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Wernicke’s encephalopathy in crack–cocaine addiction
Accepted Manuscript Wernicke’s Encephalopathy in Crack-Cocaine Addiction P.H. Sukop, F.H.P. Kessler, A.G. Valerio, M. Escobar, M. Castro, L.V. Diemen PII: DOI: Reference:
S0306-9877(16)00042-6 http://dx.doi.org/10.1016/j.mehy.2016.01.023 YMEHY 8176
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
7 November 2015 30 January 2016
Please cite this article as: P.H. Sukop, F.H.P. Kessler, A.G. Valerio, M. Escobar, M. Castro, L.V. Diemen, Wernicke’s Encephalopathy in Crack-Cocaine Addiction, Medical Hypotheses (2016), doi: http://dx.doi.org/ 10.1016/j.mehy.2016.01.023
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Wernicke’s Encephalopathy in Crack-Cocaine Addiction Sukop PH, MD1; Kessler FHP, MD PhD2; Valerio AG, MD3; Escobar M¹, MS; Castro M, MD4 Diemen LV, MD PhD4.
Graduate Program in Psychiatry and Behavior Sciences, Universidade Federal do Rio Grande do Sul, Brazil. Rua Ramiro Barcelos, 2400 Porto Alegre, RS 90035-003 Brazil Center for Alcohol and Drug Research Rua Prof. Alvaro Alvim, 400 Porto Alegre, RS 90420-020 Brazil +55 51 3359-6472
Corresponding author Paula H. Sukop e-mail: [email protected] Center for Alcohol and Drug Research Rua Prof. Alvaro Alvim, 400 Porto Alegre, RS 90420-020 Brazil +55 51 3359-6472 1
Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Brazil. 2 Psychiatry Department, Universidade Federal do Rio Grande do Sul, Brazil. 3 Center for Alcohol and Drug Research, Brazil. 4 Hospital de Clínicas de Porto Alegre, Brazil.
ABSTRACT
Hypothesis: Crack-cocaine addiction is associated with a variety of conditions that increase risk of thiamine deficiency and Wernicke’s encephalopathy. Evidence: We report a case of Wernicke’s encephalopathy in a crack-cocaine addict who did not habitually consume alcohol. We list some conditions associated with crack-cocaine addiction that may contribute to thiamine deficiency. Implications: Clinicians should bear in mind that crack-cocaine addiction may be associated with Wernicke’s encephalopathy, mainly due to malnutrition. We suggest that routine Wernicke’s encephalopathy prophylaxis with parenteral thiamine be provided to patients with chronic crack-cocaine addiction, as is already established practice in chronic alcoholics, so as to prevent cognitive damage in this population.
INTRODUCTION
Wernicke’s Encephalopathy Wernicke’s encephalopathy (WE) is a progressive neuropsychiatric syndrome characterized by clinical and subclinical episodes(1,2), both of which cause cumulative neurological damage resulting in cognitive dysfunction(3). Ophthalmoplegia, ataxia, and mental status changes are the three classical signs of WE, known as the classical triad. If not promptly recognized and treated, WE may progress in few days to chronic recent memory impairment (Korsakoff’s syndrome), coma, and death(4,5). Wernicke-Korsakoff’s syndrome (WKS) is not rare: according to post-mortem studies, its prevalence in the adult population may be as high as 2.8%(1). The etiology of WE involves deficiency of thiamine, a B-complex vitamin which is essential for glucose metabolism. Although neurons represent only 10% of brain cells, they are responsible for about 90% of brain glucose consumption. As glucose is the main source of energy for neurons, when thiamine deficiency (TD) impairs utilization of glucose as a substrate for neuronal energetic metabolism, the result is selective neuronal death(6). This leads to oxidative stress, decreased ATP synthesis,
glutamate
excitotoxicity,
inflammatory
responses,
decreased
neurogenesis, blood–brain barrier disruption, lactic acidosis, and a reduction in astrocyte functional integrity, with resulting neurodegeneration(5). Figure 1 shows a simplified illustration of glucose metabolism.
