Hemophilia and other coagulation disorders: neurologic aspects
Jun. 20, 2022
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The best characterized human neurologic disorders related to thiamine deficiency are beriberi, Wernicke encephalopathy, and Korsakoff syndrome. Thiamine deficiency is increasingly being recognized in nonalcoholics. Some neurologic complications following bariatric surgery are related to thiamine deficiency. The classic Wernicke encephalopathy triad of ocular abnormalities, gait ataxia, and mental status changes is infrequently seen. Prompt recognition and adequate therapy are key factors in improving prognosis.
• The best characterized human neurologic disorders related to thiamine deficiency are beriberi, Wernicke encephalopathy, and Korsakoff syndrome.
• Thiamine deficiency is increasingly being recognized in non-alcoholics.
• Thiamine deficiency should be considered as potential cause of neurologic deterioration in all critically ill patients.
• Early neurologic complications following bariatric surgery are related to thiamine deficiency.
• The classic Wernicke encephalopathy triad of ocular abnormalities, gait ataxia, and mental status changes is infrequently seen.
• Prompt recognition and adequate therapy are key factors in improving prognosis.
The best characterized human neurologic disorders related to thiamine deficiency are beriberi, Wernicke encephalopathy, and Korsakoff syndrome (also referred to as Korsakoff psychosis). Because of the close relationship between Wernicke encephalopathy and Korsakoff syndrome, the term Wernicke-Korsakoff syndrome is commonly used.
Beriberi has the distinction of being the first-identified human nutritional deficiency disorder. During the industrial revolution of the nineteenth century, introduction of milled rice was accompanied by epidemics of beriberi. Milling removes the husk, which is a rich source of thiamine; therefore, polished white rice is deficient in thiamine. A connection between the consumption of polished rice and beriberi was shown in the latter part of the nineteenth century. In the 1950s, universal thiamine enrichment of rice, grains, and flour products was undertaken. Wernicke encephalopathy was first described in 1881 by Carl Wernicke who described it as an acute superior hemorrhagic polioencephalitis (“polioencephalitis hemorrhagica superioris”) in 2 alcoholic men and a woman who developed recurrent vomiting due to pyloric stenosis related to sulphuric acid ingestion. In the 1940s it was established that Wernicke encephalopathy is caused by thiamine deficiency. The historical aspects of thiamine deficiency have been reviewed in detail in a publication (209).
Sources of thiamine. The highest concentrations of thiamine are found in yeast and in the pericarp of grain. Most cereals and breads are fortified with thiamine. Organ meats are a good source of thiamine; dairy products, seafood, and fruits are poor sources. Preterm breast milk is poorer in thiamine as compared to term breast milk (87). Cow’s milk and infant formula have a higher level of thiamine than human milk or evaporated milk formula (91). Prolonged cooking of food, baking of bread, and pasteurization of milk are all potential causes of thiamine loss. Thiamine does not occur in fats and oils.
Thiamine requirement. Thiamine requirement is related to the total caloric intake and proportion of calories provided as carbohydrates (225). A high caloric and high carbohydrate diet increases the demand for thiamine. According to the Food and Agriculture Organization and the World Health Organization, the recommended intake is 0.4 mg of thiamine per 1000 kcal; the Food and Nutrition Board recommends a daily allowance of 0.5 mg per 1000 kcals. The median intake of thiamine from food in the United States is approximately 2 mg/day. Thiamine requirement is also dependent on the body’s metabolic rate with the requirement being the greatest during periods of high metabolic demand. Thiamine requirements increase in children, during pregnancy and lactation, and with vigorous exercise. Increased requirements are also seen in hyperthyroidism, malignancy, systemic infections, and in the critically ill. In patients with a marginal nutritional status, the increased metabolic demand associated with these conditions can precipitate symptoms of thiamine deficiency.
Physiology. The terms vitamin B1 and thiamine are used interchangeably. At low concentrations, thiamine is absorbed in jejunum and ileum by an active, carrier-mediated, rate-limited process (267). At higher concentrations, absorption takes place by passive diffusion. Adequate blood thiamine levels can be rapidly achieved with high-dose oral thiamine (255). After gastrointestinal uptake, thiamine is transported by portal blood to the liver. Transport of thiamine across the blood-brain barrier occurs by both active and passive mechanisms (267; 159). Thiamine functions as a coenzyme in the metabolism of carbohydrates, lipids, and amino acids. It has a role in energy production by adenosine triphosphate synthesis, in myelin sheath maintenance, and in neurotransmitter production. Following cellular uptake, thiamine is phosphorylated into thiamine diphosphate, the metabolically active form that is involved in several enzyme systems (35; 171). Thiamine diphosphate is a cofactor for the pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase, and transketolase (35). Pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase are involved in the tricarboxylic acid cycle in oxidative decarboxylation of alpha-ketoacids such as pyruvate and alpha-ketoglutarate to acetyl CoA and succinate, respectively. Transketolase transfers activated aldehydes in the hexose monophosphate shunt (pentose-phosphate pathway) in the generation of nicotinamide adenine dinucleotide phosphate (NADPH) for reductive biosynthesis. Thiamine diphosphate may be further phosphorylated to thiamine triphosphate, which may activate high-conductance chloride channels and have a role in regulating cholinergic and serotonergic neurotransmission (19).
