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Last edited on February 19, 2022

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+====== Wernicke Encephalopathy and Korsakoff Syndrome ======
+{{INLINETOC}}
+===== Primer =====
+**Wernicke-Korsakoff Syndrome** (WKS) is a neuropsychiatric syndrome caused by thiamine (vitamin B1) deficiency, commonly found in chronic alcoholism. This primarily alcohol-induced disorder is characterized by amnesia, confabulation, disorientation, and neurological findings. WKS occurs due to necrotic lesions to the mammillary bodies, thalamus, and brainstem. The syndrome itself consists of 2 components: **Wernicke encephalopathy (WE)**, and **Korsakoff’s amnesia (KA)**, hence the combined name **Wernicke-Korsakoff Syndrome**.
+== History ==
+<alert type="info" icon="fa fa-book fa-lg fa-fw">
+See also: **[[https://pubmed.ncbi.nlm.nih.gov/23157990/|Isenberg-Grzeda, E. et al. (2012). Wernicke-Korsakoff-syndrome: under-recognized and under-treated. Psychosomatics, 53(6), 507-516.]]**
+</alert>
+== Epidemiology ==
+  * The prevalence is estimated to be up to 2% among the general population and as high as 12.5% in patients with alcohol use disorders.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979979/|Isenberg-Grzeda, E., Alici, Y., Hatzoglou, V., Nelson, C., & Breitbart, W. (2016). Nonalcoholic thiamine-related encephalopathy (Wernicke-Korsakoff syndrome) among inpatients with cancer: a series of 18 cases. Psychosomatics, 57(1), 71-81.]])]
+  * Autopsy studies indicate that Wernicke is frequently undiagnosed during life, and is first diagnosed postmortem in over 80% of case.[([[https://pubmed.ncbi.nlm.nih.gov/20642790/|Galvin, R., Bråthen, G., Ivashynka, A., Hillbom, M., Tanasescu, R., & Leone, M. A. (2010). EFNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. European Journal of Neurology, 17(12), 1408-1418.]])][([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578911/|Flynn, A., Macaluso, M., D’Empaire, I., & Troutman, M. M. (2015). Wernicke’s encephalopathy: increasing clinician awareness of this serious, enigmatic, yet treatable disease. The primary care companion for CNS disorders, 17(3).
+]])]
+== Prognosis ==
+  * Wernicke encephalopathy is an acute presentation that when identified and treated in a timely manner, can lead to quick improvement of symptoms.
+    * Failure to diagnose and treat Wernicke encephalopathy can result in death in up to 20% of patients
+  * If untreated, up to 75% may develop Korsakoff syndrome (irreversible cognitive impairment), and the chance of full recovery is low[([[https://www.cmaj.ca/content/186/8/E295|Day, G. S., & Del Campo, C. M. (2014). Wernicke encephalopathy: a medical emergency. Cmaj, 186(8), E295-E295.]])] (but not impossible[([[https://pubmed.ncbi.nlm.nih.gov/15746545/|Carota, A., & Schnider, A. (2005). Dramatic recovery from prolonged Wernicke-Korsakoff disease. European neurology, 53(1), 45-46.]])]).
+    * Wernicke-Korsakoff syndrome thus is sometimes referred to as alcoholic dementia or alcohol-related dementia.
+== Comorbidity ==
+  * [[addictions:alcohol:1-use-disorder|Alcohol use disorder]] is highly common.
+    * In industrialized countries, 90% of the cases of thiamine deficiency are associated with alcohol use disorder.[([[https://pubmed.ncbi.nlm.nih.gov/16384871/|Thomson, A. D., & Marshall, E. J. (2006). The natural history and pathophysiology of Wernicke's encephalopathy and Korsakoff's psychosis. Alcohol and Alcoholism, 41(2), 151-158.]])]
+    * However! This is not a disease that affects only alcohol users, most cases of missed WKS are in those without an alcohol misuse history.
+  * Thiamine deficiency also presents in several syndromes other than Wernicke’s encephalopathy, including cardiac beriberi, neuropathic beriberi.
