Alterations in Mental State: Coma and Acute Confusional States

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[edit] Alterations in Mental State: Coma and Acute Confusional States

Harold B. Schiff

Thomas D. Sabin

[edit] COMA

Coma is a disturbance of consciousness in which the patient cannot be aroused by any stimulus, no matter how vigorous. With the return of any form of responsiveness, coma ends. The recovering patient then progresses through various levels of disordered consciousness until finally attaining a clear sensorium. An understanding of the pathogenesis is essential to the clinical management of the comatose patient.

[edit] Pathogenesis

The ascending reticular activating system (RAS) is a highly complex polysynaptic region in the core of the upper pons and midbrain. These isodendritic fibers extend from the midbrain into the thalamic regions bilaterally and ultimately become widespread within the hemispheres. Specific afferent systems contribute some portion of their neuronal activity to the RAS as they pass through these brainstem structures. Specific neurotransmitter function in the RAS is not fully understood.^[1] GABAergic fibers and cholinergic systems play a role in controlling consciousness (GABA, γ-aminobutyric acid).^[2] A pathologic decrease in consciousness results from either a local anatomic or a general biochemical disturbance of the RAS.

If the brainstem is sectioned below the level of the upper pons, a disturbance in alertness does not occur. Once the ascending RAS has reached the level of the thalamus and becomes bilaterally distributed, a unilateral destructive lesion does not cause obtundation. Although extramedullary distortion of the ascending RAS in the midbrain is the major anatomic basis for disordered arousal, critically located small focal lesions from the upper pons to the mesencephalic-diencephalic junction may also produce this clinical picture. Thus small infarcts that destroy the reticular core of the brainstem may cause states of prolonged coma. In unilateral supratentorial space-occupying lesions, the medial or uncal portion of the temporal lobe is forced through the tentorial notch beside the midbrain. This distorts the reticular-activating substance in the core of the midbrain and thereby causes decreased alertness. The herniated uncus also causes compression of the oculomotor nerve. Parasympathetic pupillomotor fibers are superficially placed, and the compression may result in an ipsilateral dilated pupil that is unresponsive to light.

When the herniated uncus forces the midbrain against the rigid, contralateral tentorial margin, motor fibers within the midbrain may be affected, and signs of upper motor neuron deficits appear on the same side as the supratentorial mass lesion. Pupillary dilation, however, is a more accurate predictor of the side of supratentorial mass lesion than the side of the hemiparesis. When there is bilateral herniation of supratentorial structures, the midbrain is forced caudally and elongated in the anteroposterior direction.

The pharmacologic and biochemical vulnerability of the RAS is also well recognized. This vulnerability is reflected in the appearance of obtundation in almost every variety of severe metabolic disturbance. The most common causes of obtundation are endogenous or exogenous toxins. The numerous synapses in the ascending RAS may be the basis for the striking vulnerability of the RAS to so many classes of drugs and toxins.

Making the distinction between an intracranial structural lesion and an extracranial toxic-metabolic encephalopathy is the primary diagnostic step in evaluating the comatose patient.

[edit] Early Management of the Comatose Patient

If patients with transient loss of consciousness are excluded and coma persists for 6 hours or more, the chance of either a sedative/toxic or a hypoxic/ischemic etiology is 40%; of a cerebrovascular etiology (stroke, hemorrhage, or subarachnoid bleed), 35%; and of a metabolic etiology (e.g., diabetes, infection, renal/hepatic), 25%. The overriding concern in the early management of the comatose patient is the immediate treatment of any remedial cause of brain damage. Several steps should be taken even before a full diagnostic assessment is made.

The patient must be guaranteed an adequate airway, respiratory exchange, circulation, and metabolic substrate, glucose, and thiamine (which acts as a cofactor in the metabolism of glucose).^[3] After blood is obtained for various diagnostic studies (including glucose levels), the patient should be given 100 mg of thiamine intravenously followed by a 50-ml 50% glucose solution. Thiamine must be administered before the glucose, since a glucose load in a thiamine-deficient patient may precipitate acute Wernicke's encephalopathy and may cause sudden death from circulatory collapse. If narcotic ingestion is suspected, naloxone (Narcan) should be administered.