Thiamine deficiency affects the central nervous system, peripheral nervous system, and cardiovascular system (69; 230; 93; 147; 86; 214; 251; 136; 254). These may be involved in various combinations. The broad spectrum of clinical manifestations associated with thiamine deficiency has been referred to in the literature by the designation of thiamine deficiency disorders (254). Cardiac involvement may manifest as high-output or low-output cardiac failure. Neurologic involvement may manifest as beriberi, Wernicke encephalopathy, or Korsakoff syndrome, with or without an associated peripheral neuropathy. Wernicke encephalopathy often results from severe, short-term thiamine deficiency, whereas peripheral neuropathy is more often a consequence of prolonged mild to moderate thiamine deficiency (230). The symptoms and signs of thiamine deficiency depend on the clinical setting, patient’s age, and genetic susceptibility (230). It had also been suggested that the response to thiamine deficiency may be population-specific and may relate to transketolase deficiency (22). This has not been substantiated by subsequent studies (173). It has been suggested that Europeans develop a dry beriberi with polyneuropathy and Wernicke encephalopathy; Asians are more prone to developing a wet beriberi (22). The symptoms of subclinical thiamine deficiency are often vague and nonspecific and include fatigue, irritability, headaches, and lethargy (230).
Thiamine-responsive pyruvate dehydrogenase deficiency was reported in an adult with peripheral neuropathy and optic neuropathy (233). The following signs, often in combination, suggest pyruvate dehydrogenase complex deficiency: Leigh syndrome, fever-induced ataxia or weakness, polyneuropathy, and optic neuropathy. Thiamine responsive megaloblastic anemia syndrome is an uncommon autosomal recessive disorder due to mutations in SLC19A2, a thiamine transporter coding gene. It is characterized by diabetes mellitus and deafness in association with anemia. Cardiac conduction defects may be seen in some patients (15). Inadequate thiamine supplementation in these patients may precipitate ketoacidosis (148). Thiamine-responsive megaloblastic anemia should be considered in the differential diagnosis of diabetes presenting in the neonatal period (240). Mutations in SLC19A3 cause biotin–thiamine-responsive basal ganglia disease (09; 11). Afflicted children present with encephalopathy, and MRI shows striatal signal abnormalities.
Beriberi and thiamine deficiency neuropathy. The 3 forms of beriberi are dry beriberi, wet beriberi, and infantile beriberi. Dry beriberi is characterized by a sensorimotor, distal, axonal peripheral neuropathy often associated with calf cramps, muscle tenderness, and burning feet (199). Autonomic neuropathy may be present. Classic descriptions of beriberi have also reported hoarseness, and tongue and facial weakness. Pedal edema may be seen due to coexisting wet beriberi. Wet beriberi is associated with a high output congestive heart failure with peripheral neuropathy. This distinction is of limited significance as the wet form may be converted to the dry form after diuresis. Wet beriberi may coexist with Wernicke encephalopathy (201). The terms “wet” and “dry” beriberi have been used to describe the presence or absence of edema in neuropathic beriberi. “Shoshin” beriberi is the name given to a fulminant form that presents with tachycardia and circulatory collapse. Acute quadriplegia due to central-pontine myelinolysis has been reported in Shoshin beriberi (03). Infantile beriberi bears little resemblance to the adult form. It is seen in infants breastfed by mothers with thiamine deficiency or in infants fed on thiamine deficient diets. Infantile beriberi is seen between 2 and 12 months of age and may present with the cardiac, aphonic, or pseudomeningitic forms. Clinical features include cardiomyopathy, vomiting, diarrhea, failure to thrive, irritability, nystagmus, ophthalmoplegia, and respiratory symptoms (80). Refractory epilepsy has also been reported as a consequence of infantile thiamine deficiency (79). A report suggests 4 forms of infantile thiamine deficiency: a form associated with lactic acidosis wherein a history of reflux is followed by irritability and acidotic breathing; a form that presents with pulmonary arterial hypertension and has hoarseness and irritability; a form that resembles classic Wernicke encephalopathy; and a mixed presentation (218). The term gastrointestinal beriberi has been used to describe a primary gastrointestinal thiamine deficiency syndrome characterized by abdominal pain, vomiting, and lactic acidosis (66).
Alcoholic neuropathy is distinct from thiamine deficiency-related neuropathy (141; 138; 177). Alcoholic neuropathy is a slowly progressive, painful, predominantly sensory neuropathy with preferential involvement of small-fiber function. In contrast, thiamine deficiency-related neuropathy is often a more rapidly progressive, sensorimotor neuropathy with large-fiber predominant sensory loss. Thiamine deficiency has been reported to present with subacute sensory ataxia and optic neuropathy (256). Alcohol abuse and malnutrition can cause a severe acute axonal polyneuropathy that may mimic Guillain-Barré syndrome (292). Thiamine deficiency-related neuropathy can also mimic Guillain-Barré syndrome (139; 187; 76; 132; 184). Subperineurial edema may be more prominent in thiamine deficiency-related neuropathy, whereas segmental demyelination and remyelination resulting from widening of consecutive nodes of Ranvier may be more frequent in alcoholic neuropathy.