WE is,mainly known to affect chronic alcoholics(4,5), but may develop in any condition that interferes with adequate intake of thiamine or its absorption from the gut, reabsorption from the kidneys, and storage in the liver, as well as in states of enhanced metabolic demands(7). Thiamine is a micronutrient obtained exclusively from the diet. Its half-life is estimated at 9.5-18.5 days. Muscles account for 50% of thiamine content in the body, and body stores of this vitamin are not generally maintained above functional needs(8); in fact, they can be depleted in as soon as 18 days. Once depleted, thiamine levels cannot be restored simply by eating balanced meals, because intestinal absorption is rate-limited. Thiamine requirements are usually determined by total energy intake and the proportion of energy from carbohydrate(8,9). After periods of starvation/poor nutrition, refeeding may initiate TD (10). Diagnosis of WE remains clinical; there are no rapid, reliable, and routine diagnostic tests for this condition(7). Blood levels of thiamine can be measured, but there is no established threshold level above which patients would be safe from developing brain damage(11). Magnetic resonance imaging shows high specificity but poor (53%) sensitivity, and thus can only confirm clinical suspicion of WE(12). Despite being common and associated with severe consequences, WE is seriously underdiagnosed both in alcoholic and non-alcoholic patients. Cases seem to be missed due to the restrictive character of the classical triad and to beliefs that WE is rare and mainly related to chronic alcoholism(7). In fact, the triad is seen in only 16% of patients with WE, and about 80% percent of cases are diagnosed only after pathologic examination(13). Alcoholic WE is far more studied than WE precipitated by other conditions. A recent review of non-alcoholic WE
found that oculomotor abnormalities are more frequent, individuals are younger, have a shorter duration of precipitating illness, and more chronic cognitive impairment than in alcoholic WE(14). Mancinelli and Ceccanti warn that thiamine levels can be decreased by chronic use of drugs(15), but, to our knowledge, WE has never been described in any other form of addiction except for alcoholism. During its first year of operations, the Álvaro Alvim Addiction Service at Hospital de Clínicas de Porto Alegre (UAA/HCPA), Brazil, treated some cases of WE in individuals who were heavy crack-cocaine users. One did not drink alcoholic beverages at all, while the others abused alcohol but had no liver injury.
Crack Cocaine According to the United Nations World Drug Report, crack cocaine (CC) is consumed in at least 46 countries, in the Americas, Europe, Africa, and Asia(16). About 370,000 people are regular consumers of CC in Brazil(17). CC is a derivative of cocaine base paste that is smoked in the form of rocks. It is cheaper than cocaine powder. The effects of CC are immediate, intense, and last only a few minutes. These characteristics make it an extremely addictive form of cocaine, which should be distinguished from other forms(18,19). The urge to consume CC (craving) usually exceeds any other needs: individuals engage in extreme behavior to obtain money, buying and smoking crack uninterruptedly for days. The intense addictive effects of CC drive a significant proportion of its consumers to self-neglect: some live on the streets full-time; many do so for a few days when they binge. During binges, users miss work, have no care for their own
hygiene or health, and neither sleep nor eat(20). Cravings commonly lead to unsafe sex trade and minor criminal offenses. Crack-cocaine addicts (CCAs) have more chronic infectious diseases such as hepatitis B and C, HIV, and tuberculosis than the general population, and the binge pattern of use makes regular treatment of these conditions unfeasible(21). Thus, CCAs are exposed to an environment of high biological and social vulnerability(17). The anorectic effects of CC, coupled with cravings, seem to contribute to its users buying the drug instead of food(22). Studies have shed light on the problem of food scarcity and poor nutrient quality among drug addicts, revealing they eat relatively more carbohydrates and energy-dense foods(23–26). An ongoing study in Brazil asked a group of CCAs about consumption of thiamine-rich foods in the previous 3 weeks. Of 29 respondents, only two ate whole-grain foods once or twice a week; pork derivatives were consumed three times a week or fewer, as were black beans, lentils, or peanuts. The CCAs had a significantly lower BMI than agematched controls (mean ± SD, 21.74±2.86 in CCAs vs. 25.84±4.02 in controls; p<0.001; 95%CI -5.79 to -2.4)(27). A study conducted in Oslo found that 64% of interviewed drug addicts reported limited access to food; in the last 24 hours, 6% had not consumed any food and 47% of males had had a food intake corresponding to basal energy expenditure in a bed-rest condition(24). In a national survey about CC use in Brazil, 56.8% of CCAs reported weight loss in the preceding month and 96.92% (95%CI 95.77 to 97.76) cited “food availability” as one item a substance abuse treatment facility should offer, reflecting the problem of insufficient food(17).