+== Risk Factors ==
+  * [[addictions:alcohol:1-use-disorder|Alcohol use disorder]], cancer patients,[([[https://pubmed.ncbi.nlm.nih.gov/23157990/|Isenberg-Grzeda, E., Kutner, H. E., & Nicolson, S. E. (2012). Wernicke-Korsakoff-syndrome: under-recognized and under-treated. Psychosomatics, 53(6), 507–516.]])] gastrointestinal surgery (e.g. - bariatric, gastric bypass), hyperemesis gravidarum, and starvation/fasting are risk factors.[([[https://pubmed.ncbi.nlm.nih.gov/20642790/|Galvin, R., Bråthen, G., Ivashynka, A., Hillbom, M., Tanasescu, R., & Leone, M. A. (2010). EFNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. European Journal of Neurology, 17(12), 1408-1418.]])]
+===== Underdiagnosis =====
+  * Wernicke encephalopathy may be overlooked in 68% of patients with alcoholism and 94% of patients without alcoholism (e.g. - cancer patients).[([[https://www.cmaj.ca/content/186/8/E295|Day, G. S., & Del Campo, C. M. (2014). Wernicke encephalopathy: a medical emergency. Cmaj, 186(8), E295-E295.]])][([[https://pubmed.ncbi.nlm.nih.gov/23157990/|Isenberg-Grzeda, E., Kutner, H. E., & Nicolson, S. E. (2012). Wernicke-Korsakoff-syndrome: under-recognized and under-treated. Psychosomatics, 53(6), 507–516.]])]
+===== Diagnosis =====
+WKS is a clinical diagnosis. Although often described as a triad (oculomotor abnormalities, cerebellar dysfunction, and an altered mental state) in the classic literature, it is rare for all three clinical signs to be present. [([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979979/|Caine, D., Halliday, G. M., Kril, J. J., & Harper, C. (1997). Operational criteria for the classification of chronic alcoholics: identification of Wernicke's encephalopathy. Journal of Neurology, Neurosurgery & Psychiatry, 62(1), 51-60.]])] Less than 16% of individuals with WKS will have all three signs. Neuroimaging findings may help in confirming the diagnosis but it is not diagnostic.
+==== Caine Criteria ====
+In 1997, Caine et al. proposed that a diagnosis can be made when patients have any ''2'' of the following 4 features:[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC486695/|Caine, D., Halliday, G. M., Kril, J. J., & Harper, C. (1997). Operational criteria for the classification of chronic alcoholics: identification of Wernicke's encephalopathy. Journal of Neurology, Neurosurgery & Psychiatry, 62(1), 51-60.]])]
+  - Nutritional deficiency
+  - Ocular signs
+  - Cerebellar signs
+  - Altered mental status or mild memory impairment
+==== Signs and Symptoms ====
+  * A dramatic improvement of neurologic signs often indicates adequate treatment and confirms the clinical diagnosis of Wernicke encephalopathy.[([[https://www.cmaj.ca/content/186/8/E295|Day, G. S., & Del Campo, C. M. (2014). Wernicke encephalopathy: a medical emergency. Cmaj, 186(8), E295-E295.]])]
+===== Terminology ====
+Classically, Wernicke encephalopathy is an acute presentation, while Korsakoff syndrome is a late, chronic manifestation of Wernicke encephalopathy that typically presents as anterograde and retrograde amnesia with preserved long-term memory.
+<panel type="info" title="Wernicke vs. Korsakoff" footer="* = Cannot occur during an acute delirium or dementia and must persist beyond usual duration of intoxication or withdrawal management" no-body="true">
+<mobiletable 1>
+^                                     ^ Course                                                       ^ Symptoms                                                                                                                                                                                                                                                                                ^
+^ Wernicke Encephalopathy (WE)      | Acute, but reversible                                        | The classic triad of: \\ • Eye abnormalities (nystagmus, oculomotor paralysis, paralysis of conjugate gaze), CN VI palsy AKA lateral gaze palsy (lateral rectus) \\ • Ataxia of stance and gait \\ • Mental status changes, including withdrawal, confusion, retro/anterograde amnesia  |
+^ Korsakoff's Syndrome/Amnesia (KS)*  | Chronic and only 20% of cases are reversible with treatment  | • Anterograde amnesia \\ • Confabulations\\ • Personality changes                                                                                                                                                                                                                       |
+</mobiletable>
+</panel>
+===== Pathophysiology =====
+<alert type="info" icon="fa fa-book fa-lg fa-fw">
+See also: **[[https://pubmed.ncbi.nlm.nih.gov/16384871/|Thomson, A. D., & Marshall, E. J. (2006). The natural history and pathophysiology of Wernicke's encephalopathy and Korsakoff's psychosis. Alcohol and Alcoholism, 41(2), 151-158.]]**
+</alert>
+==== Thiamine Absorption and Storage ====
+  * The daily thiamine requirement for healthy individuals is between 1 and 2 mg per day, and is related to overall carbohydrate intake.