Wernicke encephalopathy. Wernicke encephalopathy related to alcoholism is more common in men. Wernicke encephalopathy related to bariatric surgery is more commonly reported in women. The clinical features of Wernicke encephalopathy include a subacute onset of the classic triad of ocular abnormalities, gait ataxia, and mental status changes (103; 219; 104; 38; 230; 93; 147). The onset may be gradual, and the classic triad is frequently absent. In one series the complete triad was seen in only 10% (104). Ophthalmoplegia was seen in 29% of patients and ataxia in only 23%. About 16% to 19% of patients have none of the manifestations related to the classic triad (273; 103; 104). One or more components of the triad do generally appear later in the course (281). Reliance on the described triad of ophthalmoplegia, ataxia, and confusion and not recognizing thiamine deficiency in nonalcoholics may result in missing the diagnosis (219). The diagnosis should be considered even if only one component of the classic triad is present. The presence of nonspecific or poorly recognized signs and symptoms also result in missing the diagnosis. Skin changes, tongue redness, and other features of chronic liver disease may be present. Rarely, a Marchiafava-Bignami type presentation characterized by interhemispheric disconnection and imaging evidence of callosal involvement has been reported with thiamine deficiency (131).
Ocular abnormalities include nystagmus (horizontal more common than vertical), ophthalmoparesis (commonly involving the lateral recti), and conjugate gaze palsies (usually horizontal) (195). Complete ophthalmoplegia is rare. Other reported findings include sluggish pupillary reactivity, anisocoria, miosis, light-near dissociation, optic neuropathy, central scotomas, and reduced visual acuity. Sudden bilateral blindness may occur and has been reported as a presenting manifestation (259). Retinal hemorrhages, papilledema, and macular edema have also been described (163; 210; 185; 167; 182; 281; 146; 53; 160; 44). A Miller Fisher syndrome-like presentation was noted in a patient with Wernicke encephalopathy (59).
The gait and trunk ataxia is a consequence of cerebellar and vestibular dysfunction. Vestibular dysfunction is an under-appreciated feature and may be demonstrable on caloric testing or with the head impulse maneuver (265; 94; 46). In some patients, the ataxia may be accompanied by dysarthria. A coexisting chronic peripheral neuropathy may be an additional contributing factor for the gait difficulty. Over 80% of patients may have an associated peripheral neuropathy. Also reported is an accompanying acute, rapidly progressive, peripheral neuropathy that may be misdiagnosed as Guillain-Barre syndrome (140; 117; 242). Proximal myopathy and fasciculations have been rarely reported along with the more classic manifestations of Wernicke encephalopathy (264). Mental status changes are the most constant component of the disease and include inability to concentrate, apathy, impaired awareness of the immediate situation, spatial disorientation, and confusion–including frank psychosis (219; 119; 294). Mental sluggishness and restless may be the earliest and rarely only manifestations (219). In some autopsy-confirmed cases of Wernicke encephalopathy, the only clinical manifestation was that of psychomotor retardation (37). If untreated, this can progress to stupor, coma, and death. Rarely, hypoactive delirium or coma may be the sole manifestation of Wernicke encephalopathy (285; 65; 127; 273; 277). It is important to recognize that the intoxicated patient who does not recover fully and spontaneously may be suffering from Wernicke encephalopathy (267). In terminally ill patients Wernicke encephalopathy may present as delirium (202).
Involvement of the hypothalamic and brainstem autonomic pathways may be associated with hypothermia, hypotension, or bradycardia (20; 134; 02; 158; 102; 65; 127). A hypothalamic syndrome characterized by hyponatremia, hypotension, anorexia, and apathy has been reported (303). Refractory hypotension has been reported as a presenting manifestation of Wernicke encephalopathy (286). The presence of hyperthermia usually indicates a complicating illness. The occurrence of hyperthermia of unknown cause has also been reported. Also reported is a patient with hyperthermia, chorea, and increased tone (232). Rarely, weakness, including dense quadriparesis, has been described (130; 85). Other unusual manifestations include seizures, myoclonus, catatonia, dysphagia, tinnitus, hearing loss, and micturition disturbance (276; 71; 34; 88; 250; 82; 124; 295; 04; 95). Dysphagia or acute bilateral deafness may rarely be the presenting manifestation (276; 124; 301). Palinacousis in association with hearing loss has been reported (193). In an isolated report, orthostatic tremor was the presenting manifestation of thiamine deficiency (190).
Korsakoff syndrome. About 80% of patients with Wernicke encephalopathy who survive develop Korsakoff syndrome (52; 267). Korsakoff syndrome is an amnestic-confabulatory syndrome characterized by severe anterograde and retrograde amnesia that follows Wernicke encephalopathy; Korsakoff syndrome emerges as ocular manifestations and encephalopathy subside (166; 283; 175; 219; 142; 77; 215). Korsakoff syndrome is more likely to occur when Wernicke encephalopathy is a consequence of alcohol abuse (108). Rarely, Korsakoff syndrome may be present without Wernicke encephalopathy or may be present at the time of diagnosis of Wernicke encephalopathy (21; 274; 298). In Korsakoff syndrome, memory is disproportionately impaired relative to other aspects of cognitive function. A typical finding is a striking loss of working memory and relative preservation of implicit or procedural memory. These patients can learn new motor skills or develop conditioned reactions to stimuli. Disorientation to time may be present. Minor executive dysfunction may also be seen (29). Confabulation becomes less evident with time (142). Emotional changes may develop and include apathy or mild euphoria. Structural or neurochemical abnormalities within the limbic and diencephalic circuits likely account for anterograde amnesia. Lesions in the mammillary body, mammillothalamic tract, and the anterior thalamus may be more relevant to memory dysfunction than lesions in the medial dorsal nucleus of the thalamus (143). Frontal lobe dysfunction possibly underlies the severe retrograde memory loss and emotional changes found in this syndrome (142; 29).