Another feature of cocaine addiction is that cocaine withdrawal seems to be accompanied by overeating and excess weight gain. Food may be used as a substitute for the drug during episodes of craving(28).
HYPOTHESIS
Crack-cocaine addiction is associated with a variety of conditions that increase risk of TD and WE.
EMPIRICAL DATA
In this section, we report one of the cases of WE that occurred in our substance abuse treatment unit. S., a 34-year-old male addicted to inhaled cocaine since age 15 and to CC since age 22, was voluntarily admitted to the Addiction Unit (UAA/HCPA) in September 2012 for addiction treatment. He was otherwise healthy, had no abnormalities on blood chemistry tests, and tested negative for hepatitis, syphilis, and HIV. His body mass index was 20.2 kg/m2, but he had involuntarily lost 18% of his weight in the previous months. In the first 2 days after admission, he had a fully normal mental state examination, slept well, and complained meals were insufficient.
About 48 hours after admission, he began exhibiting brief muscular tremors of the lower limbs. Some hours later, he became restless, confused, anorectic, disoriented to place, and paranoid, and appeared to experience hallucinations. Physical examination detected horizontal nystagmus and ataxia; vital signs were normal. A presumptive diagnosis of WE was made and parenteral thiamine was prescribed. On the next morning, he had no hallucinatory or paranoid behavior, slight nystagmus, was still ataxic, and had a recent memory deficit. Over the following 4 days, he showed further improvement. On day 8, against medical advice, he self-discharged due to unwillingness to remain in the hospital and lack of motivation for treatment. He was still slightly ataxic and had a persistent mild memory impairment. Because of the improvement in symptoms observed after thiamine administration and difficulties in moving the patient to the radiology suite, no imaging was obtained.
DISCUSSION
Studies have shown that drug addicts eat fewer meals and foods with reduced nutritional value. Repeated episodes of starvation/low food intake, compounded by a diet rich in carbohydrates and poor in nutrients and by increased energy expenditure due to restlessness, contribute to insufficient thiamine supply and higher metabolic demand for thiamine in CCAs(23), resulting in marginal or
frank TD. States such as withdrawal overeating and infections may demand their remaining thiamine stores and trigger WE. Our patient, S., presented with ocular signs, memory impairment, and mental confusion, which meet criteria for a clinical diagnosis of WE. S. did not habitually drink alcohol and had no chronic infectious disease or other conditions that could explain his thiamine deficit. He had lost weight recently and presented to the addiction unit in a starving condition. When he resumed eating, energy metabolism requisitioned what little thiamine was left in his body, thus triggering WE. The fact that our patient’s symptoms started soon after he resumed eating may be understood as a refeeding syndrome (RS). That is not the case: RS is characterized by preexisting hypophosphatemia and, sometimes, magnesium and potassium deficits, and correction of fluid-electrolyte imbalances is necessary to reverse symptoms(10,29). S. had no electrolyte imbalance and responded promptly to thiamine administration. Moreover, TD may be a feature of RS, but they are distinct entities(29). It is possible that WE in crack-cocaine addicts is a consequence of chronic poor feeding plus alcohol abuse. In fact, are commonly multiple drug abusers and have a high prevalence of alcohol abuse(17). However, in our three cases, alcohol may have only impaired intestinal absorption of thiamine, because none had liver injury. In alcohol dependents, hepatic damage due to chronic heavy drinking and the increased thiamine demands that occur during the hypermetabolic state of alcohol withdrawal play an important role in the development of WE(4), features that are absent in the case of S. and in CCAs in general.
The case of S. fits the pattern of non-alcoholic WE described by Scalzo et al(14). The patient was relatively young (34 years old), had consumed CC for 12 years, and developed nystagmus. We were unable to obtain information about out patient’s emergency care before his admission to UAA/HCPA. Parenteral glucose is sometimes prescribed by clinicians to patients who report prolonged starvation. This may also trigger WE. WE may also be related to genetic mutations. However, to date, all mutations known to be linked to WE require a diet deficient or marginally deficient in thiamine to trigger the syndrome(30). In any event, genetic factors would merely explain an individual predisposition.
