocysteine".)

Toxicity — Cases of peripheral neuropathy, dermatoses, photosensitivity, dizziness, and nausea have been reported with long-term megadoses of pyridoxine over 250 mg/day; a few cases of neuropathy appear to have been caused by chronic intake of 100 to 200 mg/day [114-116]

ally the reverse of the chain rule for differentiation

rearrange the integrand as a function of something times the derivative of that same something,