In wet beriberi, a rapid improvement is seen, with clearing of symptoms within days (199). Improvement in motor and sensory symptoms takes weeks or months (199; 140). Response in Wernicke encephalopathy is variable. Ophthalmoplegia improves rapidly, often so even with low doses of thiamine (50). A fine horizontal nystagmus may persist in up to 60% of patients. Gait disturbances improve over days. Mental status changes improve over days or weeks. Recovery of consciousness may be seen even in patients in deep coma (56). As the global confusional state recedes, some patients are left with Korsakoff syndrome. Prompt treatment of Wernicke encephalopathy prevents the development of Korsakoff syndrome. Korsakoff syndrome does not respond to thiamine therapy. Even with thiamine treatment, the mortality is about 20% (273; 156; 52; 267). Sudden death can occur and may be related to hemorrhagic brainstem lesions (102; 90).
A 41-year-old man with chronic diarrhea and vomiting presented with diplopia and unsteadiness. His examination was remarkable for partial ophthalmoplegia, gaze-evoked nystagmus, and gait ataxia. Brain MRI revealed increased FLAIR signal involving the midbrain periaqueductal gray matter. Thiamine administration (500 mg IV every 8 hours for 3 days followed by 100 mg IV daily) resulted in prompt resolution of ocular signs and symptoms and a gradual improvement in gait.
Thiamine deficiency can be seen in conditions associated with decreased intake, decreased absorption, defective transport, increased losses, and enhanced requirements (219; 230; 161). Thiamine deficiency is increasingly being recognized in nonalcoholics (73; 157; 178; 196; 71; 26; 81; 124; 56; 226; 214; 251; 96; 136; 206; 254). Often, multiple contributing factors may coexist. For example, thiamine deficiency may occur in a patient on parenteral nutrition who is experiencing recurrent vomiting following gastrointestinal surgery.
Thiamine deficiency is often seen in the setting of alcoholism and results from inadequate dietary intake, reduced gastrointestinal absorption, reduced liver thiamine stores, and impaired phosphorylation of thiamine to thiamine diphosphate (272; 112; 39; 220; 36; 266; 299). Additionally, alcohol metabolism raises the demand for thiamine. Studies have shown that ingestion of large amounts of alcohol does not result in Wernicke encephalopathy if dietary thiamine intake is adequate (239).
Gastrointestinal surgery directed at treating disorders like peptic ulcer disease, gastric or colon cancer, small-bowel obstruction, inflammatory bowel disease, achalasia, pancreatitis, and in particular obesity (bariatric surgery) can result in thiamine deficiency (98; 01; 236; 97; 49; 60; 140; 137; 88; 10; 224; 89; 121; 128; 160; 168; 250; 56). Though rare, it can also be seen after sleeve gastrectomy (248). Preoperative thiamine deficiency in patients undergoing bariatric surgery has also been recognized (40; 83). Wernicke encephalopathy generally occurs 1 to 8 months after surgery. Thiamine deficiency has been reported as early as 2 weeks and as late as 28 years after gastrointestinal surgery (10; 126). It is particularly common with rapid weight loss (greater than 7 kg per month). Additional risk factors include inadequate dietary supplementation and recurrent vomiting (49). Atypical clinical features may be present when Wernicke encephalopathy is seen following bariatric surgery (250). Thiamine deficiency may also be seen in patients seeking bariatric surgery (129).
Thiamine deficiency may be seen with various causes of persistent vomiting and a broad spectrum of gastrointestinal, hepatic, or pancreatic diseases associated with chronic diarrhea. Wernicke encephalopathy has been reported with recurrent vomiting in pancreatitis, migraine attacks, hyperemesis gravidarum, and other conditions (194; 153; 293; 185; 84; 289; 197; 182; 178; 43; 44; 13; 183; 193; 205; 258; 63; 207). A review of hyperemesis gravidarum noted that clinically manifest thiamine depletion was seen between 10 to 15 weeks of gestation, before onset of Wernicke encephalopathy. Vomiting had been present in patients for a median of 7 weeks prior to Wernicke encephalopathy (205). This study also noted increased occurrence of loss of pregnancy and that thiamine supplementation given was often insufficient (205). Thiamine deficiency can result from dietary restriction as seen in starvation, prolonged fasting, hunger strikes, anorexia nervosa, liquid-only diets, various psychiatric disorders, psychogenic food refusal, dietary neglect in the aged, and in patients with Alzheimer disease (72; 61; 101; 210; 70; 41; 279; 125). An outbreak of beriberi occurred at a detention center in Abidjan (05). Extreme dieting followed by binge eating has also been known to precipitate Wernicke encephalopathy in anorexia nervosa (212). Poststroke malnutrition may be complicated by thiamine deficiency in the setting of parenteral glucose administration without thiamine (155).