CONCLUSION
WE is a common disorder and is easily and inexpensively treated. There are no contraindications to thiamine prophylaxis and no severe adverse effects that would preclude it. Individuals can achieve full recovery if the diagnosis is made promptly. Therefore, prognosis relies on early diagnosis, which succeeds only when clinical suspicion is high. Unfortunately, cases are still frequently missed, resulting in permanent disability or even death. This paper sought to inform clinicians that crack-cocaine addiction appears to be one more condition associated with WE.
As in chronic alcoholism, we believe part of the cognitive decline crackcocaine addicts exhibit(31) is attributable to cumulative neuronal damage from clinical and subclinical WE episodes. Taking into account the progressive nature of WE(1,2), we raise the question: shouldn’t routine WE prophylaxis also be provided to patients with a history of chronic crack-cocaine addiction? We support the idea that CCAs are malnourished individuals and, until studies produce evidence of which CCA subgroups are at risk of WE, we suggest that routine WE prophylaxis be given to patients with chronic crack-cocaine addiction, as is already established practice for chronic alcoholics, aiming not only to prevent WE but also to decrease cognitive damage in this population. Furthermore, it is advisable to test for other B complex deficiencies that may also be present in such malnourished patients. Finally, we reiterate the need for studies addressing cognitive decline and its relation to diet and nutritional status in CCAs.
Conflicts of Interest All authors declare no conflict of interest.
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Antunez E, Estruch R, Cardenal C, Nicolas J, Fernandez-Sola J, UrbanoMarquez A. Usefulness of CT and MR imaging in the diagnosis of acute Wernicke’s encephalopathy. Am J Roentgenol. 1998;171(4):1131–7.
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Harper CG, Giles M, Finlay-Jones R. Clinical signs in the Wernicke-Korsakoff complex: a retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry. 1986;49(4):341–5.
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Scalzo SJ, Bowden SC, Ambrose ML, Whelan G, Cook MJ. WernickeKorsakoff syndrome not related to alcohol use : a systematic review. J Neurol Neurosurg Psychiatry. 2015;1–7. doi: 10.1136/jnnp-2014-309598.
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Mancinelli R, Ceccanti M. Biomarkers in alcohol misuse: their role in the prevention and detection of thiamine deficiency. Alcohol Alcohol. 2009; 44(2):177–82.
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United Nations Office on Drugs and Crime. World Drug Report 2014 [Internet]
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Bastos F, Bertoni N. Pesquisa Nacional sobre o uso de crack: Quem são os usuários de crack e/ou similares do Brasil? Quantos são nas capitais brasileiras?
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Donato EM, Rezende EP, Ribeiro M SC. Farmacologia e neurobiologia do consumo de crack. In: Ribeiro M, Laranjeira R, editors. O Tratamento do Usuário de Crack: avaliação clínica, psicossocial, neuropsicológica e de risco Terapias psicológicas, farmacoterapia e reabilitação. Ambientes de tratamento. São Paulo: Casa Leitura Médica; 2010. p. 76–89.
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DuPont R. Crack Cocaine: A Challenge for Prevention. OSAP Prevention Monograph-9. Rockville; 1991.
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Inciardi JA, Surratt HL, Pechansky F, Kessler F, von Diemen L, da Silva EM, et al. Changing patterns of cocaine use and hiv risks in the south of Brazil. J Psychoactive Drugs. 2006; 38(3):305–10.
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Sukop P, Kessler F, Valerio A, Escobar M, Silva M, Diemen L. Association between crack cocaine dependence and blood levels of thiamine and
aluminum. [Porto Alegre, Brazil]: Unpublished dataset, cited with permission; 2015. 28.
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GLUCOSE METABOLISM
TPP α-Ketoglutarate TPP
Glycolytic enzymes Glucose
KDHC
Citric acid cycle Pyruvate
PDHC
Acetyl-CoA
CS
Citrate
Succinyl-CoA
Acetylcholine NAA Fatty acid synthesis Maintenance of myelin sheaths
Figure 1. PDHC, pyruvate dehydrogenase complex; TPP, thiamine pyrophosphate; CS, citrate synthase; KDHC, ketoglutarate dehydrogenase complex. Adapted from Szutowicz 2013, Butterworth 20036,44.
