# 2008 The Authors Journal compilation # 2008 Blackwell Munksgaard
Acta Neuropsychiatrica 2008: 20: 152–156 All rights reserved DOI: 10.1111/j.1601-5215.2008.00285.x
ACTA NEUROPSYCHIATRICA
Case report
Delayed-onset delirium tremens – a diagnostic and management challenge Saddichha S, Manjunatha N, Sinha BNP, Khess CRJ. Delayed-onset delirium tremens – a diagnostic and management challenge. Background: Delirium tremens (DT) is one of the most serious complications of alcohol withdrawal, affecting 5–10% of in-patients with a mortality rate up to 15%. DT, characterised by delirium and tremors, appears within 48–72 h of abstinence and persists for about 5–10 days. Case presentation: We report a case of DT in a young man with delayed onset on the 15th day after the cessation of alcohol use, despite an uncomplicated detoxification with benzodiazepine treatment. Conclusion: We hypothesise that the intake of country liquor in our patient, which contains higher percentages of alcohol, causes a prolonged imbalance of N-methyl-D-aspartic acid and glutamate receptor activity, leading to the picture of delayed-onset DT and that an atypical presentation at the time of admission and atypicality in early course are clinical pointers to the subsequent development of delayed-onset DT.
Introduction
Delirium tremens (DT), first described by Victor and Adams (1) as well as by Isbell et al. (2), is one of the most serious complications of alcohol withdrawal, affecting 5–10% of in-patients (3). DT has high mortality rate of up to 15% (3), which has been reduced to 2–5% (4) because of improved early treatment. There are several features described (5), which in most cases appear within 48–72 h of abstinence and persist for about 5–10 days, with 62% resolving in 5 days or less (6). Although DT typically remits over a period of several days (3), cases persisting for weeks have been reported (7). The risk factors for development of DT are presence of ongoing infection, tachycardia at admission, withdrawal signs with blood alcohol level more than 1 g/l, history of seizures or delirious episodes (5) or higher-than-usual quantity and frequency of ethanol consumption. We report a case of DT in a young man with delayed onset on the 15th day after the cessation of alcohol use, with a usual course of 4–5 days, despite an uncomplicated detoxification with benzodiazepine treatment. 152
Sahoo Saddichha1, Narayana Manjunatha2, Baxi Neeraj Prasad Sinha3, Christoday R.J. Khess2 1 National Tobacco Control Program, WHO India, Kolkata, India; 2Centre for Addiction Psychiatry, Central Institute of Psychiatry, Kanke, Ranchi, India; and 3Clifton House, Teesdale South, Thornaby Place, Stockton-on-Tees, UK
Keywords: delayed onset; delirium tremens Sahoo Saddichha, National Tobacco Control Program, WHO India, Kolkata, India. Tel: +919836530262; Fax: +916742572660; Email: [email protected]
Case presentation Case history
The patient was a 34-year-old married man, who at the time of admission was living with his wife and working as an attender in a school. He hailed from a semi-urban background and belonged to middle socio-economic class. He had been attending to his duties until several months before this admission when, because of his alcohol use, he began to absent himself from his job. He described himself as having been a Ôsocial drinker’ for the last 17 years who, over the preceding 6 years, had substantially increased his drinking in response to escalating job-related stress. On admission, he reported drinking between 1 and 2 l of country liquor daily, beginning each morning. He acknowledged having withdrawal tremors and tolerance, an inability to control his intake of alcohol and the presence of alcohol-related interpersonal and vocational problems. He also described difficulty in walking and carrying out any voluntary activities such as brewing coffee or tea, eating food with a spoon, holding a glass, etc. and signing any document holding a pen for the past 4 months, resulting in significant socio-occupational
Delayed-onset DT impairment. His last drink had been about 3.5 l of country liquor 7–8 h before admission. He had never attempted to remain abstinent or undergo detoxification for alcoholism at any point of time in his life. There was no history of seizures or delirium at any time before admission. There was no history of use of any substances other than alcohol and nicotine or the use of any medications or benzodiazepines. There was no history of any psychiatric or medical problems. He had a family history of alcohol dependence in second-degree relatives and his father had a history of social drinking who had previously been in the military services. He reported that during the preceding year, he had not gone more than a day without consuming alcohol. Initial assessment
On admission, the patient was neatly dressed. He weighed 55 kg and stood 5 feet 10 inches tall. He was fully conscious and alert. His complexion was dark but healthy, and on examination, he was found to have a tremor of his tongue and extremities. Although the patient was afebrile, his pulse rate was 102 b/min, and his blood pressure was 148/100 mmHg. Physical examination at the time of admission revealed that patient had tender hepatomegaly 1 cm below the right costal margin. Results of cardiac and lung examination were normal. Furthermore, a neurological examination revealed that he had nystagmus, dysarthric speech and positive cerebellar signs such as inability to perform heel-shin test and dysdiadokinesia with a broad-based ataxic gait, impaired tandem walking, intention tremor and positive Romberg’s test. Deep tendon reflex examination revealed hyporeflexia of the distal supinator and ankle jerks, pendular knee jerk and hypotonia of lower limbs suggestive of cerebellar signs. The presence of nystagmus and ataxia with the absence of confusion led to a presumptive diagnosis of Wernicke’s encephalopathy as per Maudsley guidelines (8). Mental status examination revealed the patient to be alert, cooperative and oriented in all the spheres. He was euthymic, and his thinking was logical. He showed no evidence of gross cognitive deficits: short- and long-term memory was intact, as were attention, concentration and executive functions, and he was of average intelligence. He had no thought or perceptual disorders. He was admitted to our Center of Addiction Psychiatry. Hospital course