If ingestion of benzodiazepines is suspected, flumazenil can be used and is often effective. In cases in which the ingested substance is unknown, flumazenil can be used empirically. If there is a positive response, albeit short-lived, repeat injections can be used. The safe use of flumazenil is, however, an important factor to consider in each clinical situation.^[4]

The patient should be positioned to prevent aspiration but nevertheless should be handled as if a cervical spinal fracture is present until more is known about the patient's history and more diagnostic studies can be performed. As soon as these initial urgent needs are satisfied, a rapid general medical and neurologic examination should be performed.

[edit] Evaluation of the Comatose Patient

The neurologic examination of the comatose patient is quite different from the routine neurologic evaluation.^[5] In most common conditions associated with coma, a rostral-caudal deterioration in nervous system function tends to occur as the process worsens. This is generally the case for both structural intracranial processes and toxic metabolic encephalopathies. Rostral-caudal deterioration refers to the sequential loss of certain functions, beginning with the cerebral cortex and followed by the diencephalon, midbrain, pons, and finally the medulla. A rapid assessment of the anatomic level of a given patient can be made by examining the state of consciousness, pupils, eye movements, respirations, and remaining motor functions (Table 157-1). Before this evaluation, the physician should make a quick assessment for evidence of head trauma. An ecchymosis that surrounds the eye (“raccoon sign”), a hemotympanum, and “bogginess” with or without ecchymosis on the mastoid process just behind the ear (Battle's sign) are evidence of a basal skull fracture. The importance of looking for subtle signs of head injury must be emphasized. Slight bogginess with an area of petechiae on the scalp, which can only be identified if the patient's hair and scalp are carefully searched, may be the sole evidence for head trauma. Certain injuries, such as a blow to the head from a stocking filled with sand, can create devastating brain lesions with minimal external signs.

Table 157-1 Major Neurologic Signs Reflecting Anatomic Levels of Rostral-Caudal Progression in Coma

The level of consciousness is evaluated by repeated efforts to wake the patient and gain his or her attention. Terms such as light coma, semicoma, and stupor as defined in the literature are of little value in clinical practice and are best avoided. A clear description of the patient's behavior and clinical status is preferred.^[6]

Examination of the pupils should include size, symmetry, and response to light. In the diencephalic stage of the rostral-caudal deterioration, both pupils tend to be small. This may be noted in an expanding supratentorial mass or with widespread edema that causes midline herniation. A magnifying glass may be necessary to see if the pupillary response to light has been preserved. A unilateral supratentorial mass that causes the uncus to herniate through the tentorial notch is signaled by compression of the parasympathetic motor fibers surrounding the third cranial nerve, producing loss of constriction and thus progressive pupillary dilation and finally a widely dilated, unreactive pupil. The pupillary signs of third nerve dysfunction appear before the paralysis of extraocular muscles. The diencephalic stage is thus characterized by either unilateral pupillary dilation (with unilateral herniation syndromes) or symmetric, small pupils that respond to light (in midline herniation or most toxic metabolic encephalopathies).

Once the deterioration involves the midbrain, the pupils are no longer reactive to light; they tend to be in the midposition and may not change with progression of the syndrome to the pontine and medullary phases of deterioration. The agonal dilation of unresponsive pupils has been attributed to a widespread release of norepinephrine throughout anoxic body tissues.

Examination of the extraocular movements is another important means of assessing the anatomic level of brainstem involvement. Before the specific findings at each anatomic level and its significance in assessing coma are discussed, some of the normal physiology is reviewed. Conjugate gaze is important in the initial assessment, even before extraocular movements are assessed. In drowsiness, mild squints, which are not seen in the awake patient, may become obvious; that is, phorias become manifest tropias. Divergent squints are most common and are exaggerated with upward deviation of the eyes. These signs reflect a decreased level of consciousness, but do not have specific anatomic localization value.

With coma and depending on the level, these oculocephalic reflexes may become overly facile or disappear completely despite maximal stimulation (Fig. 157-1). When a normal conscious individual has the head passively turned to the right, the eyes move to the right. In an obtunded individual, they move to the left. This release of vestibular reflexes is believed to be the basis for the doll's head maneuver. With further involvement of the diencephalon a stronger stimulus may be necessary. Conjugate deviation of the eyes to the stimulated side can be induced by instilling cold water to the external ear canal. The maximal stimulus consists of 40 ml of ice water instilled over 30 seconds. No perforation of the drum or other process in the external ear that might be adversely affected by this irrigation should be present. In the diencephalic stage of coma, the so-called doll's head eye maneuvers become overly facile, and with rotation of the head the reflex is brisk. In the mesencephalic stage of dysfunction, the eyes can still be conjugately drawn to the side of the stimulation, although if third nerve connections are sufficiently damaged, there may be a deficit in adduction. In the mesencephalic stage, cold-calorics are almost invariably required. Once the pons and medulla have been destroyed, the lateral eye movements do not respond to the doll's head maneuver or ice water–caloric stimulation. When the patient's head is at 35 degrees to the horizontal and both ears are simultaneously stimulated with warm water at 44° C (111° F), conjugate upward deviation of the eyes occurs if the midbrain centers for vertical gaze are intact.