Table1 Conditions that may produce thiamine deficiency in crack-cocaine addicts Cause of thiamine Associated features of crack- cocaine addiction deficiency Insufficient ingestion Food deprivation in active addiction: binge pattern of use, lack of money, anorectic effect of cocaine19,20,23–25 High-carbohydrate, low-vitamin diet 23,24,29 Impaired absorption from GI complications: ischemia, inflammation, perforation, the gut obstruction, loss of villi30–34 GI alkalization leading to thiamine inactivation35 Intermittent alcohol use35 Intake of caffeic acid and tannins leading to thiamine inactivation35,36 Impaired renal Renal toxicity: acute and chronic renal failure, renal reabsorption infarction37 Decreased storage in the Lower BMI26,38 liver and muscles Hepatic complications: ischemia, necrosis, hemorrhage, viral hepatitis22 Rhabdomyolysis37 Increased demands
metabolic Refeeding10,39 Chronic infectious tuberculosis17 Restlessness40,41
diseases:
HIV,
HBV,
HCV,
GI, gastrointestinal; BMI, body mass index; HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus.
S0306-9877(16)00042-6 http://dx.doi.org/10.1016/j.mehy.2016.01.023 YMEHY 8176
To appear in:
Medical Hypotheses
Received Date: Accepted Date:
7 November 2015 30 January 2016
Please cite this article as: P.H. Sukop, F.H.P. Kessler, A.G. Valerio, M. Escobar, M. Castro, L.V. Diemen, Wernicke’s Encephalopathy in Crack-Cocaine Addiction, Medical Hypotheses (2016), doi: http://dx.doi.org/ 10.1016/j.mehy.2016.01.023
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Wernicke’s Encephalopathy in Crack-Cocaine Addiction Sukop PH, MD1; Kessler FHP, MD PhD2; Valerio AG, MD3; Escobar M¹, MS; Castro M, MD4 Diemen LV, MD PhD4.
Graduate Program in Psychiatry and Behavior Sciences, Universidade Federal do Rio Grande do Sul, Brazil. Rua Ramiro Barcelos, 2400 Porto Alegre, RS 90035-003 Brazil Center for Alcohol and Drug Research Rua Prof. Alvaro Alvim, 400 Porto Alegre, RS 90420-020 Brazil +55 51 3359-6472
Corresponding author Paula H. Sukop e-mail: [email protected] Center for Alcohol and Drug Research Rua Prof. Alvaro Alvim, 400 Porto Alegre, RS 90420-020 Brazil +55 51 3359-6472 1
Graduate Program in Psychiatry and Behavioral Sciences, Universidade Federal do Rio Grande do Sul, Brazil. 2 Psychiatry Department, Universidade Federal do Rio Grande do Sul, Brazil. 3 Center for Alcohol and Drug Research, Brazil. 4 Hospital de Clínicas de Porto Alegre, Brazil.
ABSTRACT
Hypothesis: Crack-cocaine addiction is associated with a variety of conditions that increase risk of thiamine deficiency and Wernicke’s encephalopathy. Evidence: We report a case of Wernicke’s encephalopathy in a crack-cocaine addict who did not habitually consume alcohol. We list some conditions associated with crack-cocaine addiction that may contribute to thiamine deficiency. Implications: Clinicians should bear in mind that crack-cocaine addiction may be associated with Wernicke’s encephalopathy, mainly due to malnutrition. We suggest that routine Wernicke’s encephalopathy prophylaxis with parenteral thiamine be provided to patients with chronic crack-cocaine addiction, as is already established practice in chronic alcoholics, so as to prevent cognitive damage in this population.