Infant beriberi may be seen in infants who are breastfed by thiamine-deficient asymptomatic mothers. Maternal thiamine deficiency may result from eating a staple diet of polished rice with foods containing thiaminase or anti-thiamine compounds. Commercial dietary formula, slimming diets, ketogenic diets, and food fads can all cause thiamine deficiency (178; 231; 80; 79; 238; 237; 118). An additional cause of thiamine responsive disorder in the pediatric population is defect in the SLC19A3 gene, which causes thiamine transporter-2 deficiency (150; 204). These disorders present with acute or recurrent encephalopathy in children and have collectively been referred to as biotin-thiamine-responsive basal ganglia disease. Imaging may show basal ganglia T2 hyperintensities and laboratory studies may reveal increased excretion of organic acids that are specific for thiamine-dependent mitochondrial enzymes, such as lactate, alpha-ketoglutarate, and branched-chain keto acids (74; 204). Clinical manifestations may also include seizures, dysarthria, dysphagia, supranuclear facial palsy, external ophthalmoplegia, dystonia, and quadriparesis (74). These conditions are potentially fatal or can be associated with significant neurologic morbidity. Mutations in SLC19A2 cause thiamine transporter-1 deficiency; the resulting disorder is characterized by thiamine responsive megaloblastic anemia, diabetes mellitus, and sensorineural hearing impairment (31; 161). Non-Amish SLC25A19 deficiency is characterized by acute episodes of fever-induced encephalopathy, lactic acidosis, and striatal necrosis; a milder presentation and basal ganglia involvement may antedate the acute encephalopathy permitting preventive therapy (216). Mutations in SLC25A19 affect the mitochondrial thiamine pyrophosphate transporter and result in Amish-type microcephaly or bilateral striatal necrosis with progressive peripheral neuropathy (31; 161). Another thiamine responsive disorder is due to TPK1 mutations (116). Some dietary supplements have herbal preparations that can interfere with thiamine absorption or act as thiamine antagonists (107). Certain raw fish and shellfish contain bacteria rich in thiaminases (284). These can inactivate thiamine in food, as can excessively cooking. Excess antacid use can interfere with thiamine absorption. Anti-thiamine factors are also present in betel nut, tea, and coffee (284; 186; 107). Excess amount of sulphites can destroy thiamine, and a Wernicke encephalopathy-like syndrome has been reported after prolonged feeding of dogs with sulphite-preserved meats (249).
Cancer, chemotherapy, and bone marrow transplantation are clinical settings in which Wernicke encephalopathy is being increasingly identified (213; 167; 24; 281; 85; 25; 180). Malignancy is the most common underlying disorder associated with Wernicke encephalopathy in children (281). Chemotherapeutic agents like erbulozole and ifosfamide may interfere with conversion of thiamine to thiamine pyrophosphate (280; 123; 33). Intravenous thiamine can result in effective reversal of ifosfamide-induced encephalopathy (100; 115). Wernicke encephalopathy may occur after 5-fluorouracil-based chemotherapy (45). Thiamine deficiency has rarely been reported following diuretic therapy with furosemide due to flushing out of water-soluble vitamins (189). Wernicke encephalopathy may coexist with toxidromes like the neuroleptic malignant syndrome (111).
Reports have noted thiamine deficiency in encephalopathic patients with COVID-19 infection (28). In one report, adjunctive therapy with thiamine in critically ill patients with COVID-19 was associated with survival benefit and a lower incidence of thrombosis (12). Weight loss and olfactory dysfunction following COVID-19 infection has also been reported to cause Wernicke encephalopathy (151). Stroke-like symptoms, a seventh nerve palsy, and neuroimaging findings suggestive of thiamine deficiency have been reported in a patient 2 days after testing positive for COVID-19 (08). Another patient presented with subacute vision loss due to thiamine deficiency following COVID-19 infection (241).
Wernicke encephalopathy has been reported after high-dose nitroglycerin infusion and was possibly a consequence of the effect of the diluents ethyl alcohol and propylene glycol on thiamine metabolism (247). Tolazamide can cause Wernicke encephalopathy by lowering thiamine levels in individuals with marginal stores (149).
Patients with renal failure, particularly when on peritoneal dialysis or hemodialysis may be susceptible to developing Wernicke encephalopathy (78; 163; 114; 113; 178). Factors responsible may include reduced intake due to nausea and vomiting, accelerated thiamine loss during dialysis, presence of infections, and parenteral nutrition without adequate thiamine supplementation. In some patients, uremic encephalopathy may be associated with a high concentration of guanidinosuccinic acid (30). This compound may predispose patients to Wernicke encephalopathy by inhibiting transketolase.
Other systemic diseases that have been associated with thiamine deficiency include prolonged infectious febrile diseases and hyperthyroidism (75; 198; 26). In patients with a marginal nutritional status, increased metabolic demand as is seen in periods of vigorous exercise, hyperthyroidism, malignancy, and systemic infections may precipitate symptoms. Biochemical and pathological evidence of thiamine deficiency may be seen in AIDS with or without clinical manifestations (37; 07). Thiamine deficiency may be seen in critically ill patients receiving intensive care for a variety of reasons (235; 67; 170). Thiamine supplementation in critically ill patients has been shown to reduce the incidence of ICU delirium (234).
Magnesium has a role as a cofactor in the conversion of thiamine into thiamine pyrophosphate and in the action of transketolase in the pentose phosphate pathway. Magnesium deficiency can predispose to the development of Wernicke encephalopathy and can be a cause of thiamine refractoriness in patients with Wernicke-Korsakoff syndrome (275; 176).