Figure 157-1 Doll's head maneuver. This maneuver consists of rapidly turning the head from side to side (top) or flexing and extending the neck (bottom). Conjugate movement of the eyes to the side opposite the direction of the head movement demonstrates that brainstem centers for eye movement are intact. In the bottom drawing, as in the top drawing, the eyelids are held open because the patient is comatose. (From Geller AE, Sabin TD: Med Times 106:47, 1978.)

The comatose patient may have tonic conjugate deviation of the eyes. In an acute hemispheric lesion, destruction of the fibers from the frontal gaze center for contralateral conjugate gaze occurs. This results in a relative overactivity of the contralateral intact center, causing deviation of the eyes toward the injured hemisphere. If an associated hemiplegia exists, the eyes deviate away from the side of the hemiplegia and toward the side of the lesion (Fig. 157-2). With lesions in the brainstem, these fibers have already crossed in the midbrain, and the eyes may conjugately deviate away from the side of the lesion and toward the hemiplegia.

Figure 157-2 Hemispheric, pontine, and cerebellar hemorrhage demonstrating the accompanying eye movement and pupillary responses.

The respiratory pattern is another useful marker for determining the level of remaining nervous system function. Respirations at the diencephalic stage of rostral-caudal deterioration may be normal or show periodic respiration, including Cheyne-Stokes respirations. Central neurogenic hyperventilation with continued respiratory rates of about 40 breaths/min (with appropriate changes in blood gas values) may occur with midbrain dysfunction. When pontine damage is superimposed on the midbrain syndrome, central neurogenic hyperventilation disappears and may be replaced by breathing that is apparently more normal. A pause at inspiration (apneustic breathing) is characteristic of pontine-level lesions. As the pons is destroyed, breathing becomes ataxic, irregular, and unpredictable. At this point, respiratory arrest is imminent.

Testing of motor system function in obtunded patients is different from the usual neurologic examination. Simple observation of spontaneous movements or the movements in relation to painful stimuli is done. In the diencephalic stage an associated hemiplegia is easily recognized, and bilateral decorticate posture may rarely be seen. Decorticate posturing consists of adduction at the shoulder and flexion at the elbows, wrists, and fingers, with extensor posturing of the lower extremities. A stage occurs before decorticate posturing in which fairly facile movement is away from painful stimuli, but the range of passive movement in these limbs is often limited by counterholding (gegenhalten or paratonia).

In the midbrain state of deterioration, decerebrate postures appear. Decerebration rarely appears in a florid, full-blown form but is seen more often as only fragments of the posture in response to noxious stimulation. The examiner should place the semiflexed upper extremities across the patient's abdomen and then provide a painful stimulus to the sternum. If the patient consistently reacts to the painful stimulus with only one limb, the opposite side is hemiplegic. If the patient's forearms extend away from the painful stimulus or pronate even slightly, decerebration and thus dysfunction at the mesencephalic level should be suspected. When the patient moves the limb toward the painful stimulus at the sternum, a second stimulus at the iliac crest confirms that the patient is not simply demonstrating decorticate posturing but is actually reaching for the noxious stimuli.

As the midbrain is destroyed and pontine dysfunction appears, decerebration disappears, and the limbs become flaccid. No movement appears with noxious stimulation. Disappearance of decerebration is often mistaken for improvement. The limbs remain flaccid in the medullary phase of deterioration.

With these parameters of examination in mind, the physician can quickly localize the level of nervous system dysfunction and begin consideration of the major diagnostic categories.

[edit] Differential Diagnosis

The initial diagnostic consideration is to determine whether the alteration in consciousness is caused by a primarily intracranial structural lesion or a systemic toxic or metabolic disorder.

[edit] Structural Central Nervous System Lesions.

The intracranial processes are subdivided into those in which focal signs are likely vs. those in which no focal signs may be anticipated. The major categories of intracranial processes with focal brain dysfunction include trauma, intraparenchymal hemorrhages, tumors, certain forms of infection, and brain infarction.

