To summarize, the entire group of acute confusional and delirious states is characterized principally by an alteration of consciousness and by prominent disorders of attention and perception, which interfere with the speed, clarity, and coherence of thinking, the formation of memories, and the capacity for performance of self-directed and commanded activities. Three major clinical syndromes can be recognized. One is an acute confusional state in which there is manifest reduction in alertness and psychomotor activity. A second syndrome, already alluded to as a special form of confusion, delirium, is marked by overactivity, sleeplessness, tremulousness, and prominence of vivid hallucinations, sometimes with excessive sympathetic activity. These two illnesses tend to develop acutely, to have multiple causes and, except for a few cerebral diseases, to remit within a relatively short period of time of days to weeks, leaving the patient without residual damage. The third syndrome is one in which a confusional state occurs in persons with an underlying chronic cerebral disease, particularly a dementia. Such cerebral disease may be focal or diffuse. Dr. Raymond Adams had designated this disposition to a superimposed acute confusional state in the context of dementia as a beclouded dementia but the term, while very apt, seems not to have caught on.
From the neurologic perspective, the generic term psychosis applies to states of confusion in which elements of hallucinations, delusions, and disordered thinking comprise the prominent features. An important point to be made here is that psychoses typically leave the sensorium relatively unclouded and allow for normal attentions and high-level performance of many mental tasks. These syndromes and some aspects of psychotic confusion are elaborated below.
Characteristically, these abnormalities fluctuate in severity, typically being worse at night ("sundowning"). In the mildest form, the patient appears alert and may even pass for normal; only the failure to recollect and accurately reproduce happenings of the past few hours or days reveals the subtle inadequacy of his mental function. The more obviously confused patient spends much of his time in idleness, and what he does may be inappropriate and annoying to others. Only the more automatic acts and verbal responses are performed properly, but these may permit the examiner to obtain a number of relevant replies to questions about age, occupation, and residence. Orientation to the date, day of the week, and place is imprecise, often with the date being off by several days, the year being given as several years or one decade previous, or with the last two numbers transposed, e.g., 2015 given as 2051. Such patients may, before answering, repeat every question that is put to them, and their responses tend to be brief and mechanical. It is difficult or impossible for them to sustain a conversation. Their attention wanders and they constantly have to be brought back to the subject at hand. They may even fall asleep during the interview, and if left alone are observed to sleep more hours each day than is natural or to sleep at irregular intervals.
As the confusion deepens, conversation becomes more difficult, and at a certain stage these patients no longer notice or respond to much of what is happening around them. Questions may be answered with a single word or a short phrase, spoken in a soft tremulous voice or whisper, or the patient may be mute. Asterixis is a common accompaniment if a metabolic or toxic encephalopathy is responsible for the confusional state. In the most advanced stages of the illness, confusion gives way to stupor and, finally, to coma (see Chap. 17). With improvement in the underlying condition, they may pass again through the stages of stupor and confusion in the reverse order. All this informs us that at least one category of confusion is but a manifestation of the same disease processes that
affect awakeness and alertness and, in their severest form, cause coma.
Table 20-1 lists some of the many causes of this common type of confusional state. The most frequent in general practice are drug intoxications and endogenous metabolic encephalopathies, mainly electrolyte and water imbalance (hypo- and hypernatremia, hyperosmolarity), hypercalcemia, disorders of acid–base balance, renal and hepatic failure, hyper- and hypoglycemia, febrile and septic states ("septic encephalopathy" discussed further on), and chronic cardiac and pulmonary insufficiency.