INTRODUCTION
Wernicke’s Encephalopathy Wernicke’s encephalopathy (WE) is a progressive neuropsychiatric syndrome characterized by clinical and subclinical episodes(1,2), both of which cause cumulative neurological damage resulting in cognitive dysfunction(3). Ophthalmoplegia, ataxia, and mental status changes are the three classical signs of WE, known as the classical triad. If not promptly recognized and treated, WE may progress in few days to chronic recent memory impairment (Korsakoff’s syndrome), coma, and death(4,5). Wernicke-Korsakoff’s syndrome (WKS) is not rare: according to post-mortem studies, its prevalence in the adult population may be as high as 2.8%(1). The etiology of WE involves deficiency of thiamine, a B-complex vitamin which is essential for glucose metabolism. Although neurons represent only 10% of brain cells, they are responsible for about 90% of brain glucose consumption. As glucose is the main source of energy for neurons, when thiamine deficiency (TD) impairs utilization of glucose as a substrate for neuronal energetic metabolism, the result is selective neuronal death(6). This leads to oxidative stress, decreased ATP synthesis,
glutamate
excitotoxicity,
inflammatory
responses,
decreased
neurogenesis, blood–brain barrier disruption, lactic acidosis, and a reduction in astrocyte functional integrity, with resulting neurodegeneration(5). Figure 1 shows a simplified illustration of glucose metabolism.
WE is,mainly known to affect chronic alcoholics(4,5), but may develop in any condition that interferes with adequate intake of thiamine or its absorption from the gut, reabsorption from the kidneys, and storage in the liver, as well as in states of enhanced metabolic demands(7). Thiamine is a micronutrient obtained exclusively from the diet. Its half-life is estimated at 9.5-18.5 days. Muscles account for 50% of thiamine content in the body, and body stores of this vitamin are not generally maintained above functional needs(8); in fact, they can be depleted in as soon as 18 days. Once depleted, thiamine levels cannot be restored simply by eating balanced meals, because intestinal absorption is rate-limited. Thiamine requirements are usually determined by total energy intake and the proportion of energy from carbohydrate(8,9). After periods of starvation/poor nutrition, refeeding may initiate TD (10). Diagnosis of WE remains clinical; there are no rapid, reliable, and routine diagnostic tests for this condition(7). Blood levels of thiamine can be measured, but there is no established threshold level above which patients would be safe from developing brain damage(11). Magnetic resonance imaging shows high specificity but poor (53%) sensitivity, and thus can only confirm clinical suspicion of WE(12). Despite being common and associated with severe consequences, WE is seriously underdiagnosed both in alcoholic and non-alcoholic patients. Cases seem to be missed due to the restrictive character of the classical triad and to beliefs that WE is rare and mainly related to chronic alcoholism(7). In fact, the triad is seen in only 16% of patients with WE, and about 80% percent of cases are diagnosed only after pathologic examination(13). Alcoholic WE is far more studied than WE precipitated by other conditions. A recent review of non-alcoholic WE
found that oculomotor abnormalities are more frequent, individuals are younger, have a shorter duration of precipitating illness, and more chronic cognitive impairment than in alcoholic WE(14). Mancinelli and Ceccanti warn that thiamine levels can be decreased by chronic use of drugs(15), but, to our knowledge, WE has never been described in any other form of addiction except for alcoholism. During its first year of operations, the Álvaro Alvim Addiction Service at Hospital de Clínicas de Porto Alegre (UAA/HCPA), Brazil, treated some cases of WE in individuals who were heavy crack-cocaine users. One did not drink alcoholic beverages at all, while the others abused alcohol but had no liver injury.
