THE CLINICAL PICTURE NICOLE D. CRESCE, BS KATHLEEN A. McMANUS, MD, MS COSTI D. SIFRI, MD BARBARA B. WILSON, MD School of Medicine, University of Virginia Department of Medicine, University of Virginia School of Medicine and Department of School of Medicine and Department of Health System, Charlottesville, VA Health System, Charlottesville, VA Medicine, University of Virginia Health Dermatology, University of Virginia Health System, Charlottesville, VA System, Charlottesville, VA

The Clinical Picture despite repletion during withdrawal

anaging a patient with chronic M who is beginning to withdraw is a situation in which to expect the unexpected. A 61-year-old man with a 40-year history of alcohol abuse was admitted to the hospital after presenting with a 6-month history of weakness and increasing frequency of falls, as well as a 2-day history of myalgias and fatigue. He had and chronic , and he reported an unintentional 100-lb over the past year. He consumed at least three to five alcoholic drinks daily, including a daily “eye-opener,” and his diet was essentially devoid of meat, bread, fruits, and vegetables. His last drink had been on the morning of admission. On physical examination, his vital signs were no- table for marked orthostatic hypotension. He had an- gular cheilitis, an erythematous, scaly facial rash, and poorly healing severe sunburn on the dorsal surface of the left forearm, acquired 1 month earlier after mini- mal sun exposure while driving his car (FIGURE 1). The neurologic examination noted decreased sen- sation in a stocking distribution, reduced propriocep- tion in both great toes, and an intention tremor. His upper extremities were slightly hyperreflexic, he had down-going toes, he did not have clonus, and his gait was wide-based. Laboratory results were notable for mild anemia, with an elevated mean corpuscular volume of 109.2 fL and a normal thyrotropin level. Urinalysis and urine culture were normal. Stool testing for Clostridium dif- ficile toxin was negative. Computed tomography of the head was unremarkable. He was placed on the Clinical Institute Withdrawal Assessment for Alcohol revised protocol,1 and he was started on careful fluid, electrolyte, and nutritional management, including intravenous supplementation FIGURE 1. The patient had an erythematous, scaly rash on his face and a nonhealing sunburn on the with thiamine 100 mg daily, folic acid 1 mg twice daily, left forearm. doi:10.3949/ccjm.81a.13103

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and an oral multivitamin. Despite these inter- systems most commonly affected (ie, the gastro- ventions, he became delirious and developed intestinal tract, nervous system, and skin). Gas- horizontal , visual hallucinations, trointestinal may include dizziness, and increasing weakness. Benzodiaz- anorexia, diarrhea, stomatitis, and abdominal epine toxicity, which may cause similar find- discomfort.4 Neurologic signs and symptoms are ings, was thought unlikely, as he had received the most frequent clinical manifestations of pel- only a maximum of 4 mg of lorazepam in any lagra but are often overlooked in alcoholics with single 24-hour period. His ongoing , altered mental status.5,6 Early neurologic find- orthostatic hypotension, , and nystagmus ings may include apathy, depression, paresthe- raised concern for . sias, dizziness, and falling.4,5 Later findings may Thiamine was increased to 500 mg intrave- include hallucinations, seizures, and psychosis.4,5 nously three times daily for 2 days, followed by If severe enough, this may progress to coma and 500 mg daily for 2 days, as recommended for to a fourth “D”—death—if left untreated. acute Wernicke encephalopathy by the Royal Skin findings, if present, are typically the College of Physicians.2 most characteristic of .5,6 They include Although his ocular findings resolved and a photosensitive eruption that most commonly his blood pressure improved with high-dose appears on the face, arms, and the “V” of the thiamine, he remained confused. Other causes neck (“Casal’s necklace”).3,6 Erythema devel- of delirium were considered, including other ops on areas of sun-exposed skin and may be micronutrient deficiencies. He was evaluated painful or pruritic.6 It may take up to four times for , as magnesium is a as long to resolve as a normal sunburn.6 On re- 3 necessary in thiamine metabolism, peated exposure, the skin becomes thickened, but his level was within normal limits. The hyperkeratotic, and hyperpigmented.6 constellation of symptoms, including per- sistent delirium, diarrhea, and skin findings, ■■ DIAGNOSIS AND TREATMENT appeared to be consistent with pellagra, and OF PELLAGRA niacin deficiency became a concern. Suspicion of pellagra should be high in any pa- Micronutrient ■■ PELLAGRA AND ALCOHOL ABUSE tient with chronic alcohol abuse with changes in mental status.5 Pellagra is typically diagnosed deficiencies Niacin is a water-soluble converted to clinically. Although testing of serum levels of are common two important coenzymes involved in carbo- niacin or urine levels of niacin metabolites can 4 in chronic hydrate metabolism and fatty-acid synthesis. be performed,4,5 these tests are not commonly Body stores are minimal, although the 4 used, as they are neither widely available nor can convert tryptophan to niacin. reliable.3,4 Because there is little downside to In the United States, pellagra has become giving niacin, treatment should be started if rare since niacin enrichment of bread and there is clinical suspicion of pellagra.3,4 The di- flour began in the 1940s. However, the risk agnosis is confirmed by clinical improvement is increased in those with chronic alcohol after niacin replacement begins.4 dependency, metabolic disease such as car- Pellagra is easy and inexpensive to treat cinoid syndrome, and malabsorptive states once the diagnosis has been established. Sup- such as Crohn disease.5 Alcohol abuse is plementation can be given orally at 50 mg to commonly associated with micronutrient de- 100 mg three times daily, with a maximum of ficiencies. Even in alcoholics with sufficient 500 mg daily for 3 to 4 weeks.3,5 The multivi- food intake, their ability to absorb niacin tamin our patient initially received provided may be impaired both directly and indirectly because of the toxic effects of alcohol on the only 30 mg of niacin, which was insufficient gastrointestinal tract.5 to treat his deficiency. Other micronutrient deficiencies are also The three D’s of niacin deficiency common in pellagra, such as the suspected thi- The clinical picture of pellagra includes the amine deficiency in this patient. Although rare three “D’s” of niacin deficiency—diarrhea, de- in adults, pyridoxine deficiency should be con- mentia, and dermatitis—representing the organ sidered because pyridoxine plays an important