+    * The thiamine requirement increases with alcohol misuse.
+    * There are several mechanisms behind this, including inadequate dietary intake, malabsorption of thiamine from the gastrointestinal tract due to alcohol’s effects, and impaired utilization of thiamine in the cells.
+  * Since the body stores are only between 30 and 50 mg of thiamine, it is estimated that this store is depleted in 4–6 weeks.[([[https://pubmed.ncbi.nlm.nih.gov/16384871/|Thomson, A. D., & Marshall, E. J. (2006). The natural history and pathophysiology of Wernicke's encephalopathy and Korsakoff's psychosis. Alcohol and Alcoholism, 41(2), 151-158.]])]
+==== Vitamin B1 (Thiamine) Deficiency ====
+<WRAP group>
+<WRAP half column>
+  * Thiamine is a cofactor in the decarboxylation of pyruvate. Thiamine is needed for pyruvate to enter the citric acid cycle, which allows for aerobic metabolism of glucose to adenosine triphosphate (ATP).
+  * Lack of ATP production in areas of the brain susceptible to thiamine depletion thus leads to neuronal death
+    * This can result in damage to the limbic system, specifically the mammillary bodies and anterior/medial thalamus.
+</WRAP>
+<WRAP half column>
+<callout type="tip" title="A Quick Review on Vitamins" icon="true">
+Vitamins are either water-soluble (vitamins B and C), or fat-soluble (vitamins A, D, E, K)
+  * **Fat-soluble vitamins** are dependent on absorption from the ileum and pancreas. Toxicity is easier with fat soluble vitamins because these vitamins accumulate in fat. Malabsorption syndromes such as cystic fibrosis and/or celiac disease) can result in fat-soluble vitamin deficiencies.
+  * **Water-soluble vitamins** are usually important coenzymes in cellular processes or precursors to coenzymes. All are excreted easily from the body, except for vitamins B12 and B9. B vitamin deficiency can result in glossitis, dermatitis, and diarrhea. For certain vitamin B deficiencies (B1 and B12), there can be neuropsychiatric and cognitive symptoms as well. Broadly, the B vitamins include:
+    * [[cl:wernicke-korsakoff|B1 (thiamine)]]
+    * B2 (riboflavin)
+    * B3 (niacin)
+    * B5 (pantothenic acid)
+    * [[meds:antidepressants:maoi:home#vitamin-b6-pyridoxine-deficiency|B6 (pyridoxine)]]
+    * B7 (biotin)
+    * B9 (folate)
+      * Is stored in the liver between 3 to 4 months
+    * [[cl:vitamin-b12-cyanocobalamin-deficiency|B12 (cobalamin)]]
+      * Is stored in the liver between 3 to 4 years
+</callout>
+</WRAP>
+</WRAP>
+===== Differential Diagnosis =====
+  * **Other medical issues resulting in thiamine deficiency**
+    * Although thiamine deficiency often occurs in the context of alcohol use disorders, it can also occur in eating disorders, malnutrition, hyperemesis gravidarum, chronic vomiting, extreme dieting, and cancer patients[([[https://pubmed.ncbi.nlm.nih.gov/23157990/|Isenberg-Grzeda, E., Kutner, H. E., & Nicolson, S. E. (2012). Wernicke-Korsakoff-syndrome: under-recognized and under-treated. Psychosomatics, 53(6), 507–516.]])] undergoing chemotherapy.
+  * **[[cl:1-delirium|Delirium]]**
+    * Confusion and memory impairment may be due to delirium
+  * **[[cl:tbi|Traumatic brain injury]]**
+    * There is a risk of the Wernicke being missed in patients with acute head injury. A history of alcohol use may not be available, and the signs and symptoms of Wernicke encephalopathy may be misattributed to the head injury.[([[https://pubmed.ncbi.nlm.nih.gov/9719389/|Cook, C. C., Hallwood, P. M., & Thomson, A. D. (1998). B vitamin deficiency and neuropsychiatric syndromes in alcohol misuse. Alcohol and Alcoholism, 33(4), 317-336.]])]