[edit] With Focal Signs

[edit] Trauma.

Concussion refers to a transient loss of consciousness. If there is associated brain contusion, unconsciousness may be more lasting. Focal signs such as hemiplegia, aphasia, or other signs of cortical injury are usually obvious. In addition, blood may be found in cerebrospinal fluid (CSF).

Frequent consequences of closed-head trauma are hematomas in the subdural or epidural space or in the brain parenchyma. Neuroimaging has greatly simplified the diagnosis of this problem. However, an apparently negative computed tomography (CT) scan in an appropriate clinical setting should not dissuade the physician from diagnosing subdural hematoma, since this lesion may be isodense with brain tissue but is seen on the more sensitive magnetic resonance imaging (MRI). Since the mass lesion produces a widely dispersed force over the convexity of one side of the brain, there are often no focal cortical signs. However, the distortion of the ascending RAS, secondary to the mass effect, causes abnormal drowsiness, which may be the only feature present.

[edit] Hemorrhage.

Spontaneous hemorrhages into brain parenchyma are occurring less frequently as the assiduous treatment of hypertension becomes more widely practiced. Brain hemorrhages may occur in a variety of disorders, such as anticoagulation, end-stage leukemias, hepatic disease, amyloid angiopathy, and intracranial aneurysms; however, the major association is still with hypertension. Symptoms and signs usually appear suddenly, but occasionally the onset of these hemorrhagic syndromes may progress in severity, taking several days to develop. Hypertensive hemorrhages tend to occur in five sites (see Fig. 157-2). The lateral ganglionic or putaminal areas of the hemisphere are most often affected. Hemorrhage at these sites results in severe headache, hemiplegia, conjugate deviation of the eyes away from the hemiplegia, and signs of progressive uncal herniation with rostral-caudal deterioration.

The thalamus is a second common site of hypertensive hemorrhage and also produces headache and hemiplegia. The hemorrhage frequently dissects into upper midbrain structures, which may explain why the eyes are often conjugately deviated toward the hemiplegia. A rarer but highly characteristic tonic downward convergence of the eye has also been reported with thalamic hemorrhage (see Fig. 157-2).

Pontine hemorrhage is usually fatal within 48 hours. Since the initial lesion is in the pons, the clinical picture is different from that seen with rostral-caudal deterioration. There is bilateral flaccid paralysis of the limbs, and the doll's head maneuver or the ice water–caloric test fails to cause lateral conjugate eye deviation, although some vertical gaze may remain because of intact midbrain centers. Peculiar vertical conjugate eye movements known as ocular bobbing may be witnessed. The eyes drift downward and then more rapidly elevate upward, slightly above the resting level, before descending once again to the resting level. The movements often occur in brief bursts. Pontine hemorrhage is usually also associated with pinpoint pupils, resulting from destruction of the descending sympathetic fibers at a time when midbrain parasympathetic fibers are still functioning. The pinpoint pupils respond to light but so minimally that a magnifying glass may be necessary to see the constriction (see Fig. 157-2).

The prompt diagnosis of hypertensive cerebellar hemorrhage is most important because of the urgency of surgical intervention as a lifesaving procedure. Cerebellar hemorrhage presents with acute ataxia, nausea, vomiting, and severe headache. On examination, both truncal ataxia and hemiataxia may be present. Nystagmus usually occurs, and there may be forced deviation of gaze opposite the side of the hematoma (see Fig. 157-2). An acute cerebellar mass can compress medullary respiratory centers and cause sudden death. Surgical evacuation of cerebellar hemorrhages can be lifesaving.

[edit] Tumors.

Most intracranial tumors are now diagnosed early enough that patients do not come to medical attention in a coma. However, one should keep certain situations in mind.

Tumors in the midline of the neuraxis either within or outside the ventricular system may cause minimal neurologic symptoms or signs until CSF flow is obstructed, and then obtundation occurs with acute hydrocephalus and a rapid deterioration in clinical status. Patients with posterior cranial fossa lesions may have respiratory arrest as the first manifestation of foramen magnum herniation. The evaluation of patients suspected of having posterior fossa mass lesions should reflect this possibility. Papilledema is usually present in these patients. Since papilledema takes about 24 hours to develop fully, it is not seen in massive acute hemorrhages, but if the patient has a slowly growing tumor, he or she is more apt to have papilledema when seen with an acute deterioration in level of consciousness. Midline, posterior fossa or intraventricular tumor–associated hydrocephalus should be treated with emergency ventricular drainage or ventriculostomy.