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role in niacin metabolism, and in patients such days later he was no longer delirious. His di- as this, the signs and symptoms of pellagra will arrhea resolved, but his peripheral neuropa- not resolve with niacin administration alone.3,4 thy improved only modestly, and we believe Neurologic symptoms can begin to resolve that this was the result of his long history of as soon as 24 to 48 hours after replacement alcohol abuse. therapy is started, although skin symptoms Although there are guidelines to help with take longer to respond.6 the management of patients undergoing alco- hol withdrawal, our experience with this pa- ■■ OUR PATIENT’S MANAGEMENT tient illustrates that important clinical condi- AND LESSONS LEARNED tions, including micronutrient deficiencies, Our patient was treated with extended- can easily be overlooked or misattributed, with release niacin 500 mg daily. He was signifi- potentially dangerous consequences. It is cru- cantly less confused within 24 hours, and 2 cial to be mindful of these considerations. ■ ■■ REFERENCES 4. World Health Organization, United Nations High Commissions for Refugees. Pellagra and its prevention and control in major emergen- 1. Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assess- cies. 2000. http://www.who.int/nutrition/publications/emergencies/ ment of alcohol withdrawal: the revised clinical institute withdrawal WHO_NHD_00.10/en/index.html. Accessed April 26, 2014. assessment for alcohol scale (CIWA-Ar). Br J Addict 1989; 84:1353–1357. 5. Oldham MA, Ivkovic A. Pellagrous encephalopathy presenting as 2. Thomson AD, Cook CC, Touquet R, Henry JA; Royal College of Physi- alcohol withdrawal delirium: a case series and literature review. Addict cians, London. The Royal College of Physicians report on alcohol: Sci Clin Pract 2012; 7:12. guidelines for managing Wernicke’s encephalopathy in the accident 6. Karthikeyan K, Thappa DM. Pellagra and skin. Int J Dermatol 2002; and Emergency Department. Alcohol Alcohol 2002; 37:513–521. 41:476–481. 3. Weathers AL, Lewis SL. Rare and unusual ... or are they? Less com- monly diagnosed associated with systemic disease. ADDRESS: Costi D. Sifri, MD, Department of Medicine, University of Virginia Health Semin Neurol 2009; 29:136–153. System, PO Box 800341, Charlottesville, VA 22908; e-mail: [email protected]

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