Relative thiamine deficiency may be seen in high-risk patients during periods of high carbohydrate intake as is seen with nasogastric feeding, total parenteral nutrition, or intravenous hyperalimentation (16; 188; 144; 162; 287; 210; 135; 89; 180). In these circumstances, a high percentage of calories is derived from glucose, and the amount of corresponding thiamine replacement is inadequate. This is particularly common when there is preceding starvation or where several days of intravenous nutrition without adequate vitamin replacement is followed by oral food intake (72; 243). This “refeeding syndrome” is an additional risk factor for thiamine deficiency and may have been an explanation for sudden death seen in prisoners of war (219; 214; 32). Wernicke encephalopathy secondary to anorexia nervosa complicated by refeeding syndrome can be associated with a takotsubo cardiomyopathy (32).
Postulated factors that may predispose to the development of Wernicke-Korsakoff syndrome while on a marginal thiamine diet include individual variations in the biochemical activity of transketolase, variations in transketolase affinity for thiamine, susceptibility mediated by GABAA receptor subunit gene cluster, changes in thiamine transport systems, variants in genes encoding enzymes involved in alcohol metabolism, and gene polymorphisms with a potential modifying effect (22; 23; 154; 230).
Thiamine deficiency leads to brain lesions in selective vulnerable areas that have a high thiamine content and turnover (such as the caudal brain and cerebellum) (221). It has been suggested that given the daily requirement of thiamine of approximately 1 to 2 mg per day, and body stores of approximately 30 to 50 mg, it takes approximately 4 to 6 weeks for body stores to be depleted (268). A severe thiamine-deficient diet may result in depletion of body stores, reduced blood thiamine levels, clinical manifestations of thiamine deficiency, and related brain lesions in as early as 2 to 3 weeks (228; 252). This may occur even earlier in individuals with marginal stores, particularly so if the diet is rich in carbohydrates (135).
It has been suggested that decreased alpha-ketoglutarate dehydrogenase, rather than decreased pyruvate dehydrogenase complex, constitutes the primary biochemical lesion in thiamine deficiency encephalopathy (35; 36; 106; 105). Alpha-ketoglutarate dehydrogenase is the rate-limiting enzyme in the tricarboxylic acid cycle that is involved in the synthesis of high-energy phosphates. Decreased alpha-ketoglutarate dehydrogenase activity in astrocytes is the earliest biochemical change and has been noted after 4 days of experimental thiamine deficiency (pyrithiamine-induced thiamine deficiency) (105). This is also the “reversible biochemical lesion” stage. Reduction in transketolase activity is noted after 7 days, and reduction in pyruvate dehydrogenase is noted after 10 days. Impaired pyruvate dehydrogenase activity impairs conversion of pyruvate into acetyl CoA and increases lactate production. Glucose loading has been shown to precipitate focal lactic acidosis in the vulnerable medial thalamus of thiamine-deficient rats (191).
These biochemical events result in reduced cerebral glucose utilization and impaired cellular energy metabolism (99). Thiamine-deficient membranes are unable to maintain osmotic gradients. Intracellular and extracellular swelling results. Astrocyte-related functions are impaired. These include intracellular and extracellular glutamate concentrations, maintenance of ionic gradients across cell membranes, and blood-brain barrier permeability (106). Proposed mechanisms that lead to neurotoxicity also include glutamate-mediated excitotoxicity, DNA fragmentation and apoptotic cell death, decreased synaptic transmission, mitochondrial dysfunction, and intracellular oxidative stress with free radical and cytokine production (35; 36; 174; 270; 271; 71; 230).
Due to the rapid turnover rates and absence of significant storage amounts, a continuous dietary supply of thiamine is necessary. Parenteral administration of thiamine creates a steep concentration gradient between the plasma and brain. This facilitates passive diffusion and rapid correction of brain thiamine deficiency (267). The half-life of thiamine after intravenous administration is 96 minutes, whereas the elimination half-life after oral administration is 154 minutes (262). In a healthy individual, the calculated maximum amount of thiamine that can be absorbed from a single oral dose is about 4.5 mg, and in an individual with chronic malabsorption this amount is reduced by 70% (267). These pharmacokinetic factors explain the need for 3-times-a-day dosing of thiamine by the parenteral route in patients with Wernicke encephalopathy or in patients at risk of Wernicke encephalopathy.
Beriberi. Pathologic studies of beriberi in nonalcoholics are limited (199). Axonal degeneration has been noted in distal nerves. Chromatolysis of dorsal root ganglion neurons and anterior horn cell neurons may be seen due to axonal degeneration. Segmental demyelination is rare and likely secondary to axonal degeneration. Severe cases may have involvement of the vagus and phrenic nerves. Degeneration of the posterior columns may be present.
Wernicke encephalopathy. Wernicke encephalopathy is commonly underdiagnosed. The frequency of Wernicke encephalopathy in various autopsy studies ranges from 0.8% to 2.8%, far in excess of what would be expected from clinical studies (55; 283; 102; 103; 273; 219; 104; 157; 281). The underdiagnosis is particularly common in children, alcoholics, patients with AIDS, and with coexisting hepatic encephalopathy or alcohol intoxication. The clinical features of Wernicke encephalopathy may be difficult to differentiate from alcohol intoxication. In a neuropathological series of 131 cases, only 20% were diagnosed during life (103; 104).
The neuropathologic changes in Wernicke encephalopathy involve the mammillary bodies, hypothalamus and thalamus, superior cerebellar vermis, brainstem (including the periaqueductal grey matter, pontine tegmentum, and midbrain reticular formation), walls of the third ventricle, and floor of the fourth ventricle (283; 145). There is involvement of the third and sixth nerve nuclei, vestibular nuclei, locus ceruleus, and, rarely, vagal nuclei. Also described is involvement of the colliculi, fornices, septal region, hippocampi, and cerebral cortex. In Wernicke encephalopathy the characteristic finding is mammillary body involvement; patients with Korsakoff syndrome typically have involvement of the dorsal median nucleus of the thalamus. In a nonhuman primate model of thiamine deficiency lesions involving the inferior colliculi were the earliest findings (Witt and Goldman-Rakic 1983).
A symmetric grayish discoloration involving the periaqueductal grey matter, mamillary bodies, and medial thalami is typically seen and is accompanied by congestion and pinpoint hemorrhages (283). Gross hemorrhage is rare. Microscopically acute lesions are characterized by multiple small hemorrhages with intervening spongiosis and edema without interstitial infiltration or capillary proliferation (283). Prominent vessels result from hypertrophy and hyperplasia. Extravasated red blood cells and hemosiderin-laden macrophages may be seen. Chronic lesions show loosening of the neuropil accompanied by activated microglia, reactive astrocytes, gliosis, and vascular proliferation. There is relative neuronal and axonal sparing.
It has been suggested that the response to thiamine deficiency may be population-specific (22). Europeans develop a dry beriberi with polyneuropathy and Wernicke encephalopathy; Asians are more prone to developing a wet beriberi (22).
Intravenous glucose infusion in patients with thiamine deficiency may consume the available thiamine and precipitate an acute Wernicke encephalopathy (227). At-risk patients should receive parenteral thiamine prior to administration of glucose or parenteral nutrition.
Parenteral thiamine administration in Wernicke encephalopathy is commonly employed; the available guidelines, however, vary in their recommendations, and there are limited evidence-based recommendations for thiamine use in patients with alcohol use disorder (217; 253; 62). Thiamine supplementation is, however, underutilized in patients with alcohol use disorder or patients with critical illness (208).
Patients suspected of having beriberi or Wernicke encephalopathy should promptly receive parenteral thiamine, intravenously or intramuscularly. It has been suggested that a large amount of thiamine supplementation may be harmful for cancer patients because it could promote tumor cell growth (27). The clinical significance of this requires further studies. Adverse effects are rare and include pruritus, transient local irritation, or, rarely, anaphylaxis. These occur during or shortly after parenteral administration, more so with intravenous administration. Thiamine supplementation has been reported to cause normonatremic central pontine myelinolysis (133; 300). Thiamine for parenteral use should be diluted in 100 mL of normal saline or 5% glucose and be infused over 30 minutes (52; 267). The thiamine solution should be freshly prepared. Old solutions exposed to heat may be inactivated (219).
A commonly used thiamine replacement regimen is 100 mg intravenously every 8 hours for 3 to 5 days (88; 152; 86). A Cochrane review suggests that clinically significant thiamine deficiency be treated with at least 200 mg of parenteral thiamine daily for 2 days (58). Higher doses may be required in Wernicke encephalopathy, particularly when Wernicke encephalopathy occurs in the setting of alcoholism (269). Lower doses may suffice with predominantly nutritional thiamine deficiency. It has been suggested that patients with signs of Wernicke encephalopathy should receive 500 mg thiamine hydrochloride (diluted in 100 mL of normal saline) by infusion over 30 minutes, 3 times a day, for 2 to 3 days (52; 110; 51; 266; 267; 268; 269; 230; 206). Subsequently, the dose may be reduced to 250 mg of thiamine given intravenously or intramuscularly daily for 3 to f days. Similar doses may be given prophylactically in conditions of alcohol withdrawal or severe malnutrition. The parenteral form is used when there is doubt about adequate gastrointestinal absorption. Long-term oral maintenance with 50 to 100 mg thiamine is commonly employed. Higher enteral thiamine intake is not toxic (110). A lipophilic form of thiamine (benfotiamine) has been used in chronic alcoholism-related neuropathy in a dose of 320 mg/day for 4 weeks followed by 120 mg/day for an additional 3 weeks (291).
Wernicke encephalopathy often develops in a predisposed individual because of increased metabolic demands related to coexisting conditions, like an infection, that need independent attention. Deficiency of other vitamins, like niacin, need correction; niacin deficiency causes an encephalopathy indistinguishable from Wernicke encephalopathy. Magnesium deficiency leads to a refractory response to thiamine and if present needs concurrent correction (275; 176; 230; 54).
Included in the differential diagnosis are a broad spectrum of conditions including paramedian thalamic infarction as seen in the top-of-the-basilar syndrome, central nervous system lymphoma, Leigh disease, variant Creutzfeldt-Jakob disease, paraneoplastic encephalitis, ventriculoencephalitis, Miller-Fisher syndrome, severe hypophosphatemia, alcoholic pellagra encephalopathy, multiple sclerosis, Behçet disease, Whipple disease, other CNS infections, and a variety of acute and chronic intoxications (230). Creutzfeldt-Jakob disease may coexist with Wernicke encephalopathy (18). Wernicke encephalopathy-like lesions have been reported in cerebral hypoxia (120). Symmetric signal intensity alterations involving the red nuclei, dentate nuclei, splenium, vestibular nuclei, and abducens nuclei can be seen in metronidazole toxicity (306). These conditions merit consideration particularly when the response to thiamine is absent or when a predisposing condition is absent.