Considering his age, the extent of his alcohol consumption and the degree of tolerance that he
reported, the patient was considered to be at risk for a moderate-to-severe alcohol withdrawal syndrome. Consequently, treatment was initiated with 100 mg i.m. of thiamine, oral lorazepam at a dose of 2 mg every 6 h, metadoxil 500 mg b.i.d. and oral multivitamin preparation once daily. Metadoxil (metadoxine) is a pyridoxine-pyrrolidone carboxylate, which is useful in treatment of alcoholic liver disease by accelerating the elimination of alcohol from the blood and tissues, helping restore the functional structure of the liver and relieving neuropsychological disorders associated with alcohol intoxication. Admission laboratory work revealed an elevated serum glutamic oxaloacetic transaminase (SGOT) (103 mg/ml), gamma glutamyl transpeptidase (GGT) (225 mg/dl) and total bilirubin (1.7 mg %); otherwise, the complete blood count (CBC), electrolytes and renal function test results were all within normal limits. Urine screening for other substances including benzodiazepines was negative. On the first hospital day, his vitals were stable but he had repeated falls while going to the toilet. He had difficulty in getting up from the bed and walking unsupported. There was, however, no signs suggestive of head trauma or raised intracranial pressure or other neurological signs to suggest a neurological disorder. On the second day, his pulse was 96 b/min, and his blood pressure was 140/90 mmHg along with persisting cerebellar signs. On the fourth day, his vitals stabilised, but he developed moderate-grade fever for which he was treated with antibiotics and antipyretics up to the next 5 days. Routine work up for fever was non-specific including negative test on the malarial parasite quantitative buffy coat (QBC) and negative blood cultures. However, all vitals and neurological signs returned to normal including cerebellar signs by the end of the first week, consistent with the usual course of uncomplicated alcohol withdrawal. Medications during this period included lorazepam 2 mg p.o. every 6 h on days 1–4, tapered to 2 mg p.o. every 8 h on day 5. The patient received a total of 8 mg of lorazepam over the first 24-h period, 8 mg over the second, third and fourth days, with it being tapered off by the end of the first week. After an initial 100 mg i.m. of thiamine, he continued to receive 100 mg/day i.m. of thiamine daily for the first week, and metadoxil and multivitamin capsules were continued. Although, throughout this period, the patient continued to have a mild tremor, he ate and slept well and was alert and oriented, with a clear sensorium and intact cognitive functioning. He remained asymptomatic until the 14th day including absence of any seizures. 153
Saddichha et al. On the 14th hospital day, the patient’s condition deteriorated. He started complaining of seeing things (visual hallucinations) and an unknown fear for his life (delusion of persecution). He became increasingly confused, agitated and disoriented to place, person and time. The confusion and agitation were more pronounced in the evening and necessitated the use of sedation. Although the presentation of marked disorientation, global confusion, inability to fall asleep, suspiciousness, paranoid ideation, feelings of guilt, visual hallucinations, tremulousness of whole body and periods of agitation alternating with a decreased level of consciousness was consistent with DT, a search was initiated for other medical causes of the delirium considering the delayed onset. Physical examination revealed no evidence of infection or trauma, and there were no neurological signs consistent with a cerebral insult or Wernicke’s encephalopathy. However, cerebellar signs reappeared and continued till resolution of delirium 4 days later. Results of all laboratory work did not reveal any abnormality. Electrocardiogram did not reveal any abnormality. A working diagnosis of DTdelayed onset was made with the available clinical information. Parenteral administration of thiamine was resumed, and injectable haloperidol 10 mg and lorazepam 4 mg/day i.m. were initiated. Autonomic instability was well controlled with injectable lorazepam, and the benzodiazepine was gradually tapered over the next 7 days of hospitalisation. Intravenous hydration became necessary because the patient’s agitation limited his ability to take oral fluids or nutrition. Injectable haloperidol 5 mg b.i.d. was given to manage the agitation and presence of psychotic symptoms. On the 18th hospital day (i.e. the fourth day of DT), increased cooperation of the patient enabled us to perform a computed tomography (CT) – plain and contrast scan of the head, to rule out any intracranial lesion. The results of this were unremarkable; there was no evidence of the presence of a mass or fluid collection and no evidence of cerebral atrophy. Quantitative electroencephalogram (EEG) revealed no abnormality except lowamplitude beta waves. The onset of delirium in an individual dependent on alcohol consistent with the normal course of 4–5 days for DT, as well as the absence of evidence for an alternative diagnosis, supported the working diagnosis of DT. During the next 2 weeks (18–30 days from admission), the patient’s level of alertness, psychomotor activity, orientation and understanding remained at admission levels. On the basis of this evidence of improvement, the treating team decided that continued services could be provided in a less intensive setting. 154
Consequently, on the 35th hospital day, the patient was discharged with multivitamin capsules daily and naltrexone 50 mg/day as anti-craving medication. He remained oriented, fully conscious and alert. Physical examination was unremarkable, and cerebellar signs had almost resolved. DSM-IV axis I discharge diagnoses were as follows: alcohol dependence and alcohol withdrawal delirium and axis III diagnosis of Wernicke’s encephalopathy. On two subsequent follow-ups in the next 3 months, the patient was maintaining well with naltrexone and multivitamins.
