OBSERVATION Development of Wernicke- After Long Intervals Following

Tatsuo Shimomura, MD; Etsuro Mori, MD; Nobutsugu Hirono, MD; Toru Imamura, MD; Hikari Yamashita, MA

Background: Surgical exclusion of portions of the gas- Conclusions: In addition to a long-standing latent trointestinal tract is a predisposing risk factor for the deficiency in thiamin levels due to defective absorp- development of Wernicke-Korsakoff syndrome. When this tion following gastrectomy or gastrojejunostomy, disease occurs, it is usually within weeks after the gas- other minor factors that may influence the intake of trointestinal surgery. However, it is not well known that thiamin and the need for thiamin in subjects who have Wernicke-Korsakoff syndrome may occur after a long la- undergone gastrectomy may cause a state of thiamin tent interval following gastrectomy. deficiency resulting in Wernicke-Korsakoff syndrome. Results from our study indicate that the following Setting: A research-oriented hospital. measures are mandatory: educating patients about proper dietary habits, carefully monitoring their thia- Patients: Three patients without a history of alcoholism min intake, recognizing Wernicke-Korsakoff syn- or dietary deprivation developed Wernicke-Korsakoff syn- drome early, and treating it immediately with appro- drome 2 to 20 years after undergoing gastrectomy. In these priate measures. patients, minor changes in dietary habit led to the devel- opment of Wernicke-Korsakoff syndrome. Arch Neurol. 1998;55:1242-1245

ERNICKE-Korsakoff reasons.4-9 However, it is not well known syndrome, which is that the syndrome may develop after a characterized by long latent interval following a resection nystagmus, abdu- of the . We describe 3 patients cent and conjugate without a history of alcoholism or dietary Wgaze palsies, , mental confusion, and deprivation who developed Wernicke- amnesia, is caused by a deficiency in lev- Korsakoff syndrome 2 to 20 years after els of thiamin and is observed mainly al- undergoing gastrectomy. In these pa- though not exclusively in persons who tients, minor changes in habit, together with abuse alcohol. Recognized predisposing a long-standing latent deficiency in levels conditions other than alcoholism in- of thiamin induced by a gastrointestinal clude chronic dietary deprivation (unbal- condition, may have led to the develop- anced diet, dietary faddism, and pro- ment of Wernicke-Korsakoff syndrome. longed intravenous feeding without adequate vitamin B supplementation), and REPORT OF CASES impaired absorption or intake of dietary nutrients (celiac sprue, gastrointestinal PATIENT 1 tract disorders, recurrent vomiting due to pyloric obstruction, hyperemesis gravida- A 51-year-old male truck driver with no rum, etc).1,2 An excessive intake of carbo- history of alcoholism was referred to our From the Departments of hydrates relative to the supply of thiamin hospital on October 26, 1995, because of Clinical Neurosciences and an increased need for nutrients (due behavioral derangement and an unsteady (Drs Shimomura, Mori, to , growth, pregnancy, or infec- gait that had lasted for 8 days. The pa- Hirono, and Imamura and tion) contribute to the development of a tient had undergone a total resection of the Mr Yamashita) and 1-3 Service (Drs Shimomura, Mori, state of thiamin deficiency. When it oc- stomach and gastrojejunostomy because Hirono, and Imamura), Hyogo curs, Wernicke-Korsakoff syndrome usu- of gastric adenocarcinoma in 1990. After Institute for Aging Brain and ally develops within weeks after surgical the surgery, he remained in good health Cognitive Disorders, exclusion of portions of the gastrointes- and had regularly taken a vitamin supple- Himeji, Japan. tinal tract for treatment of or other ment (10 mg/d of thiamin and 13 µg/d of

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 cyanocobalamine). He experienced an episode of con- nosis of . After he ceased drinking, the pa- fusion in April 1995, which subsided after a few days with tient became less confused and the disturbance in his gait a residual retrograde amnesia in relation to the preced- improved slightly, but a problem with his memory be- ing 10 days. On October 5, 1995, 3 weeks after the pa- came apparent. tient had discontinued taking the vitamin supplement, On admission, the patient was alert. His weight was he became confused and developed gait ataxia. He was 44.0 kg and his height was 151 cm. The results of his gen- treated with oral vitamin B complex tablets prescribed eral physical examination were not remarkable. A neu- by a physician. Serum levels of thiamin and vitamin B12 rologic examination revealed hyporeflexia at the ankles, determined prior to the treatment were 65 nmol/L (nor- dysesthesia on the feet, and truncal ataxia. There was no mal range, 77-199 nmol/L) and 159 pmol/L (normal range, evidence of oculomotor disturbance or nystagmus. The 184-692 pmol/L), respectively. patient scored a 21 on the Mini-Mental State Examina- On admission, the patient was confused and disori- tion. Serum levels of thiamin and vitamin B12 were 65 ented. His weight was 38.6 kg and his height was 159 nmol/L and 314 pmol/L, respectively. Results from a rou- cm. A neurologic examination revealed gaze-evoked hori- tine examination of blood and urine were otherwise nor- zontal nystagmus, ataxia, and hyporeflexia at the ankles. mal. A yielded normal Anterograde amnesia and retrograde memory loss in re- findings. An electroencephalogram showed diffuse theta lation to the preceding several years were apparent. The activities. Motor and sensory nerve conduction veloci- patient’s verbal response included many confabula- ties were within normal ranges. Cranial magnetic reso- tions. He scored a 22 on the Mini-Mental State Exami- nance imaging scans demonstrated mild brain atrophy nation. A routine laboratory examination revealed mild but no focal abnormality. A 99mTc–ethyl cysteinate dimer macrocytic ( count, 3.16 ϫ 1012/L; single photon emission computed tomographic scan dem- hemoglobin, 110 g/L; and hematocrit, 0.33). Results from onstrated no abnormality in regional cerebral blood flow. a lumbar puncture revealed normal cerebrospinal fluid There was no evidence of cancer recurrence. The pa- findings. An electroencephalogram showed diffuse tient’s episodic memory was not functioning properly, slow activities. Motor and sensory nerve conduction and he had retrograde amnesia relative to the 2-year pe- velocities were within normal ranges. Cranial magnetic riod prior to the onset of his condition. The patient was resonance imaging scans demonstrated mild brain atro- disoriented in space and time, and his confabulations were phy but no focal abnormality. There was no evidence of remarkable. On the Wechsler Memory Scale–Revised, the cancer recurrence. patient scored a 61 on the general memory index, 61 on The patient was immediately treated with intrave- the verbal memory index, 76 on the visual memory in- nous high-dose thiamin and cyanocobalamine, fol- dex, and 57 on the delayed recall index. His intellectual lowed by oral vitamin B complex tablets. Soon after treat- function had declined to a subnormal level; he had a ver- ment was initiated, the patient’s confusion disappeared bal IQ of 81 and a performance IQ of 77 on the Wech- and his nystagmus and ataxia gradually subsided. How- sler Adult Intelligence Scale–Revised. ever, there was only a slight improvement in his memory The patient was diagnosed as having Wernicke and disorientation. Two months later, the patient scored encephalopathy. Following treatment with intravenous less than 50 on the general memory index of the Wech- high-dose thiamin for 2 weeks and then oral thiamin, he sler Memory Scale–Revised, 53 on the verbal memory in- gradually recovered from hyporeflexia and dysesthesia. dex, 64 on the visual memory index, and less than 50 on Although the patient’s disorientation and confabulation the delayed recall index. There was no improvement in became less severe 2 months later, his amnesia re- his retrograde amnesia. The patient’s intellectual func- mained unchanged. tion had declined to a subnormal level; he had a verbal IQ of 89 and a performance IQ of 78 on the Wechsler PATIENT 3 Adult Intelligence Scale–Revised. There was a mild de- crease in regional cerebral blood flow and the oxygen A 60-year-old businessman with no history of alcohol- metabolic ratio in the patient’s frontal lobes, as deter- ism was referred to our hospital on July 8, 1997, be- mined by a positron emission tomographic scan and the cause of the onset of an acute memory impairment 11 oxygen 15–labeled gas inhalation steady state method. days earlier. The patient had undergone a partial gas- trectomy and gastrojejunostomy in July 1995 for gastric PATIENT 2 adenocarcinoma and had been in good health thereaf- ter. Two weeks before the onset of the patient’s memory A 65-year-old male factory worker was admitted to our problems, he had an upper respiratory tract infection and hospital on May 7, 1996, because of memory problems poor appetite. A family physician had given him a single and an unsteady gait that had developed 1 month ear- dose of vitamin B complex (containing 50 mg of thia- lier. The patient had had a partial gastrectomy and gas- min hydrochloride) with fluid under the suspected di- trojejunostomy in 1976 because of gastric adenocarci- agnosis of mild undernourishment and dehydration. noma and was in good health thereafter. He suffered from On admission, the patient was alert but severely am- and inveterate insomnia in March 1996, and his nestic and disoriented. Some confabulations were noted. daily alcohol consumption had increased to twice his ha- The results of the general physical examination were un- bitual drinking level for 30 years of 400 mL of wine per remarkable. The patient’s weight was 47.3 kg and his day. One month later, the patient became confused, de- height was 157 cm. A neurologic examination revealed veloped an unsteady gait, and was treated under a diag- truncal ataxia and hyporeflexia at the ankles. There was