Crack Cocaine According to the United Nations World Drug Report, crack cocaine (CC) is consumed in at least 46 countries, in the Americas, Europe, Africa, and Asia(16). About 370,000 people are regular consumers of CC in Brazil(17). CC is a derivative of cocaine base paste that is smoked in the form of rocks. It is cheaper than cocaine powder. The effects of CC are immediate, intense, and last only a few minutes. These characteristics make it an extremely addictive form of cocaine, which should be distinguished from other forms(18,19). The urge to consume CC (craving) usually exceeds any other needs: individuals engage in extreme behavior to obtain money, buying and smoking crack uninterruptedly for days. The intense addictive effects of CC drive a significant proportion of its consumers to self-neglect: some live on the streets full-time; many do so for a few days when they binge. During binges, users miss work, have no care for their own
hygiene or health, and neither sleep nor eat(20). Cravings commonly lead to unsafe sex trade and minor criminal offenses. Crack-cocaine addicts (CCAs) have more chronic infectious diseases such as hepatitis B and C, HIV, and tuberculosis than the general population, and the binge pattern of use makes regular treatment of these conditions unfeasible(21). Thus, CCAs are exposed to an environment of high biological and social vulnerability(17). The anorectic effects of CC, coupled with cravings, seem to contribute to its users buying the drug instead of food(22). Studies have shed light on the problem of food scarcity and poor nutrient quality among drug addicts, revealing they eat relatively more carbohydrates and energy-dense foods(23–26). An ongoing study in Brazil asked a group of CCAs about consumption of thiamine-rich foods in the previous 3 weeks. Of 29 respondents, only two ate whole-grain foods once or twice a week; pork derivatives were consumed three times a week or fewer, as were black beans, lentils, or peanuts. The CCAs had a significantly lower BMI than agematched controls (mean ± SD, 21.74±2.86 in CCAs vs. 25.84±4.02 in controls; p<0.001; 95%CI -5.79 to -2.4)(27). A study conducted in Oslo found that 64% of interviewed drug addicts reported limited access to food; in the last 24 hours, 6% had not consumed any food and 47% of males had had a food intake corresponding to basal energy expenditure in a bed-rest condition(24). In a national survey about CC use in Brazil, 56.8% of CCAs reported weight loss in the preceding month and 96.92% (95%CI 95.77 to 97.76) cited “food availability” as one item a substance abuse treatment facility should offer, reflecting the problem of insufficient food(17).
Another feature of cocaine addiction is that cocaine withdrawal seems to be accompanied by overeating and excess weight gain. Food may be used as a substitute for the drug during episodes of craving(28).
HYPOTHESIS
Crack-cocaine addiction is associated with a variety of conditions that increase risk of TD and WE.
EMPIRICAL DATA
In this section, we report one of the cases of WE that occurred in our substance abuse treatment unit. S., a 34-year-old male addicted to inhaled cocaine since age 15 and to CC since age 22, was voluntarily admitted to the Addiction Unit (UAA/HCPA) in September 2012 for addiction treatment. He was otherwise healthy, had no abnormalities on blood chemistry tests, and tested negative for hepatitis, syphilis, and HIV. His body mass index was 20.2 kg/m2, but he had involuntarily lost 18% of his weight in the previous months. In the first 2 days after admission, he had a fully normal mental state examination, slept well, and complained meals were insufficient.
About 48 hours after admission, he began exhibiting brief muscular tremors of the lower limbs. Some hours later, he became restless, confused, anorectic, disoriented to place, and paranoid, and appeared to experience hallucinations. Physical examination detected horizontal nystagmus and ataxia; vital signs were normal. A presumptive diagnosis of WE was made and parenteral thiamine was prescribed. On the next morning, he had no hallucinatory or paranoid behavior, slight nystagmus, was still ataxic, and had a recent memory deficit. Over the following 4 days, he showed further improvement. On day 8, against medical advice, he self-discharged due to unwillingness to remain in the hospital and lack of motivation for treatment. He was still slightly ataxic and had a persistent mild memory impairment. Because of the improvement in symptoms observed after thiamine administration and difficulties in moving the patient to the radiology suite, no imaging was obtained.
DISCUSSION
Studies have shown that drug addicts eat fewer meals and foods with reduced nutritional value. Repeated episodes of starvation/low food intake, compounded by a diet rich in carbohydrates and poor in nutrients and by increased energy expenditure due to restlessness, contribute to insufficient thiamine supply and higher metabolic demand for thiamine in CCAs(23), resulting in marginal or
frank TD. States such as withdrawal overeating and infections may demand their remaining thiamine stores and trigger WE. Our patient, S., presented with ocular signs, memory impairment, and mental confusion, which meet criteria for a clinical diagnosis of WE. S. did not habitually drink alcohol and had no chronic infectious disease or other conditions that could explain his thiamine deficit. He had lost weight recently and presented to the addiction unit in a starving condition. When he resumed eating, energy metabolism requisitioned what little thiamine was left in his body, thus triggering WE. The fact that our patient’s symptoms started soon after he resumed eating may be understood as a refeeding syndrome (RS). That is not the case: RS is characterized by preexisting hypophosphatemia and, sometimes, magnesium and potassium deficits, and correction of fluid-electrolyte imbalances is necessary to reverse symptoms(10,29). S. had no electrolyte imbalance and responded promptly to thiamine administration. Moreover, TD may be a feature of RS, but they are distinct entities(29). It is possible that WE in crack-cocaine addicts is a consequence of chronic poor feeding plus alcohol abuse. In fact, are commonly multiple drug abusers and have a high prevalence of alcohol abuse(17). However, in our three cases, alcohol may have only impaired intestinal absorption of thiamine, because none had liver injury. In alcohol dependents, hepatic damage due to chronic heavy drinking and the increased thiamine demands that occur during the hypermetabolic state of alcohol withdrawal play an important role in the development of WE(4), features that are absent in the case of S. and in CCAs in general.