Discussion
The management of DT poses many medical challenges, which begin from the time of diagnosis. An accurate history is therefore vitally important for diagnosis and treatment of DT. It is imperative for the clinician to maintain a high level of suspicion and closely monitor this syndrome that can lead to an increased length of hospital stay and increased number of medications being used.
Diagnostic dilemma
In the above case, the onset and progression of the confusional state described herein were consistent with DT, although the delayed onset was a hindering factor. Hence, it was clinically necessary to consider other medical and surgical problems that might have caused the patient’s altered mental status. Metabolic or endocrinal abnormalities, hepatic encephalopathy, infection and an intracranial lesion such as a subdural haematoma deserved special consideration. Physical examination, blood work and a normal CT of the head excluded these conditions as being of aetiological significance. Given the concern that covert use of benzodiazepines might have contributed to the patientÔs confusional state, it was specifically ruled out in the history and urine screening. Because medical illness appears to increase both the likelihood that DT will develop and its severity and duration, rapid identification and treatment of infections, hepatic insufficiency and traumatic injuries are crucial. The detection and correction of metabolic abnormalities such as hyponatraemia or hypernatraemia, hypokalaemia, hypomagnesaemia and hypocalcaemia are also important because these conditions may contribute to mental status changes that may predispose the individual to DT (9).
Delayed-onset DT While the EEG in the delirious patient usually shows diffuse slowing of background activity, in the case of alcohol withdrawal delirium, the EEG often shows excessive low-amplitude fast activity (10), which was consistent with our findings. Although CT scan of our patient did not reveal any abnormalities, neuroimaging has been noted to detect changes not only in alcohol dependence and withdrawal (11) but also in recreational users (12). Although DSM-IV has not specified the duration during which DT can be diagnosed after cessation or stoppage of alcohol, literature allows that withdrawal delirium can persist for up to 4 weeks (7,13). Miller (7) described a case of two episodes of protracted DT. The first episode lasted approximately 6 weeks and was complicated by neurosurgical problems. The second episode, occurring almost a year later, persisted for nearly 3 weeks in the absence of comorbid medical or surgical illness. Therefore, although available literature makes out a case for protracted DT, the same is not the case with delayed-onset DT. The presence of Wernicke’s encephalopathy is diagnosed by the classical triad of ataxia, nystagmus and confusion. However, this clinical triad is present in only 14–16% of patients (14), including our patient who had only ataxia and nystagmus. Wernicke’s encephalopathy is an underdiagnosed entity (15): one large autopsy study of alcoholics found that only 20% had been correctly diagnosed ante-mortem (15). Thus, a high index of suspicion is required: in this regard, one must not be fooled by the age of the patient as Wernicke’s encephalopathy has occurred in alcoholics as young as 18 years old (16). Pathophysiology
DT is caused by the direct effect that ethanol has on the benzodiazepine-gamma-aminobutyric acid (A)chloride receptor complex. Persistent effects of ethanol lead to the downregulation of the receptor complex. When ethanol is withdrawn, a functional decrease in the inhibitory neurotransmitter gammaaminobutyric acid is seen. This results in an unopposed increase in sympathetic activity with a resultant increase in plasma and urinary catecholamines. Ethanol also acts as an N-methyl-D-aspartate receptor antagonist. Withdrawal of ethanol leads to increased activity of these excitatory neural receptors (17,18) causing the clinical picture of delirium. There is also evidence that chronic heavy drinkers (up to 10 years) may have alterations in their gamma-aminobutyric acid benzodiazepine system, rendering them less responsive to benzodiazepines (19). However, in our case, the patient had developed DT after 6 years of
regular heavy drinking, which is an atypical feature. We hypothesise that the intake of country liquor in our patient, which contains higher percentages of alcohol (20), causes a prolonged imbalance of Nmethyl-D-aspartic acid and glutamate receptor activity, leading to the picture of delayed-onset DT. Country liquor, in any case, is one of the most prevalent forms of alcohol used in rural and semi-urban areas of India with rates up to 70% noted (21,22). The development of delirium in spite of an uncomplicated detoxification period and relatively delayed onset in a young patient and the fact that the patient was in a deaddiction centre with strict abstinence assured, however, raises several clinical questions about the other pathophysiologies involved. It has been hypothesised that whereas withdrawal symptoms such as autonomic hyperactivity are the result of recent physical dependence on alcohol, DT results from irreversible, cumulative changes in the central nervous system caused by years of heavy alcohol consumption. Therefore, a pre-set Ôpoint of no return’ determined by the patient’s drinking and withdrawal history may exist and for some individuals may make delirium an inevitable result of the abrupt cessation of alcohol intake (23). Another factor to be considered is the development of fever in our patient during detoxification, albeit for a short period. This may have led to a dysregulation of atrial natriuretic peptide (ANP) plasma levels (24), which may contribute to symptoms of protracted withdrawal such as craving, anxiety and confusion. The presence of severe cerebellar signs in this patient may be because of thiamine deficiency, which improved significantly when abstinence was maintained and thiamine administered parenterally (25). It may, however, act as a clinical marker for the possible development of DT in the future. Management
The detoxification of this patient was carried out with lorazepam – a short-acting benzodiazepine as he had hepatomegaly in accordance with clinical guidelines (8). When in DT, the patient was treated with both lorazepam and injectable haloperidol to control psychiatric symptoms associated with DT such as anxiousness, hallucinations and delusion. Furthermore, comorbidity is often noted in such patients and will require combined pharmacological and psychological treatment approaches (26). The use of naltrexone as anti-craving agent also helps in relapse prevention in the long run (27). However, we believe that the management needs to be individualised every time as is the case with many things in life, nothing is guaranteed to work every time. 155
Saddichha et al. Hypothesis
We hypothesise that an atypical presentation at the time of admission (viz. in this case, neurological complications of chronic alcohol use – Wernicke’s encephalopathy and cerebellar signs) and atypicality in early course (viz. in this case febrile illness) are clinical pointers to the subsequent development of delayed-onset DT. Future direction
Considering the clinical course and atypical presentation in this patient and other reported literature (7,13) as well as the absence of definite diagnostic criteria, clinicians should be cautious about DT, even after detoxification is over, especially when there is an atypical presentation during the early course of the detoxification period. It may be worthwhile to consider revising the time period for onset of DT up to 1 month after abstinence of alcohol to diagnose DT in future nosology, when no other cause of delirium is found. Conclusion
This is the first case of delayed-onset DT in any patient, especially a young man, reported in the literature and reflects the difficulty of deriving a conclusive clinical diagnosis for delayed-onset DT in an alcohol-dependent patient. Although the available evidence points to an alcohol withdrawal delirium, the absence of a pathologic diagnosis prevents us from drawing a definitive conclusion as to the aetiology of the delirium. It underscores the potential for a case of routine treatment of alcohol withdrawal, which is increasingly being conducted on an out-patient basis, to develop into a complex diagnostic problem that strains the clinical decisionmaking process and requires intensive in-patient management. References 1. VICTOR M, ADAMS RD. The effect of alcohol on the nervous system. Res Publ Assoc Res Nerv Ment Dis 1953; 32:526–573. 2. ISBELL H, FRASER HF, WIKLER A et al. An experimental study of the etiology of rum fits and delirium tremens. Q J Stud Alcohol 1955;16:1–33. 3. SCHUCKIT MA, BARUNWALD E. Alcohol and alcoholism. In: BRAUNWALD E, FAUCI AS, KASPER DL, HAUSER SL, LONGO DL, JAMESON JL, eds. Harrison’s principle of internal medicine, 15th edn. New York: McGraw-Hill, 2001–2004: 387, 1036. 4. GUTHRIE SK. The treatment of alcohol withdrawal. Pharmacotherapy 1989;9:131–143. 5. MYRICK H, ANTON RF. Treatment of alcohol withdrawal. Alcohol Health Res World 1998;22:38–43. 6. FEUERLEIN W, REISER E. Parameters affecting the course and results of delirium tremens treatment. Acta Psychiatr Scand 1986;329:120–123.
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7. MILLER FT. Protracted alcohol withdrawal delirium. J Subst Abuse Treat 1994;11:127–130. 8. TAYLOR D, PATON C, KERWIN R. Substance misuse. In: The Maudsley prescribing guidelines, 8th edn. New York: Taylor & Francis, 2005–2006: 236–237. 9. BEROZ E, CONRAN P, BLANCHARD RW. Parenteral magnesium in the prophylaxis and treatment of delirium tremens. Am J Psychiatry 1962;118:1042–1043. 10. BRENNER RP. The electroencephalogram in altered states of consciousness. Neurol Clin 1985;3:615–631. 11. HAMDI E, AL-SUHAILI A, ABOU-SALEH MT, AMIN Y, PRAIS V. Cerebral blood flow in alcohol withdrawal: relation to severity of dependence and cognitive impairment. Acta Neuropsychiatr 2003;15:55–62. 12. YU¨CEL M, LUBMAN DI, VELAKOULIS D et al. Structural brain correlates of alcohol and cannabis use in recreational users. Acta Neuropsychiatr 2006;18:226–229. 13. HERSH D, KRANZLER HR, MEYER RE. Persistent delirium following cessation of heavy alcohol consumption: diagnostic and treatment implications. Am J Psychiatry 1997;54:846–851. 14. 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;49:341–345. 15. HARPER CG. The incidence of Wernicke’s encephalopathy in Australia – a neuropathological study of 131 cases. J Neurol Neurosurg Psychiatry 1983;46:593–598. 16. TURNER S, DANIELS L, GREER S. Wernicke’s encephalopathy in an 18-year-old woman. Br J Psychiatry 1989;154:261–262. 17. TREVISAN LA, BOUTROS N, PETRAKIS IL, KRYSTAL JH. Complications of alcohol withdrawal: pathophysiological insights. Alcohol Health Res World 1998;22:61–66. 18. TSAI G, GASTFRIEND DR, COYLE JT. The glutamatergic basis of human alcoholism. Am J Psychiatry 1995;152:332–340. 19. NUTT D, ADINOFF B, LINNOILA M. Benzodiazepines in the treatment of alcoholism. Recent Dev Alcohol 1989;7: 283–313. 20. LAL R. Substance use disorder – manual for physicians. New Delhi: National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, 2005. 21. MEENA KP, VOHRA AK, RAJPUT R. Prevalence and pattern of alcohol and substance abuse in urban areas of Rohtak city. Ind J Psychiatry 2002;44:348–352. 22. SINGH J, SINGH G, MOHAN V, PADDA AS. Comparative study of prevalence of regular alcohol users among the male individuals in an urban and rural area of Distt. Amritsar, Punjab. Indian J Commun Med 2000;25:73–78. 23. KANZOW WT. The clinical stages of alcoholic delirium and their therapeutic significance. Acta Psychiatr Scand 1986; 73:124–128. 24. KIEFER F, ANDERSOHN F, JAHN H, WOLF K, RAEDLER TJ, WIEDEMANN K. Involvement of plasma atrial natriuretic peptide in protracted alcohol withdrawal. Acta Psychiatr Scand 2002;105:65. 25. MANN KF. Alcohol and psychiatric and physical disorders. In: GELDER MG, LOPEZ-IBOR JJ, ANDREASEN NC, eds. New Oxford Textbook of Psychiatry. Oxford: Oxford University Press, 2004: 491. 26. ABOU-SALEH MT. Psychopharmacology of substance misuse and comorbid psychiatric disorders. Acta Neuropsychiatr 2004;16:19–25. 27. KIEFER F, ANDERSOHN F, OTTE C, WOLF K, JAHN H, WIEDEMANN K. Long-term effects of pharmacotherapy on relapse prevention in alcohol dependence. Acta Neuropsychiatr 2004;16:233–238.
Acta Neuropsychiatrica 2008: 20: 152–156 All rights reserved DOI: 10.1111/j.1601-5215.2008.00285.x
ACTA NEUROPSYCHIATRICA
Case report
Delayed-onset delirium tremens – a diagnostic and management challenge Saddichha S, Manjunatha N, Sinha BNP, Khess CRJ. Delayed-onset delirium tremens – a diagnostic and management challenge. Background: Delirium tremens (DT) is one of the most serious complications of alcohol withdrawal, affecting 5–10% of in-patients with a mortality rate up to 15%. DT, characterised by delirium and tremors, appears within 48–72 h of abstinence and persists for about 5–10 days. Case presentation: We report a case of DT in a young man with delayed onset on the 15th day after the cessation of alcohol use, despite an uncomplicated detoxification with benzodiazepine treatment. Conclusion: We hypothesise that the intake of country liquor in our patient, which contains higher percentages of alcohol, causes a prolonged imbalance of N-methyl-D-aspartic acid and glutamate receptor activity, leading to the picture of delayed-onset DT and that an atypical presentation at the time of admission and atypicality in early course are clinical pointers to the subsequent development of delayed-onset DT.
Introduction
Delirium tremens (DT), first described by Victor and Adams (1) as well as by Isbell et al. (2), is one of the most serious complications of alcohol withdrawal, affecting 5–10% of in-patients (3). DT has high mortality rate of up to 15% (3), which has been reduced to 2–5% (4) because of improved early treatment. There are several features described (5), which in most cases appear within 48–72 h of abstinence and persist for about 5–10 days, with 62% resolving in 5 days or less (6). Although DT typically remits over a period of several days (3), cases persisting for weeks have been reported (7). The risk factors for development of DT are presence of ongoing infection, tachycardia at admission, withdrawal signs with blood alcohol level more than 1 g/l, history of seizures or delirious episodes (5) or higher-than-usual quantity and frequency of ethanol consumption. We report a case of DT in a young man with delayed onset on the 15th day after the cessation of alcohol use, with a usual course of 4–5 days, despite an uncomplicated detoxification with benzodiazepine treatment. 152
Sahoo Saddichha1, Narayana Manjunatha2, Baxi Neeraj Prasad Sinha3, Christoday R.J. Khess2 1 National Tobacco Control Program, WHO India, Kolkata, India; 2Centre for Addiction Psychiatry, Central Institute of Psychiatry, Kanke, Ranchi, India; and 3Clifton House, Teesdale South, Thornaby Place, Stockton-on-Tees, UK
Keywords: delayed onset; delirium tremens Sahoo Saddichha, National Tobacco Control Program, WHO India, Kolkata, India. Tel: +919836530262; Fax: +916742572660; Email: [email protected]
Case presentation Case history
The patient was a 34-year-old married man, who at the time of admission was living with his wife and working as an attender in a school. He hailed from a semi-urban background and belonged to middle socio-economic class. He had been attending to his duties until several months before this admission when, because of his alcohol use, he began to absent himself from his job. He described himself as having been a Ôsocial drinker’ for the last 17 years who, over the preceding 6 years, had substantially increased his drinking in response to escalating job-related stress. On admission, he reported drinking between 1 and 2 l of country liquor daily, beginning each morning. He acknowledged having withdrawal tremors and tolerance, an inability to control his intake of alcohol and the presence of alcohol-related interpersonal and vocational problems. He also described difficulty in walking and carrying out any voluntary activities such as brewing coffee or tea, eating food with a spoon, holding a glass, etc. and signing any document holding a pen for the past 4 months, resulting in significant socio-occupational
Delayed-onset DT impairment. His last drink had been about 3.5 l of country liquor 7–8 h before admission. He had never attempted to remain abstinent or undergo detoxification for alcoholism at any point of time in his life. There was no history of seizures or delirium at any time before admission. There was no history of use of any substances other than alcohol and nicotine or the use of any medications or benzodiazepines. There was no history of any psychiatric or medical problems. He had a family history of alcohol dependence in second-degree relatives and his father had a history of social drinking who had previously been in the military services. He reported that during the preceding year, he had not gone more than a day without consuming alcohol. Initial assessment
On admission, the patient was neatly dressed. He weighed 55 kg and stood 5 feet 10 inches tall. He was fully conscious and alert. His complexion was dark but healthy, and on examination, he was found to have a tremor of his tongue and extremities. Although the patient was afebrile, his pulse rate was 102 b/min, and his blood pressure was 148/100 mmHg. Physical examination at the time of admission revealed that patient had tender hepatomegaly 1 cm below the right costal margin. Results of cardiac and lung examination were normal. Furthermore, a neurological examination revealed that he had nystagmus, dysarthric speech and positive cerebellar signs such as inability to perform heel-shin test and dysdiadokinesia with a broad-based ataxic gait, impaired tandem walking, intention tremor and positive Romberg’s test. Deep tendon reflex examination revealed hyporeflexia of the distal supinator and ankle jerks, pendular knee jerk and hypotonia of lower limbs suggestive of cerebellar signs. The presence of nystagmus and ataxia with the absence of confusion led to a presumptive diagnosis of Wernicke’s encephalopathy as per Maudsley guidelines (8). Mental status examination revealed the patient to be alert, cooperative and oriented in all the spheres. He was euthymic, and his thinking was logical. He showed no evidence of gross cognitive deficits: short- and long-term memory was intact, as were attention, concentration and executive functions, and he was of average intelligence. He had no thought or perceptual disorders. He was admitted to our Center of Addiction Psychiatry. Hospital course
Considering his age, the extent of his alcohol consumption and the degree of tolerance that he
reported, the patient was considered to be at risk for a moderate-to-severe alcohol withdrawal syndrome. Consequently, treatment was initiated with 100 mg i.m. of thiamine, oral lorazepam at a dose of 2 mg every 6 h, metadoxil 500 mg b.i.d. and oral multivitamin preparation once daily. Metadoxil (metadoxine) is a pyridoxine-pyrrolidone carboxylate, which is useful in treatment of alcoholic liver disease by accelerating the elimination of alcohol from the blood and tissues, helping restore the functional structure of the liver and relieving neuropsychological disorders associated with alcohol intoxication. Admission laboratory work revealed an elevated serum glutamic oxaloacetic transaminase (SGOT) (103 mg/ml), gamma glutamyl transpeptidase (GGT) (225 mg/dl) and total bilirubin (1.7 mg %); otherwise, the complete blood count (CBC), electrolytes and renal function test results were all within normal limits. Urine screening for other substances including benzodiazepines was negative. On the first hospital day, his vitals were stable but he had repeated falls while going to the toilet. He had difficulty in getting up from the bed and walking unsupported. There was, however, no signs suggestive of head trauma or raised intracranial pressure or other neurological signs to suggest a neurological disorder. On the second day, his pulse was 96 b/min, and his blood pressure was 140/90 mmHg along with persisting cerebellar signs. On the fourth day, his vitals stabilised, but he developed moderate-grade fever for which he was treated with antibiotics and antipyretics up to the next 5 days. Routine work up for fever was non-specific including negative test on the malarial parasite quantitative buffy coat (QBC) and negative blood cultures. However, all vitals and neurological signs returned to normal including cerebellar signs by the end of the first week, consistent with the usual course of uncomplicated alcohol withdrawal. Medications during this period included lorazepam 2 mg p.o. every 6 h on days 1–4, tapered to 2 mg p.o. every 8 h on day 5. The patient received a total of 8 mg of lorazepam over the first 24-h period, 8 mg over the second, third and fourth days, with it being tapered off by the end of the first week. After an initial 100 mg i.m. of thiamine, he continued to receive 100 mg/day i.m. of thiamine daily for the first week, and metadoxil and multivitamin capsules were continued. Although, throughout this period, the patient continued to have a mild tremor, he ate and slept well and was alert and oriented, with a clear sensorium and intact cognitive functioning. He remained asymptomatic until the 14th day including absence of any seizures. 153
Saddichha et al. On the 14th hospital day, the patient’s condition deteriorated. He started complaining of seeing things (visual hallucinations) and an unknown fear for his life (delusion of persecution). He became increasingly confused, agitated and disoriented to place, person and time. The confusion and agitation were more pronounced in the evening and necessitated the use of sedation. Although the presentation of marked disorientation, global confusion, inability to fall asleep, suspiciousness, paranoid ideation, feelings of guilt, visual hallucinations, tremulousness of whole body and periods of agitation alternating with a decreased level of consciousness was consistent with DT, a search was initiated for other medical causes of the delirium considering the delayed onset. Physical examination revealed no evidence of infection or trauma, and there were no neurological signs consistent with a cerebral insult or Wernicke’s encephalopathy. However, cerebellar signs reappeared and continued till resolution of delirium 4 days later. Results of all laboratory work did not reveal any abnormality. Electrocardiogram did not reveal any abnormality. A working diagnosis of DTdelayed onset was made with the available clinical information. Parenteral administration of thiamine was resumed, and injectable haloperidol 10 mg and lorazepam 4 mg/day i.m. were initiated. Autonomic instability was well controlled with injectable lorazepam, and the benzodiazepine was gradually tapered over the next 7 days of hospitalisation. Intravenous hydration became necessary because the patient’s agitation limited his ability to take oral fluids or nutrition. Injectable haloperidol 5 mg b.i.d. was given to manage the agitation and presence of psychotic symptoms. On the 18th hospital day (i.e. the fourth day of DT), increased cooperation of the patient enabled us to perform a computed tomography (CT) – plain and contrast scan of the head, to rule out any intracranial lesion. The results of this were unremarkable; there was no evidence of the presence of a mass or fluid collection and no evidence of cerebral atrophy. Quantitative electroencephalogram (EEG) revealed no abnormality except lowamplitude beta waves. The onset of delirium in an individual dependent on alcohol consistent with the normal course of 4–5 days for DT, as well as the absence of evidence for an alternative diagnosis, supported the working diagnosis of DT. During the next 2 weeks (18–30 days from admission), the patient’s level of alertness, psychomotor activity, orientation and understanding remained at admission levels. On the basis of this evidence of improvement, the treating team decided that continued services could be provided in a less intensive setting. 154
Consequently, on the 35th hospital day, the patient was discharged with multivitamin capsules daily and naltrexone 50 mg/day as anti-craving medication. He remained oriented, fully conscious and alert. Physical examination was unremarkable, and cerebellar signs had almost resolved. DSM-IV axis I discharge diagnoses were as follows: alcohol dependence and alcohol withdrawal delirium and axis III diagnosis of Wernicke’s encephalopathy. On two subsequent follow-ups in the next 3 months, the patient was maintaining well with naltrexone and multivitamins.
Discussion
The management of DT poses many medical challenges, which begin from the time of diagnosis. An accurate history is therefore vitally important for diagnosis and treatment of DT. It is imperative for the clinician to maintain a high level of suspicion and closely monitor this syndrome that can lead to an increased length of hospital stay and increased number of medications being used.
Diagnostic dilemma
In the above case, the onset and progression of the confusional state described herein were consistent with DT, although the delayed onset was a hindering factor. Hence, it was clinically necessary to consider other medical and surgical problems that might have caused the patient’s altered mental status. Metabolic or endocrinal abnormalities, hepatic encephalopathy, infection and an intracranial lesion such as a subdural haematoma deserved special consideration. Physical examination, blood work and a normal CT of the head excluded these conditions as being of aetiological significance. Given the concern that covert use of benzodiazepines might have contributed to the patientÔs confusional state, it was specifically ruled out in the history and urine screening. Because medical illness appears to increase both the likelihood that DT will develop and its severity and duration, rapid identification and treatment of infections, hepatic insufficiency and traumatic injuries are crucial. The detection and correction of metabolic abnormalities such as hyponatraemia or hypernatraemia, hypokalaemia, hypomagnesaemia and hypocalcaemia are also important because these conditions may contribute to mental status changes that may predispose the individual to DT (9).
Delayed-onset DT While the EEG in the delirious patient usually shows diffuse slowing of background activity, in the case of alcohol withdrawal delirium, the EEG often shows excessive low-amplitude fast activity (10), which was consistent with our findings. Although CT scan of our patient did not reveal any abnormalities, neuroimaging has been noted to detect changes not only in alcohol dependence and withdrawal (11) but also in recreational users (12). Although DSM-IV has not specified the duration during which DT can be diagnosed after cessation or stoppage of alcohol, literature allows that withdrawal delirium can persist for up to 4 weeks (7,13). Miller (7) described a case of two episodes of protracted DT. The first episode lasted approximately 6 weeks and was complicated by neurosurgical problems. The second episode, occurring almost a year later, persisted for nearly 3 weeks in the absence of comorbid medical or surgical illness. Therefore, although available literature makes out a case for protracted DT, the same is not the case with delayed-onset DT. The presence of Wernicke’s encephalopathy is diagnosed by the classical triad of ataxia, nystagmus and confusion. However, this clinical triad is present in only 14–16% of patients (14), including our patient who had only ataxia and nystagmus. Wernicke’s encephalopathy is an underdiagnosed entity (15): one large autopsy study of alcoholics found that only 20% had been correctly diagnosed ante-mortem (15). Thus, a high index of suspicion is required: in this regard, one must not be fooled by the age of the patient as Wernicke’s encephalopathy has occurred in alcoholics as young as 18 years old (16). Pathophysiology
DT is caused by the direct effect that ethanol has on the benzodiazepine-gamma-aminobutyric acid (A)chloride receptor complex. Persistent effects of ethanol lead to the downregulation of the receptor complex. When ethanol is withdrawn, a functional decrease in the inhibitory neurotransmitter gammaaminobutyric acid is seen. This results in an unopposed increase in sympathetic activity with a resultant increase in plasma and urinary catecholamines. Ethanol also acts as an N-methyl-D-aspartate receptor antagonist. Withdrawal of ethanol leads to increased activity of these excitatory neural receptors (17,18) causing the clinical picture of delirium. There is also evidence that chronic heavy drinkers (up to 10 years) may have alterations in their gamma-aminobutyric acid benzodiazepine system, rendering them less responsive to benzodiazepines (19). However, in our case, the patient had developed DT after 6 years of
regular heavy drinking, which is an atypical feature. We hypothesise that the intake of country liquor in our patient, which contains higher percentages of alcohol (20), causes a prolonged imbalance of Nmethyl-D-aspartic acid and glutamate receptor activity, leading to the picture of delayed-onset DT. Country liquor, in any case, is one of the most prevalent forms of alcohol used in rural and semi-urban areas of India with rates up to 70% noted (21,22). The development of delirium in spite of an uncomplicated detoxification period and relatively delayed onset in a young patient and the fact that the patient was in a deaddiction centre with strict abstinence assured, however, raises several clinical questions about the other pathophysiologies involved. It has been hypothesised that whereas withdrawal symptoms such as autonomic hyperactivity are the result of recent physical dependence on alcohol, DT results from irreversible, cumulative changes in the central nervous system caused by years of heavy alcohol consumption. Therefore, a pre-set Ôpoint of no return’ determined by the patient’s drinking and withdrawal history may exist and for some individuals may make delirium an inevitable result of the abrupt cessation of alcohol intake (23). Another factor to be considered is the development of fever in our patient during detoxification, albeit for a short period. This may have led to a dysregulation of atrial natriuretic peptide (ANP) plasma levels (24), which may contribute to symptoms of protracted withdrawal such as craving, anxiety and confusion. The presence of severe cerebellar signs in this patient may be because of thiamine deficiency, which improved significantly when abstinence was maintained and thiamine administered parenterally (25). It may, however, act as a clinical marker for the possible development of DT in the future. Management
The detoxification of this patient was carried out with lorazepam – a short-acting benzodiazepine as he had hepatomegaly in accordance with clinical guidelines (8). When in DT, the patient was treated with both lorazepam and injectable haloperidol to control psychiatric symptoms associated with DT such as anxiousness, hallucinations and delusion. Furthermore, comorbidity is often noted in such patients and will require combined pharmacological and psychological treatment approaches (26). The use of naltrexone as anti-craving agent also helps in relapse prevention in the long run (27). However, we believe that the management needs to be individualised every time as is the case with many things in life, nothing is guaranteed to work every time. 155
Saddichha et al. Hypothesis
We hypothesise that an atypical presentation at the time of admission (viz. in this case, neurological complications of chronic alcohol use – Wernicke’s encephalopathy and cerebellar signs) and atypicality in early course (viz. in this case febrile illness) are clinical pointers to the subsequent development of delayed-onset DT. Future direction
Considering the clinical course and atypical presentation in this patient and other reported literature (7,13) as well as the absence of definite diagnostic criteria, clinicians should be cautious about DT, even after detoxification is over, especially when there is an atypical presentation during the early course of the detoxification period. It may be worthwhile to consider revising the time period for onset of DT up to 1 month after abstinence of alcohol to diagnose DT in future nosology, when no other cause of delirium is found. Conclusion
This is the first case of delayed-onset DT in any patient, especially a young man, reported in the literature and reflects the difficulty of deriving a conclusive clinical diagnosis for delayed-onset DT in an alcohol-dependent patient. Although the available evidence points to an alcohol withdrawal delirium, the absence of a pathologic diagnosis prevents us from drawing a definitive conclusion as to the aetiology of the delirium. It underscores the potential for a case of routine treatment of alcohol withdrawal, which is increasingly being conducted on an out-patient basis, to develop into a complex diagnostic problem that strains the clinical decisionmaking process and requires intensive in-patient management. References 1. VICTOR M, ADAMS RD. The effect of alcohol on the nervous system. Res Publ Assoc Res Nerv Ment Dis 1953; 32:526–573. 2. ISBELL H, FRASER HF, WIKLER A et al. An experimental study of the etiology of rum fits and delirium tremens. Q J Stud Alcohol 1955;16:1–33. 3. SCHUCKIT MA, BARUNWALD E. Alcohol and alcoholism. In: BRAUNWALD E, FAUCI AS, KASPER DL, HAUSER SL, LONGO DL, JAMESON JL, eds. Harrison’s principle of internal medicine, 15th edn. New York: McGraw-Hill, 2001–2004: 387, 1036. 4. GUTHRIE SK. The treatment of alcohol withdrawal. Pharmacotherapy 1989;9:131–143. 5. MYRICK H, ANTON RF. Treatment of alcohol withdrawal. Alcohol Health Res World 1998;22:38–43. 6. FEUERLEIN W, REISER E. Parameters affecting the course and results of delirium tremens treatment. Acta Psychiatr Scand 1986;329:120–123.
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