Table 20-1 Classification of Delirium and Acute Confusional States ||Download (.pdf)
Table 20-1 Classification of Delirium and Acute Confusional States
I. Acute confusional states associated with psychomotor underactivity
A. Associated with a medical or surgical disease (no focal or lateralizing neurologic signs; cerebrospinal fluid [CSF] clear)
1. Metabolic disorders (hepatic stupor, uremia, hypo- and hypernatremia, hypercalcemia, hypo- and hyperglycemia, hypoxia, hypercapnia, porphyria, and some endocrinopathies)
2. Infectious illnesses (pneumonia, endocarditis, urosepsis, peritonitis, and other illnesses causing bacteremia and septicemia—septic encephalopathy)
3. Congestive heart failure
4. Postoperative and posttraumatic states
B. Associated with drug intoxication (no focal or lateralizing signs; CSF clear): opiates, anticholinergics, barbiturates and other sedatives, trihexyphenidyl, corticosteroids, anticonvulsants, L-dopa, dopaminergic agonists, serotonergic antidepressants
C. Associated with diseases of the nervous system (with focal or lateralizing neurologic signs or CSF changes)
1. Cerebrovascular disease, tumor, abscess (especially of the right parietal, left temporal and occipital, and inferofrontal lobes)
2. Subdural hematoma
5. Cerebral vasculitis (e.g., granulomatous, lupus)
6. Hypertensive encephalopathy
7. Postconvulsive state
A. In a medical or surgical illness (no focal or lateralizing neurologic signs; CSF usually clear)
2. Septicemia and bacteremia (septic encephalopathy)
3. Postoperative and postconcussive states
4. Thyrotoxicosis and corticosteroid excess (exogenous or endogenous)
5. Infectious fevers such as typhoid, malaria
B. In neurologic disease that causes focal or lateralizing signs or changes in the CSF
1. Vascular, neoplastic, or other diseases, particularly those involving the temporal lobes and upper part of the brainstem
2. Concussion and contusion (traumatic delirium)
3. Meningitis of acute purulent, fungal, tuberculous, and neoplastic types (Chap. 32)
4. Encephalitis from viral (e.g., herpes simplex, infectious mononucleosis), bacterial (mycoplasma), and other causes (Chaps. 32 and 33)
5. Subarachnoid hemorrhage
C. Abstinence states, exogenous intoxications, and postconvulsive states (signs of other medical, surgical, and neurologic illnesses absent or coincidental)
1. Withdrawal of alcohol (delirium tremens), barbiturates, and nonbarbiturate sedative drugs, following chronic intoxication (Chaps. 42 and 43)
2. Drug intoxications: scopolamine, amphetamine, cocaine, and other drugs, particularly hallucinogens, phencyclidine, etc.
3. Postconvulsive delirium
III. Psychosis, particularly with manic characteristics
IV. Confusional states caused by focal cerebral lesions (see Chap. 22)
V. Beclouded dementia, i.e., dementing or other brain disease in combination with infective fevers, drug reactions, trauma, heart failure, or other medical or surgical diseases
Diffuse or multifocal disease of the cerebral hemispheres is another class of transient or persisting confusional states. Concussion and seizures, especially petit mal or psychomotor status, and certain focal (e.g., right parietal and temporal) cerebral lesions may also be followed by a period of confusion. Focal lesions, most often infarctions but also hemorrhages, of the right cerebral hemisphere may evoke an acute confusional state. Such syndromes have been described with strokes mainly in the territory of the right middle cerebral artery (Mesulam et al; Caplan et al; Mori and Yamadori); usually the infarcts have involved the posterior parietal lobe or inferior frontostriatal regions, but they have also occurred with strokes in the territory of one posterior cerebral artery. A variety of more generalized or multifocal cerebral diseases may be associated with transient or persistent confusional states. Among these are meningitis, encephalitis, thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation, tumors, subdural hematoma, and cranial trauma.
A more restricted group of focal cerebral diseases, including drug and alcohol withdrawal and systemic infections cause delirium, as discussed below.
Pathophysiology of Confusional States
All that has been said on this subject in Chap. 17 regarding coma is applicable to at least one subgroup of the confusional states. In most cases, no consistent pathologic change is found because the abnormalities are metabolic and subcellular. As discussed in Chap. 2, the electroencephalogram (EEG) is almost invariably abnormal in even mild forms of this syndrome, in contrast to delirium, where the changes may be relatively minor. Bilateral high-voltage slow waves in the range of 2 to 4 per second (delta) or 5 to 7 per second (theta) are the usual findings with confusion. These changes surely reflect one aspect of the central problem—the diffuse impairment of the cerebral mechanisms governing alertness and attention and the property of coherence imparted by these functions. If only metaphorically, this mental incoherence and the disorganized thinking and behavior of the confusional states reflect the loss of integrated activity of all of the associative regions of the cortex as mentioned earlier in the chapter.
This is best depicted in the patient undergoing withdrawal from alcohol after a sustained period of intoxication. The symptoms usually develop over a period of 2 or 3 d. The first indications are difficulty in concentration, restless irritability, increasing tremulousness, and insomnia. There may be momentary disorientation, an occasional inappropriate remark, or transient illusions or hallucinations.