Urine and blood. Wernicke encephalopathy is largely a clinical diagnosis (164). Urinary thiamine excretion and serum thiamine levels may be decreased in Wernicke encephalopathy, but they do not accurately reflect tissue concentrations and are, therefore, not reliable indicators of thiamine status. Whole blood thiamine levels are more sensitive than plasma thiamine. A low blood thiamine level may also identify patients at risk of developing Wernicke encephalopathy. Thirty percent to 80% of alcoholics may have low levels of thiamine (52). The erythrocyte transketolase activation assay is an assay of functional status and is based on measurement of transketolase activity in hemolysates of red blood cells in the absence of (and in the presence of) added excess cofactor (thiamine diphosphate) (263). It is an indirect assessment with limited specificity as factors other than thiamine deficiency can decrease transketolase activity. Thiamine diphosphate is the active form of thiamine. It is present in erythrocytes and measurement of thiamine diphosphate in human erythrocytes by high-performance liquid chromatography has improved reproducibility and is suitable for clinical and research purposes (169). Because these laboratory abnormalities normalize quickly, a blood sample should be drawn before initiation of treatment. An anion-gap metabolic acidosis accompanied by a primary respiratory alkalosis may be present (68). Thiamine deficiency may manifest as unexplained metabolic acidosis (257).
CSF and EEG. CSF may show raised protein concentration in later stages (230). EEG may show nonspecific slowing (230).
CT. CT has poor sensitivity and is of limited utility. Low-density abnormalities may be seen in the paraventricular regions of the thalamus (14; 281).
MRI. MRI is the imaging modality of choice. In one series, MRI was noted to have a sensitivity and specificity of 53% and 93%, respectively (14). It is important to remember that it is not uncommon for the brain MRI to be normal (181). Typical MRI findings include increased T2 or proton density or FLAIR signal in the paraventricular region of the thalamus, hypothalamus, mammillary body, periaqueductal midbrain, tectal plate, pons, fourth ventricle floor, medulla, midline cerebellum, and, rarely, in the splenium of the corpus callosum or caudate and other basal ganglia structures (92; 282; 197; 165; 260; 14; 57; 245; 17; 64; 71; 288; 302; 85; 278; 82; 222; 179). Signal alterations involving the red nucleus, dentate, or substantia nigra have rarely been reported (122). Increased signal may involve the hypoglossal, medial vestibular, facial, abducens, red, and dentate nuclei (304; 305; 307). Involvement of cortical regions on MRI has also been reported (282; 296; 57; 130; 64; 88; 302; 81; 56). Cortical involvement and selective involvement of cranial nerve nuclei are features of nonalcoholic Wernicke encephalopathy (305; 307). These changes are seen in conjunction with the more typical sites of involvement that have been described in alcoholic Wernicke encephalopathy. Cerebellar involvement may be seen in either alcoholic or nonalcoholic Wernicke encephalopathy. Cortical involvement may indicate irreversible lesions and poor prognosis (302; 81; 211). A study of MRI in patients with nonalcoholic Wernicke encephalopathy noted that patients with no disturbance in consciousness or only drowsiness had lesions confined to the periaqueductal area and patients with lethargy or mild coma had the more typical MR appearance of paraventricular involvement (81). In another study of MRI in nonalcoholic Wernicke encephalopathy, medial thalami and caudate involvement was noted in comatose patients (302). Contrast enhancement may be present in the early stages (229; 246; 172; 245; 17; 288; 88). Mammillary body enhancement on MR has been reported as being the only imaging abnormality in Wernicke encephalopathy (246). Hemorrhagic lesions are rare (229; 203; 244). In one report, midbrain swelling was accompanied by hydrocephalus that required shunting (71). In another report, periaqueductal swelling resulted in hydrocephalus that improved with thiamine replacement; that patient also had hemorrhage involving both inferior colliculi (244). Bilateral anterior thalami and fornix macrohemorrhage have been reported in Wernicke-Korsakoff syndrome (192). Though rare, intraventricular hemorrhage may also be seen (06). Susceptibility-weighted MRI may show cortical laminar necrosis and hemorrhage (211). The neuropathology corresponding to the T2-signal change is spongy degeneration of the neuropil (260). The signal abnormalities resolve with treatment, but shrunken mamillary bodies may persist as sequelae. Additional findings in the chronic stages include dilated aqueduct and third ventricles with atrophy of the midbrain tegmentum, and paramedian thalamic nuclei (42; 297). Frontal or generalized or vermian atrophy may also be seen (302).
In patients with Wernicke encephalopathy, abnormalities may be seen on diffusion-weighted MRI in the early stages (261; 17; 200; 47; 64; 109; 48). These may disappear after successful thiamine therapy, suggesting underlying vasogenic edema. Both cytotoxic and vasogenic edema may be concurrently present (278; 222). The abnormalities attributed to cytotoxic edema may also be reversible (47). Proton MR spectroscopy may show evidence of lactate accumulation (223).
Thiamine requirements increase during pregnancy and lactation. Maternal thiamine deficiency may result from eating a staple diet of polished rice with foods containing thiaminase or anti-thiamine compounds.
Neeraj Kumar MD
Dr. Kumar of the Mayo Clinic and the Mayo College of Medicine has no relevant financial relationships to disclose.See Profile
Douglas J Lanska MD FAAN MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health, the Medical College of Wisconsin, and IM Sechenov First Moscow State Medical University has no relevant financial relationships to disclose.See Profile
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