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 no evidence of oculomotor palsy, nystagmus, or sen- tion of our patients was not excessive and their diet was sory disturbance. He scored a 25 on the Mini-Mental State appropriate and balanced. Although a single case report of Examination. On the Wechsler Memory Scale–Revised, a similar condition appeared in the Japanese medical lit- the patient scored less than 50 on the general memory erature,16 no report was found in the Western literature. index, 54 on the verbal memory index, 59 on the visual For each of our patients, we noted the following memory index, and less than 50 on the delayed recall in- trivial predisposing events that occurred just before the dex. He could not correctly recall events that had oc- onset of Wernicke-Korsakoff syndrome: patient 1 had dis- curred up to 1 year before the onset of his condition. The continued taking vitamin supplements 3 weeks prior to patient’s intellectual function was normal; he had a ver- onset; patient 2 had increased alcohol consumption and bal IQ of 97 and a performance IQ of 108 on the Wech- experienced a loss of appetite 1 month prior to onset; and sler Adult Intelligence Scale–Revised. Serum levels of vi- patient 3 had developed an upper respiratory tract in- tamin B1 (163 nmol/L) and vitamin B12 (12 912 pmol/L) fection and a poor appetite 2 weeks prior to onset. Each were elevated because he had been administered a supple- of these minor factors alone does not generally cause a ment prior to admission. Findings from a routine labo- deficiency in thiamin levels. A gastrojejunostomy makes ratory examination were unremarkable. Results from a the foodstuff passage circumvent the duodenum, where lumbar puncture yielded normal cerebrospinal fluid find- the absorption of thiamin mainly takes place. In our pa- ings. Findings from an electroencephalogram were also tients, minimal levels of thiamin were barely main- normal. Motor and sensory nerve conduction velocities tained for long periods after surgery. All of our patients were within normal ranges. Cranial magnetic resonance showed signs of mild , including dimin- imaging scan findings were normal. There was no ab- ished ankle jerks and of the feet, suggesting normal finding on a measurement of regional cerebral a marginal prior to surgery, since long sur- blood flow and oxygen metabolic ratio as determined by vival after gastrectomy is often associated with a nutri- a positron emission tomographic scan and the oxygen tional polyneuropathy.17 We may better understand the 15–labeled gas inhalation steady state method. clinical form of Wernicke-Korsakoff syndrome when mi- The patient was immediately treated with intrave- nor episodes comprising combinations of such subtle fea- nous high-dose thiamin and then oral thiamin. All neu- tures are reported in other patients. A decrease in thia- rologic impairments improved to normal, and memory min supply, an increase in the need for thiamin, and impairment became less severe. Two months later, the inefficient absorption promote a state of thiamin defi- patient’s scores were 63 on the general memory index of ciency. Aging, which reportedly increases the need for the Wechsler Memory Scale–Revised, 63 on the verbal thiamin,3 may contribute to the development of a rela- memory index, 92 on the visual memory index, and less tive . In addition, the Japanese diet than 50 on the delayed recall index. His memories re- consists mainly of highly milled rice, which has an ex- turned except for events that occurred during the sev- cessive proportion of carbohydrates relative to the sup- eral months prior to the onset of his condition. ply of thiamin and thus may favor the development of a state of thiamin deficiency. In each of our patients, a rela- COMMENT tively mild increase in thiamin deficiency was sufficient to convert a mild chronic athiaminotic state to an acute In our 3 patients, the onset of acute characteristic signs athiaminotic state, (ie, Wernicke-Korsakoff syndrome). and symptoms, a low serum level of thiamin (docu- Among our patients, one (patient 1) had a premoni- mented in 2 patients), and the patients’ responses to thia- tory transient episode of confusion and residual retro- min supported the diagnosis of Wernicke-Korsakoff syn- grade amnesia, which were disregarded by the patient’s drome. The marked disparity between the memory physician. The initial treatment