These initial symptoms rapidly give way to a clinical picture that is one of the most colorful in medicine. The patient is inattentive and unable to perceive the elements of his situation. He may talk incessantly and incoherently, and look distressed and perplexed; his expression may be in keeping with vague notions of being annoyed or threatened by someone. From his manner and the content of speech, it is evident that he misinterprets the meaning of ordinary objects and sounds, misidentifies the people around him, and is experiencing vivid visual, auditory, and tactile hallucinations, often of a most unpleasant type. At first the patient can be brought into touch with reality and may identify the examiner and answer other questions correctly; but almost at once he relapses into a preoccupied, confused state, giving incorrect answers and being unable to think coherently. As the process evolves, the patient cannot shake off his hallucinations and is unable to make meaningful responses to the simplest questions and is profoundly distracted and disoriented. Sleep is impossible or occurs only in brief naps. Speech is reduced to unintelligible muttering.
The signs of overactivity of the autonomic nervous system, more than any others, distinguish delirium from other confusional states. Tremor of fast frequency and jerky restless movements are practically always present and may be violent. The face is flushed, the pupils are dilated, and the conjunctivae are injected; the pulse is rapid, blood pressure elevated, and the temperature may be raised. There is excessive sweating. Most of these signs are reflections of overactivity of the sympathetic nervous system.
The most certain indication of the subsidence of the attack is the occurrence of lucid intervals of increasing length and sound sleep. Recovery is usually complete. In retrospect, the patient has only a few vague memories of his illness or none at all. Single seizures may punctuate the syndrome at any time, including before its development.
Fragments of the full syndrome are common. Brief disorientation, isolated hallucinations, or restlessness with mild hypersympathetic features all occur in withdrawal states, febrile illnesses, and with various intoxications.
The brains of patients who have died in delirium tremens without associated disease or injury usually show no pathologic changes of significance. Intoxication with a number of medications, particularly those with atropinic effects, and certain abused drugs, such as the hallucinogens, causes a delirious state. Delirium may also occur in association with a number of recognizable cerebral diseases, such as viral (herpes) encephalitis or meningoencephalitis, Wernicke disease, cerebral trauma, cerebral hemorrhage after surgery for craniopharyngioma or other tumors in the same region, or multiple embolic strokes caused by subacute bacterial endocarditis, cholesterol or fat embolism, or following cardiac or other surgery. An unusual type arises in young women with ovarian teratomas and circulating antibodies against the NMDA receptor.
The topography of the lesions in most of the deliriums that are symptomatic of underlying destructive processes is of interest; they tend to be localized in the rostral midbrain and hypothalamus or in the temporal lobes, where they involve the reticular activating and limbic systems. Involvement of the hypothalamus perhaps accounts for the autonomic hyperactivity that characterizes delirium in some cases of cerebral disease and the autoantibody condition. That these are not the only sites implicated is emphasized by the observations that an acute agitated delirium has occurred, albeit infrequently, with lesions involving the fusiform and lingual gyri and the calcarine cortex (Horenstein et al); the hippocampal and lingual gyri (Medina et al); or the middle temporal gyrus (Mori and Yamadori).
Electrical stimulation studies of the human cerebral cortex during surgical exploration and studies by positron emission tomography (PET) have emphasized the importance of the temporal lobe in the genesis of complex visual, auditory, and olfactory hallucinations. Subthalamic and midbrain lesions may give rise to visual hallucinations that are not unpleasant and are accompanied by good insight ("peduncular hallucinosis" of Lhermitte). For reasons not easily explained, with pontine-midbrain lesions, there may be unformed auditory hallucinations.
The EEG in delirium may show symmetrical mild generalized slow activity in the range of 5 to 10 per second. In milder degrees of delirium, there is usually no abnormality at all; this is in stark contrast to the generalized slowing and disruption of EEG activity that accompany most other forms of confusion in proportion to the severity of the clinical state.