+  * **[[addictions:alcohol:4-other|Alcohol-induced psychosis]]**
+  * **[[geri:dementia:home|Neurodegenerative disorders]]**
+===== Investigations =====
+  * B12, thiamine (not all laboratories may have thiamine available)
+  * CBC, electrolytes, creatinine, GGT (indicator of acute liver injury from alcohol use, for individuals drinking > 4 drinks/day), AST, ALT, ALP, GGT
+  * Elevated AST/ALT ratio may be suggestive of alcoholic liver disease.[([[https://pubmed.ncbi.nlm.nih.gov/15208167/|Nyblom, H., Berggren, U., Balldin, J., & Olsson, R. (2004). High AST/ALT ratio may indicate advanced alcoholic liver disease rather than heavy drinking. Alcohol and alcoholism, 39(4), 336-339.]])]
+  * INR
+===== Physical Exam =====
+  * Nystagmus and ophthalmoplegia are the most common ocular findings in Wernicke.[([[https://pubmed.ncbi.nlm.nih.gov/20642790/|Galvin, R., Bråthen, G., Ivashynka, A., Hillbom, M., Tanasescu, R., & Leone, M. A. (2010). EFNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. European Journal of Neurology, 17(12), 1408-1418.]])]
+  * In patients with chronic alcohol use disorder with //only// an ataxic gait and stance found on physical exam, and no other neurological findings, they most likely have alcoholic cerebellar degeneration (midline cerebellar degeneration).
+==== Neuroimaging ====
+  * [[neurology:mri|MRI]] brain may show mammillary body atrophy, volume loss in the thalamus, volume loss in the corpus callosum.
+    * Lesions from Wernicke are characterized by petechial hemorrhages and can be often found with a symmetrical distribution around the cerebral aqueduct, third ventricle, and fourth ventricle.[([[https://pubmed.ncbi.nlm.nih.gov/27799475/|Hattingen, E., Beyle, A., Müller, A., Klockgether, T., & Kornblum, C. (2016). Wernicke encephalopathy: SWI detects petechial hemorrhages in mammillary bodies in vivo. Neurology, 87(18), 1956-1957.]])]
+  * CT head are unfortunately poor at identifying mammillary body lesions and thus not recommended.[([[https://pubmed.ncbi.nlm.nih.gov/20642790/|Galvin, R., Bråthen, G., Ivashynka, A., Hillbom, M., Tanasescu, R., & Leone, M. A. (2010). EFNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. European Journal of Neurology, 17(12), 1408-1418.]])]
+===== Treatment ======
+<alert type="info" icon="fa fa-book fa-lg fa-fw">
+See also:
+  * **[[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578911/|Flynn, A. et al. (2015). Wernicke’s encephalopathy: increasing clinician awareness of this serious, enigmatic, yet treatable disease. The primary care companion for CNS disorders, 17(3).]]**
+  * **[[https://pubmed.ncbi.nlm.nih.gov/15746545/|Carota, A., & Schnider, A. (2005). Dramatic recovery from prolonged Wernicke-Korsakoff disease. European neurology, 53(1), 45-46.]]**
+</alert>
+<alert icon="fa fa-arrow-circle-right fa-lg fa-fw" type="success">
+See also article: **[[addictions:alcohol:home]]**
+</alert>
+Thiamine resupplementation is the primary treatment. Oculomotor deficits should resolve over hours to days, while cognitive impairment may resolve within days to weeks. Most patients will exhibit some residual deficits.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1031727/|Foster, J. B. (1989). The Wernicke-Korsakoff Syndrome and Related Neurologic Disorders Due to Alcoholism and Malnutrition. Journal of Neurology, Neurosurgery, and Psychiatry, 52(10), 1217.]])]
+==== IV Thiamine ====
+  * Treatment is with intravenous thiamine therapy, but the optimum dosage remains controversial.[([[https://pubmed.ncbi.nlm.nih.gov/17681641/|Donnino, M. W., Vega, J., Miller, J., & Walsh, M. (2007). Myths and misconceptions of Wernicke’s encephalopathy: what every emergency physician should know. Annals of emergency medicine, 50(6), 715-721.]])] Some clinicians base dosing from a study published by Cook et al. in 1998, which recommended up to 1 g of thiamine daily to achieve a clinical response.[([[https://pubmed.ncbi.nlm.nih.gov/9719389/|Cook, C. C., Hallwood, P. M., & Thomson, A. D. (1998). B vitamin deficiency and neuropsychiatric syndromes in alcohol misuse. Alcohol and Alcoholism, 33(4), 317-336.]])][([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354137/|Nishimoto, A., Usery, J., Winton, J. C., & Twilla, J. (2017). High-dose parenteral thiamine in treatment of Wernicke's encephalopathy: case series and review of the literature. in vivo, 31(1), 121-124.]])][([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545191/|Thomson, A. D., Guerrini, I., & Marshall, E. J. (2012). The evolution and treatment of Korsakoff's syndrome. Neuropsychology review, 22(2), 81-92.]])]
+  * In individuals with suspected clinical signs of Wernicke, they should be prescribed thiamine 500mg IV x 3 days (some may prescribe as high as 500mg TID), followed by 250mg IV x 3 days (some may prescribe as high as 250mg TID) followed by oral supplementation 100mg PO daily.[([[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545191/|Thomson, A. D., Guerrini, I., & Marshall, E. J. (2012). The evolution and treatment of Korsakoff's syndrome. Neuropsychology review, 22(2), 81-92.]])]
+    * A significant improvement in neurologic symptoms or cognitive function helps confirm the diagnosis.
+  * Most patients should thereafter have indefinite oral thiamine supplementation (i.e. - 100 mg thiamine daily) until there is resolution of their nutritional compromise.[([[https://pubmed.ncbi.nlm.nih.gov/17681641/|Donnino, M. W., Vega, J., Miller, J., & Walsh, M. (2007). Myths and misconceptions of Wernicke’s encephalopathy: what every emergency physician should know. Annals of emergency medicine, 50(6), 715-721.]])]
+==== Oral Thiamine ====
+  * Remember that oral thiamine is difficult to absorb, so even for individuals with adequate oral intake, IV administration is recommended. In individuals with gut absorption changes (e.g. - bariatric surgery), IV supplementation is a must.
+    * It could also be argued that in general, the oral doses of thiamine are so low, and that is that it would provide a negligible effect on symptoms.
+  * In situations where IV thiamine is not available, thiamine 300mg PO TID could be prescribed.
+  * In low risk patients, thiamine 100mg TID should be prescribed as ongoing supplementary therapy in alcohol use disorder patients identified as at risk for thiamine deficiency.[([[http://rebelem.com/should-you-prescribe-oral-thiamine-for-chronic-alcoholics/|RebelEM:Should You Prescribe Oral Thiamine for Chronic Alcoholics?]])]
+===== Guidelines =====
+<alert icon="fa fa-arrow-circle-right fa-lg fa-fw" type="success">
+See also: **[[teaching:clinical-practice-guidelines-cpg|]]**
+</alert>
+{{page>teaching:clinical-practice-guidelines-cpg#wernicke-encephalopathy&nouser&noheader&nodate&nofooter}}
+===== Resources =====
+  * [[https://www.emra.org/emresident/article/wernicke/|EM Resident: Detecting Wernicke-Korsakoff Syndrome]]
+  * [[https://www.cmaj.ca/content/186/8/E295|Day, G. S., & Del Campo, C. M. (2014). Wernicke encephalopathy: a medical emergency. Cmaj, 186(8), E295-E295.]]
+  * [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545191/|Thomson, A. D., Guerrini, I., & Marshall, E. J. (2012). The evolution and treatment of Korsakoff's syndrome. Neuropsychology review, 22(2), 81-92.]]
+  * [[https://www.cochrane.org/CD004033/DEMENTIA_thiamine-for-prevention-and-treatment-of-wernicke-korsakoff-syndrome-in-people-who-abuse-alcohol|Day, E. et al. (2013). Thiamine for prevention and treatment of Wernicke‐Korsakoff Syndrome in people who abuse alcohol. Cochrane Database of Systematic Reviews, (7).]]