of all our patients was quotients and general IQs of our patients also indicated inadequate. Early recognition of Wernicke-Korsakoff syn- the Korsakoff amnesitic disorder.10 Neuroimaging stud- drome is crucial, considering the poor prognosis with- ies ruled out other causes, including vascular and de- out appropriate treatment. A delay of treatment can cause generative diseases. Although a decreased serum vita- death or serious permanent deficits. It should be recog- min B12 concentration and macrocytic anemia were found nized that undergoing gastrectomy or gastrojejunos- in patient 1, it was unlikely that a vitamin B12 deficiency tomy is not an uncommon risk factor for Wernicke- had caused his neurologic manifestations. Korsakoff syndrome. Minor factors that may influence Although Wernicke-Korsakoff syndrome is most com- the intake of thiamin and the need for thiamin in indi- monly associated with chronic alcoholism, it has also been viduals who have undergone gastrectomy or gastrojeju- recognized to occur with a variety of abnormalities of the nostomy can cause a state of thiamin deficiency result- .1,2 It generally develops weeks after ing in this syndrome. Moreover, it is important to educate gastric plication for morbid obesity4-5 or gastrectomy for patients who have undergone gastrectomy in proper di- neoplasm11 in association with starvation,12 anorexia,13 re- etary habits, carefully monitor their thiamin intake, rec- current vomiting,8,9,14 and/or prolonged parenteral feed- ognize Wernicke-Korsakoff syndrome early, and treat it ing.15 However, in our patients, Wernicke-Korsakoff syn- immediately with appropriate measures. drome occurred after long latent intervals ranging from 2 to 20 years following gastrectomy or gastrojejunostomy. Accepted for publication December 12, 1997. Neither chronic anorexia, restriction of diet, nor recur- Reprints: Etsuro Mori, MD, Clinical Neurosciences, rent vomiting was associated with the development of Hyogo Institute for Aging Brain and Cognitive Disorders, Wernicke-Korsakoff syndrome. The alcohol consump- 520 Saisho-ko, Himeji 670-0981, Japan.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 plications after gastric restriction surgery for morbid obesity. Neurology. 1987; REFERENCES 37:196-200. 10. Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff Syndrome. 2nd ed. 1. Reuler JB, Girard DE, Cooney TG. Wernicke’s encephalopathy. N Engl J Med. Philadelphia, Pa: FA Davis Co Publishers; 1989:10, 46-50. 1985;312:1035-1039. 11. Batori M, Ciulli A, Lazzaro M, Casella MC. Wernicke’s encephalopathy 2. Adams RD, Victor M, Ropper AH. Disease of the nervous system due to nutri- post subtotal extended gastrectomy. Riv Eur Sci Med Farmacol. 1995;17: tional deficiency. In: Adams RD, Victor M, eds. Principles of Neurology. 6th ed. 81-83. New York, NY: McGraw-Hill Book Co; 1997:1138-1165. 12. Drenick EJ, Joven CB, Swendseid ME. Occurrence of acute Wernicke’s encepha- 3. Marcus R, Coulston AM. Water-soluble vitamins. In: Hardman JG, Limbird LE, lopathy during prolonged starvation for the treatment of obesity. N Engl J Med. Molinoff PB, Ruddon RW, Gilman AG, eds. Goodman and Gilman’s The Phar- 1966;274:937-939. macological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill Book Co; 13. Handler CE, Perkins GD. Anorexia nervosa and Wernicke’s encephalopathy: an 1996:1555-1572. underdiagnosed association. Lancet. 1982;2:771-772. 4. Haid RW, Gutmann L, Crosby TW. Wernicke-Korsakoff encephalopathy after gas- 14. Nightingale S, Bates D, Heath PD, Barron SL. Wernicke’s encephalopathy in hy- tric plication. JAMA. 1982;247:2566-2567. peremesis gravidarum. Postgrad Med J. 1982;58:558-559. 5. Maclean JB. Wernicke’s encephalopathy after gastric plication. JAMA. 1982;248: 15. Nadel AM, Burger PC. following prolonged intrave- 1311. nous therapy. JAMA. 1976;235:2403-2405. 6. Seehra H, MacDermott N, Lascelles RG, Taylor TV. Wernicke’s encephalopathy 16. Okino S, Sakajiri KI, Fukushima K, Ide Y, Takamori M. A case of Wernicke- after vertical banded gastroplasty for morbid obesity. BMJ. 1996;312:434. Korsakoff syndrome caused by gastrojejunostomy: specific findings of MRI and 7. Paulson GW, Martin EW, Mojzisik C, Carey LC. Neurologic complications of gas- SPECT. Rinsho Shinkeigaku. 1993;33:530-534. tric partitioning. Arch Neurol. 1985;42:675-677. 17. Victor M, Rothstein JD. Neurologic manifestations of hepatic and gastrointesti- 8. Oczkowski WJ, Kertesz A. Wernicke’s encephalopathy after gastroplasty for mor- nal diseases. In: Asbury AK, McKhann GM, McDonald WI, eds. Diseases of the bid obesity. Neurology. 1985;35:99-101. Nervous System: Clinical Neurobiology. 2nd ed. Philadelphia, Pa: WB Saunders 9. Abarbanel JM, Berginer VM, Osimani A, Solomon H, Charuzi I. Neurologic com- Co; 1992:1442-1455.

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