Analysis of the conditions conducive to delirium suggests several physiologic mechanisms. Alcohol and sedative drugs are known to have a strong depressant effect on certain regions of the central nervous system; presumably, the disinhibition and overactivity of these parts after withdrawal of the drug are the basis of delirium. Another mechanism is operative in the case of bacterial infections with sepsis and poisoning by certain drugs, such as atropine and scopolamine, in which visual hallucinations are a prominent feature. Here the delirious state probably results from the direct action of the toxin or chemical agent on the same parts of the brain. It has long been suggested that some persons are much more liable to delirium than others, but there is reason to doubt this. Many years ago, Wolff and Curran showed that randomly selected persons developed delirium if the causative mechanisms were strongly operative. This is not surprising, for any normal person may, under certain circumstances, experience phenomena akin to those of delirium. A healthy person can be induced to hallucinate by being isolated for several days in an environment free of sensory stimulation (sensory deprivation). A relationship of delirium to dream states has also been postulated; both are characterized by a loss of appreciation of time, a richness of visual imagery, indifference to inconsistencies, and "defective reality testing." Formulations in the field of dynamic psychiatry seem more reasonably to explain the topical content of delirium than its occurrence. Wolff and Curran, having observed the same content in repeated attacks of delirium from different causes, concluded that the content depends more on the age, gender, intellectual endowment, occupation, personality traits, and past experiences than on the cause of the delirium.
Confusional States and Delirium Induced by Medications (See Also Chap. 43)
In considering the pathophysiology of delirium and confusion, it must be again emphasized that drug intoxication—predominantly with drugs prescribed by physicians—is among the most common causes in practice. The most distinctive syndromes are those from drugs that have direct or indirect anticholinergic properties. The delirium associated with these agents is centrally mediated but may be accompanied by peripheral anticholinergic manifestations. This point is critical in the differential assessment of agitated confusional states because other compounds, particularly serotonergic agents used to treat depression, also can produce delirium. Thus, in addition to confusion, toxic levels of anticholinergic compounds typically cause dry skin, dry mouth, diminished bowel motility, and urinary hesitancy, if not frank retention. (The clinical maxim that applies is "red as a beet, dry as a bone, blind as a bat, hot as a hare, and mad as a hatter." The last part of this mnemonic has been also attached to the dementia of mercury intoxication [see Mintzer and Burns].) By contrast, in the toxic serotonergic syndrome associated with excessive doses of the newer antidepressant drugs, salivation is normal, sweating is increased, and the gut is hyperactive; diarrhea is common. Moreover, the deep tendon reflexes may be exaggerated, and there may be clonus and myoclonus as described by Birmes and associates. Drugs with dopaminergic activity used in the treatment of Parkinson disease are notorious for the induction of confusion or delirium, but it appears that the underlying disease provides an important substrate. Allied compounds with sympathomimetic actions such as cocaine and phencyclidine produce a hallucinatory delirium and yet others with different pharmacologic properties such as glutaminergic activity may result in a variety of delirious fragments or pure hallucinosis. Another entity that arises in this context is the neuroleptic malignant syndrome, a state associated with an agitated confusion followed by stupor. However, the characteristic features in neuroleptic malignant syndrome (NMS) are progressive muscle rigidity and evidence of myonecrosis as indicated by elevations of the serum creatine kinase; usually there is in addition some elevation of body temperature. The clinical examination and a thorough history aid greatly in determining which category of drug is implicated.
Diffuse Cerebral and Dementing Disease Complicated by Confusional States
Physicians are all too familiar with the situation of an elderly patient who enters the hospital with a medical or surgical illness or begins a prescribed course of medication and displays a newly acquired mental confusion. Presumably, the liability to this state is determined by preexisting brain disease, most often Alzheimer disease but sometimes Parkinson disease, multiple small deep cerebral infarctions, or another dementing process, which may or may not have been obvious to the family before. All the clinical features that one observes in the acute confusional states may be present, but their severity varies greatly. Confusion may be reflected only in the patient's inability to relate the history of the illness sequentially, or it may be so severe that the patient is virtually non compos mentis.
Although almost any complicating illness may bring out a confusional state in an elderly person, the most common are febrile infectious diseases; trauma, notably concussive brain injuries; surgical operations, general anesthesia and pre- and postoperative medication; even small amounts of pain or sedative medications used for any cause; and congestive heart failure, chronic respiratory disease, and severe anemia, especially pernicious anemia. With regard to medications, those with atropinic effects have the highest tendency to cause confusion, but others, even seemingly innocuous ones, may do the same (e.g., histamine blockers used to reduce gastric acid, anticonvulsants, corticosteroids, and L-dopa as mentioned earlier and described in Chap. 39).
Very often, it is difficult to determine which of several possible factors is responsible for the patient's confusion, and often there may be more than one. In a cardiac patient, for example, fever, hypoxia or hypercarbia, one or more drugs, and electrolyte imbalance each may contribute.
Infectious and Postoperative Confusional States
In the instance of fever and confusion, particularly in the elderly person, the problem of "septic encephalopathy" is offered as an explanation, but it may simply be a rephrasing of the well-known problem of infection such as pneumonia leading to a global confusion or delirium. Young has called attention to the high frequency of this disorder in critically ill patients, 70 percent of their bacteremic patients, and its accompaniment by a polyneuropathy in a high proportion of cases. Paratonic rigidity of the limbs (an oppositional action on the patient's part that is proportioned to the effort of the examiner in moving the limbs) is an almost universal accompaniment; according to these authors, focal cerebral or cranial nerve signs are not encountered. All other potential causes of a confusional state must, of course, be excluded before attributing the state to an underlying infection. The EEG is slowed in approximation to the level of consciousness, but it shows mild changes even in the bacteremic patient who is fully alert. The spinal fluid is normal or has a slightly elevated protein concentration. While there is no doubt that young and healthy patients may become confused when affected with high fever and overwhelming infections such as pneumonia, most cases of septic encephalopathy are of the "beclouded dementia" type in the older patient. The point made by Young is that subtle degrees of confusion are ubiquitous with serious infections of many varieties. Among the most perplexing cases of this type have been healthy older persons we have observed who acquired an agitated delirium following spinal column infection after surgery. The delirium ceased within hours of drainage of an abscess. The older literature contains similar examples with closed space infection in other locations. The chapter by Young can be consulted for an exposition of the various theories of pathogenesis of this state. High fever itself (above 40.6°C [105°F]) is probably an adequate explanation for confusion in some cases. A similar global confusional state occurs in patients with severe burns (burn encephalopathy).
All that has been stated above is true of the patient with a nondescript postoperative confusional state, in which a number of factors, such as fever, infection, dehydration, and drug and anesthetic effects, are implicated. In a study of 1,218 postoperative patients by Moller and colleagues, older age was by far the most important factor associated with persistent confusion after an operation; but a number of other factors—including the duration of anesthesia, need for a second operation soon after the first, postoperative infection, and respiratory complications—were also predictive of mental difficulty in the days after the procedure. Unacknowledged alcoholism and withdrawal effects undoubtedly cause the same problem quite often on surgical services (see also "Stroke with Cardiac Surgery" in Chap. 34).
When such patients recover from the medical or surgical illness, they usually return to their premorbid state, though their shortcomings, now drawn to the attention of the family and physician, are far more obvious than before. For this reason, families will date the onset of a dementia to the time of the medical illness or surgical procedure, and continue to minimize the previous gradual decline in cognition. In other cases, however, the acute medical illness seemingly marks the beginning of a persistent decline in mental clarity that over time can be identified as a dementing illness. A related problem that has recently come under study is persistent cognitive loss after critical illness. The rates of this irreversible change are apparently high, up to one-quarter of severely ill patients in some series, but accurate estimates are difficult to obtain because of the lack of pre-illness psychometric testing.
Nonconvulsive Status Epilepticus
This problem has attracted increasing attention in the past decades as a cause of otherwise obscure confusional states. It is discussed in Chaps. 16 and 17, but here we only comment that the process may be portrayed clinically only because of small myoclonic twitches or eyelid fluttering. The only certain way to arrive at, or exclude the diagnosis is with EEG monitoring for more than the usual 30 minute recording if possible. One suspects nonconvulsive seizures particularly in known epileptics, septic patients, and in certain medical diseases such as TTP.
Schizophrenic or Bipolar Psychosis during a Medical or Surgical Illness
A small proportion of psychoses of schizophrenic or bipolar type first become manifest during an acute medical illness or following an operation or parturition and need to be distinguished from an acute confusional state. Rarely, a catatonic state will make its first appearance in these circumstances. A causal relationship between the psychosis and medical illness is sought but cannot be established. The psychosis may have preceded the medical illness but was not recognized. The diagnostic study of the psychiatric illness must then proceed along the lines suggested in Chaps. 52 and 53. Close observation will usually disclose a clear sensorium and relatively intact memory, features that permit differentiation from an acute confusional or delirious state or dementia.