The case of S. fits the pattern of non-alcoholic WE described by Scalzo et al(14). The patient was relatively young (34 years old), had consumed CC for 12 years, and developed nystagmus. We were unable to obtain information about out patient’s emergency care before his admission to UAA/HCPA. Parenteral glucose is sometimes prescribed by clinicians to patients who report prolonged starvation. This may also trigger WE. WE may also be related to genetic mutations. However, to date, all mutations known to be linked to WE require a diet deficient or marginally deficient in thiamine to trigger the syndrome(30). In any event, genetic factors would merely explain an individual predisposition.
CONCLUSION
WE is a common disorder and is easily and inexpensively treated. There are no contraindications to thiamine prophylaxis and no severe adverse effects that would preclude it. Individuals can achieve full recovery if the diagnosis is made promptly. Therefore, prognosis relies on early diagnosis, which succeeds only when clinical suspicion is high. Unfortunately, cases are still frequently missed, resulting in permanent disability or even death. This paper sought to inform clinicians that crack-cocaine addiction appears to be one more condition associated with WE.
As in chronic alcoholism, we believe part of the cognitive decline crackcocaine addicts exhibit(31) is attributable to cumulative neuronal damage from clinical and subclinical WE episodes. Taking into account the progressive nature of WE(1,2), we raise the question: shouldn’t routine WE prophylaxis also be provided to patients with a history of chronic crack-cocaine addiction? We support the idea that CCAs are malnourished individuals and, until studies produce evidence of which CCA subgroups are at risk of WE, we suggest that routine WE prophylaxis be given to patients with chronic crack-cocaine addiction, as is already established practice for chronic alcoholics, aiming not only to prevent WE but also to decrease cognitive damage in this population. Furthermore, it is advisable to test for other B complex deficiencies that may also be present in such malnourished patients. Finally, we reiterate the need for studies addressing cognitive decline and its relation to diet and nutritional status in CCAs.
Conflicts of Interest All authors declare no conflict of interest.
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GLUCOSE METABOLISM
TPP α-Ketoglutarate TPP
Glycolytic enzymes Glucose
KDHC
Citric acid cycle Pyruvate
PDHC
Acetyl-CoA
CS
Citrate
Succinyl-CoA
Acetylcholine NAA Fatty acid synthesis Maintenance of myelin sheaths
Figure 1. PDHC, pyruvate dehydrogenase complex; TPP, thiamine pyrophosphate; CS, citrate synthase; KDHC, ketoglutarate dehydrogenase complex. Adapted from Szutowicz 2013, Butterworth 20036,44.
Table1 Conditions that may produce thiamine deficiency in crack-cocaine addicts Cause of thiamine Associated features of crack- cocaine addiction deficiency Insufficient ingestion Food deprivation in active addiction: binge pattern of use, lack of money, anorectic effect of cocaine19,20,23–25 High-carbohydrate, low-vitamin diet 23,24,29 Impaired absorption from GI complications: ischemia, inflammation, perforation, the gut obstruction, loss of villi30–34 GI alkalization leading to thiamine inactivation35 Intermittent alcohol use35 Intake of caffeic acid and tannins leading to thiamine inactivation35,36 Impaired renal Renal toxicity: acute and chronic renal failure, renal reabsorption infarction37 Decreased storage in the Lower BMI26,38 liver and muscles Hepatic complications: ischemia, necrosis, hemorrhage, viral hepatitis22 Rhabdomyolysis37 Increased demands
metabolic Refeeding10,39 Chronic infectious tuberculosis17 Restlessness40,41
diseases:
HIV,
HBV,
HCV,
GI, gastrointestinal; BMI, body mass index; HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus.