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Tuesday, 27.10.2020

Peter R. Martin: Historical Vocabulary of Addiction

Delirium Tremens

 

           According to the current electronic edition of the Oxford English Dictionary (OED), delirium tremens is directly taken from medical Latin and means “trembling or quaking delirium.”  The complete OED definition is: “A species of delirium induced by excessive indulgence in alcoholic liquors, and characterized by tremblings and various delusions of the senses.”  The first use of the term delirium tremens was by the English physician Thomas Sutton (1767-1835) in his Tracts on Delirium Tremens, on Peritonitis, and on Some other Internal Inflammatory Affections, and on the Gout (1813), in which he presented several case reports with careful clinical descriptions linking the syndrome to over indulgence in alcohol and described the important diagnostic features that differentiated delirium tremens from phrenitis, the then-prevailing term for delirium due to inflammation of the brain or from mania.  Sutton prominently cited the work of the Scottish physician William Saunders (1743-1817), whom Sutton credited with first describing the syndrome he would call delirium tremens.  The French physician Pierre Francois Olive Rayer (1793-1867) acknowledged both Sutton and Saunders on the very first page of his treatise Mémoire sur le delirium tremens (1819).  Eventually, the eponym for delirium tremens became the Saunders-Sutton syndrome (Cutshall 1965). 

           To appreciate the essence of delirium tremens and its history requires understanding of the meaning of its root, as well as the conditions from which it primarily needed to be differentiated in clinical practice.  According to OED, the noun delirium is derived from the Latin dēlīrium attributed to the 2nd century Greek physician/philosopher Celsus (1935), meaning “madness, derangement” and was derived from dēlīrāre, meaning, “To be deranged” in distinction to the verb delire meaning, “To go astray, go wrong, err,” signifying that this condition was indeed involuntary.  The primary definition of delirium in OED is: “A disordered state of the mental faculties resulting from disturbance of the functions of the brain, and characterized by incoherent speech, hallucinations, restlessness, and frenzied or maniacal excitement.”  According to OED, the first documented use of the word was theological, echoing the experience of a descent into hell,  Master Broughton’s letters, especially his last pamphlet to and against the Lord Archbishop of Canterbury, about Sheol and Hades, for the descent into Hell, answered in their kind (1599): “It is but the franticke delirium of one, whose pride hath made him ϕρεναπατᾶν [frenzied].”  The first documented use in medical context was by the 17th century English physician John Smith (1656):  “The signs are a weak Pulse…delirium.”  The historical noun phrenitis is defined in OED as: “Delirium, especially when associated with or attributed to inflammation of the brain; inflammation of the brain or of the meninges, encephalitis or meningitis.”  Phrenitis is also borrowed from Latin, according to OED.  Its meaning is succinctly stated in the first apparent use in English (Barrough 1583): “Phrenitis in Greeke and in Latin is a disease, wherin the mind is hurte.”  Of note is use of the word phrenitis in description of melancholia by the English writer Robert Burton (1621): “Phrenitis,… is a Disease of the Minde, with a continuall Madnesse or Dotage,… or els an inflammation of the Braine.”  Burton’s mention of melancholia in association with phrenitis rather than delirium is insightful as we now know that hyperthymic mood disorders and alcoholism frequently co-occur and may represent a difficult differential diagnostic challenge (Rich and Martin 2014).

           Understanding the pathogenesis of delirium tremens has reflected the evolution of medical science over the two centuries since the syndrome was first described, especially advances in the neurosciences and elucidation of the pharmacological actions of alcohol.  American physician John Ware who, with Dr. Walter Channing, was editor of the New England Journal of Medicine and Surgery from 1824 to 1827,  wrote (1832): “Morbid anatomy has thrown no light upon the nature of that affection of the brain and nervous system, which gives rise to the peculiar symptoms of delirium tremens.  Indeed, its history would rather lead us to expect that these symptoms do not depend on any organic changes discoverable by dissection, but merely on a disturbance in their functions.”  Robley Dunglison, an English physician who moved to America to join the first faculty of the University of Virginia, the personal physician to Thomas Jefferson and considered the “Father of American Physiology,” proposed (1860): “that the irregularity of nervous action is usually induced by the withdrawal of an accustomed stimulus, and that the recuperative powers are generally entirely sufficient to bring about the necessary equalization — we have treated the mass of the cases which have fallen under our care without either excitants proper, or opiates.”

           By mid-19th century it was clear that delirium tremens was characterized by confusion, motoric activation, sensory hyperarousal and autonomic hyperactivity in individuals who had consumed significant quantities of alcohol.  Additionally, it was demonstrated that the disorder did not benefit from the then-accepted medical practice of bloodletting (Renton 1829).  State-of-the-art treatment of delirium tremens was sedation with opium as described in the New Sydenham Society Lexicon (1881).  Identification of more effective and specific treatment approaches became the key to understanding the mechanistic underpinnings of delirium tremens.  For example, Fletcher (1870) described an attempt “…to try hydrate of chloral as a tentative remedy in delirium tremens… being unwilling to give opium except as a dernier ressort, I gave half-drachm doses of hydrate of chloral every two hours until sleep was secured.”  He concluded: “Truly, the effects of chloral in this case were almost miraculous.”  Since chloral hydrate, then used as a sedative-hypnotic, had been synthesized by chlorination of ethanol as first reported by Justus von Liebig (1832), it has very similar, though more potent, pharmacologic actions as ethanol. Hence, the beneficial effect of chloral hydrate on delirium tremens is not unexpected if the condition is actually a consequence of discontinuing to drink alcohol, a novel conjecture at the time of this observation.    

           How alcohol consumption was mechanistically related to development of delirium tremens came into sharp focus with an important observation: “The proof of the pudding is in the eating, and the proof that delirium tremens is due to the sudden deprivation of alcohol is shown by the fact that the attack of delirium can be cut short in an early stage by administration of the normal quantity of alcohol (Anonymous 1917).”  A fundamental experiment was conducted at the Addiction Research Center in Lexington, Kentucky, involving former morphine addicts that formally tested the association between drinking and delirium tremens (Isbell, Fraser, Wikler et al. 1955).  (It should be underscored that such an experiment, despite its importance, would never be conducted in the present day due to ethical concerns.)  Under experimental conditions, subjects consumed alcohol continuously for many weeks and when alcohol consumption was discontinued, alcohol withdrawal symptoms emerged in all, while some developed delirium tremens with the “intensity of symptoms roughly correlated with length of intoxication and amount of alcohol consumed.”  This work unequivocally demonstrated that delirium tremens is caused by precipitously stopping heavy drinking and the major determinant of severity is the quantity of alcohol consumed while the individual was actively drinking.  However, this experiment left unresolved why alcohol can “cut short” delirium tremens, but only “in an early stage” of the disorder (Anonymous 1917).  This observation suggests that physiologic stress responses to discontinuing alcohol consumption are distinct from the simple absence of alcohol (Selye 1937) and the notion of providing alcohol to a patient in delirium tremens hardly seems a wise or practical approach to treatment (Piker 1937), especially as the course of the condition progresses. 

           By the mid-20th century there was consensus that treatment of delirium tremens could be accomplished using any of the available central nervous system depressants given in a timely fashion in combination with proper hydration, nutrition and replacement of vitamins and electrolytes (Smith 1953).  Further elucidation of the pathophysiology of alcohol withdrawal and delirium tremens have led to rational pathogenesis-based treatment strategies (Sellers and Kalant 1976) and most recently, “evidence-based treatment” (Mayo-Smith, Beecher, Fischer et al. 2004).  These treatment approaches fall into two broad categories: 1) use of pharmacological agents that are cross-tolerant to and cross-dependent with alcohol and are more slowly eliminated from the body to replace alcohol (substitution); and 2) use of agents that minimize the neuronal hyperexcitability and the associated autonomic hyperarousal that ensue from acute disturbance of neuroadaptive alterations due to chronic alcohol consumption (stress response).  Substitution is the most straightforward approach and after chloral hydrate (mentioned above) there followed a series of trials of any number of central nervous system depressants as each was introduced into clinical use, including barbiturates (Essig, Jones and Lam 1969), the sedative-hypnotic chlormethiazole(Giacobini and Salum 1961) and benzodiazepines (Frommel, Fleury, Schmidt-Ginzkey and Beguin 1960).  Determining whether one pharmacological class or individual members of a given class were superior in head-to-head comparisons then became the focus.  Additionally, as various non-barbiturate hypnosedatives were introduced into the pharmacopeia and were joined by more specific anxiolytic benzodiazepines, it became very clear that the delirium tremens-like syndrome was characteristic not only of the discontinuation of alcohol but of all but the most slowly eliminated central nervous system depressants (Ewart and Priest 1967, Martin, Bhushan, Kapur et al. 1979). 

           The second approach to treatment of delirium tremens requires additional understanding of the consequences of chronic alcohol consumption and the pathophysiologic underpinnings of each sign and symptom of the syndrome. The first such consequence of alcohol consumption was thought to be depletion of B-vitamins (Mainzer and Krause 1939):  “Formerly these disturbances were thought to be due to the toxic effects of alcohol, but it has now been demonstrated that they are for the most part signs of a nutritional deficiency (avitaminosis).”    Whether depletion of thiamine plays a specific role in the pathophysiology of delirium tremens per se or is involved indirectly via a possible role in modulating alcohol consumption (Mardones, Segovia and Onfray 1946) or its well-recognized nutritional influence on alcohol-induced neurotoxicity (Victor, Adams and Collins 1971) were likely reasons for synthesis of a sedative-hypnotic, chlormethiazole, which is structurally related to thiamine (Osterman, Bellander-Lofvenberg and Lassenius 1959).  All the same, standard of care now involves replacement of thiamine immediately upon entry to care and there is little evidence of the superiority of chlormethiazole (Sychla, Gründer and Lammertz 2017).  Depletion during chronic alcohol consumption of specific electrolytes was also recognized to be associated with the severity of delirium tremens (Flink, Stutzman, Anderson  et al. 1954; Wadstein and Skude 1978); these electrolytes are now implicated in neuronal depolarization and thus their depletion may explain the hyperexcitability of the nervous system well-document in alcohol withdrawal.  As the focus in biological psychiatry turned to biogenic amines in the pathogenesis of brain dysfunction in psychiatric disorders, Giacobini, Izikowitz and Wegmann (1960) suggested, “The high excretion of urinary catecholamines [in delirium tremens] may reflect the sympathetic hyperactivity observed clinically. This is probably a result of central stimulation.”  This important observation was further investigated and substantiated over ensuing years, clearly supporting that ethanol withdrawal was a state of autonomic hyperarousal which if severe enough could lead to alteration of the sensorium (Linnoila, Mefford, Nutt and Adinoff 1987).  Consequently, various sympatholytic agents were investigated in treatment of alcohol withdrawal (Björkqvist 1975; Sellers and Kalant 1976).  Additionally, post-mortem comparisons between Addison's disease and delirium tremens led to attempts to augment overwhelmed stress responses in delirium tremens using steroids, particularly components of the adrenal cortical system (Dowden and Bradbury 1952).  

           Various other pathophysiological abnormalities were identified that explained the proclivity among certain drinkers to develop delirium tremens and hence, provided strategies for its treatment, including abnormalities in endogenously produced alcohol (Ostrovsky 1986), levels of body and brain hydration (Smith, Chick, Kean et al. 1985; Bezzegh, Nyuli and Kovács 1991), abnormalities in cerebral blood flow (Hemmingsen, Vorstrup, Clemmesen et al. 1988) and cortical atrophy (Maes, Vandoolaeghe, Degroote et al. 2000) among others.  Gross, Tobin, Kissin et al. (1964) used auditory evoked potentials to understand the disturbed sensorium so characteristic of delirium tremens and concluded: “…acute disturbances of acoustic response may be present in delirium tremens and when present may have a significant relationship to the formation of auditory hallucinations.” Based on a literature that electroconvulsive treatments may be effective in treatment of various delirious states,  Dudley and Williams (1972) conducted a retrospective controlled study of ECT in delirium tremens and found that: “A prompt response to ECT was observed in all cases.”  This finding seems difficult to explain based on what we now know about the pathophysiology of the alcohol discontinuation syndrome (see above) but may act through resetting of excitatory/inhibitory neurotransmission or immune-inflammatory responses resulting from induced convulsions. A recent case report (Kranaster, Aksay, Bumb et al. 2017) provides guarded support for this approach:  “It has to be emphasized that we do not want to encourage… uncritical usage of ECT for alcohol withdrawal delirium, but we hope that the reported case might contribute to an alternative approach in very severe and prolonged alcohol withdrawal delirium.”  Electrochemical disturbances from repeated episodes of heavy alcohol consumption and withdrawal resulting in changes in synaptic efficacy during a lifetime formed the basis of the “kindling” hypothesis of Ballenger and Post (1978) and the shared elements of tolerance with learning and memory (Kalant, LeBlanc and Gibbins 1971).  Genetic approaches to gain insights into interindividual differences in susceptibility to severe alcohol withdrawal and development of syndrome components of delirium tremens are currently of considerable research interest (Kosobud and Crabbe 1986; Sander, Harms, Rommelspache et al. 1998; Gorwood, Limosin, Batel et al. 2003). 

           Due to the clinical presentation of delirium tremens and the association of alcoholism with other psychiatric disorders (Rich and Martin 2014), it remained controversial whether this condition was not a psychotic disorder in its own right (Soyka 1990).  Krystal  (1959) studied 700 patients with delirium tremens and concluded that this condition, “was found to be a combination of a physiological disturbance and an emotional stress in an individual whose relation to reality is, at best, tenuous.”  Therefore, it seemed reasonable to determine whether delirium could be effectively managed with phenothiazines.  In a formal comparison of promazine and paraldehyde, Thomas and Freedman (1964) addressed this controversy and conclusively demonstrated that paraldehyde was superior. In contrast to findings that might be expected in patients with schizophrenia and related psychoses, they concluded: “Our experience in this trial suggests that promazine might be regarded as a dangerous drug when given to severely ill delirium tremens patients.”  Nevertheless, neuroleptics continue to be studied and used in treatment of alcohol withdrawal delirium without regard to the underlying pathophysiology of diminished inhibitory (Nestoros 1980) and accentuated excitatory (Lovinger, White and Weight 1989) neurotransmission predicted from the pharmacologic actions of alcohol and the pharmacologic propensity of neuroleptics to lower the seizure threshold.  This unfortunate choice of pharmacotherapy is likely due to partially overlapping phenomenology of delirium tremens with psychotic disorders and common co-occurrence of alcoholism with almost any other psychiatric disorder.

 

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August 22, 2019