Patients with pituitary adenomas can lapse into acute coma when spontaneous hemorrhagic necrosis of the tumor occurs. Patients with pituitary apoplexy have headaches, visual loss, stiff neck, obtundation, extraocular palsies, and acute hypotension. The recognition and treatment of the acute hypoadrenal state caused by the failure of adrenocorticotrophic hormone (ACTH) production are essential lifesaving maneuvers. An enlarged sella seen on plain skull films is an important clue to the diagnosis of pituitary apoplexy. MRI or CT scans have proved to be extremely useful in diagnosing most intracranial tumors.

Cerebellar abscess usually presents as a mass lesion. The appearance is often characteristic on MRI or CT scan. A small bubble of air in the low-density center of a lesion with a ringlike enhancement is diagnostic of abscess. Brain abscesses alone do not necessarily result in fever, and the CSF may be normal.

[edit] Infarction.

Hemispheric infarcts may produce lethargy or confusion acutely, but unilateral lesions seldom cause complete coma. An exception occurs when a massive, acute hemispheric infarction results in severe brain edema; herniation and fatal rostral-caudal deterioration of brain function can occur in 1 to 2 hours. Small infarcts of the brainstem can interrupt the RAS and produce lasting coma. In the “locked-in” syndrome, extensive paralysis occurs because of bilateral destruction of the motor pathways in the basis pontis. The patient is conscious, but the medical staff may not realize it. These patients are able to develop a code, using eye blinks to communicate.

[edit] Without Focal Signs.

In certain other intracranial processes that cause coma, such as meningitis, encephalitis, and subarachnoid hemorrhage, no focal signs may be present. The physician depends greatly on careful examination of the spinal fluid for the correct diagnosis. Focal signs may be present but are a bonus for the diagnostician. Aneurysms of the posterior communicating artery often cause an acute third nerve palsy. Bacterial meningitis may cause cerebral thrombophlebitis with hemiplegias and focal seizures. Similarly, the predilection of the herpes simplex virus for the temporal lobe often assists in the diagnosis of that variety of viral encephalitis.

This category of intracranial processes without obvious focal signs should serve as a forceful reminder that every comatose patient must have a CSF examination performed unless lumbar puncture is contraindicated. If the patient is deemed too ill for a lumbar puncture, some other diagnostic procedure must be substituted on an emergency basis. An MRI or CT scan before lumbar puncture is advisable in many circumstances. Standard CSF studies may be complemented by brain creatine kinase and neuron-specific enolase tests, which may be useful in prognostication.

[edit] Toxic-Metabolic Causes.

The differential diagnosis of endogenous metabolic derangement is extensive and includes disturbances in all organ systems. Box 157-1 presents a logical schema for the approach to the differential diagnosis of endogenous metabolic encephalopathies.

The toxic encephalopathies are most often caused by drug overdose, and some patients, especially elderly ones, may be unusually sensitive to the side effects of many drugs, even at standard dosages.

Some sedative drugs have special effects on the eyes that may help with the diagnosis. Glutethimide (Doriden) may cause large pupils that are unresponsive to light. Morphine produces pupilloconstriction. Atropine-like effects cause dilated, fixed pupils. Severely obtunded patients with drug overdose may be capable of brushing away painful stimuli and even muttering a few sounds but may have no eye movements even with ice water–caloric stimulation. This disparity of rostral-caudal localization is highly suggestive of sedative drug overdose. A toxic screen and an electroencephalogram (EEG) that shows characteristic effects of sedative medication are useful in confirming the diagnosis.

Patients with endogenous metabolic encephalopathies usually have no focal signs, but exceptions occur when clinically inapparent, earlier neurologic lesions once again become manifest as metabolic derangement occurs. Hemiplegia may reappear when a patient who has had a previous cerebral infarct with complete recovery begins to develop, for example, carbon dioxide narcosis of chronic pulmonary disease. Focal seizures apparently arising from the supplementary motor area, with fencing postures and groping movements of the extended arm, have proved to be highly suggestive of nonketotic hyperglycemic coma.

One of the most important practical distinctions between the toxic-metabolic encephalopathies and the structural intracranial processes relates to the pupillary light response. In all the toxic-metabolic encephalopathies except anoxic encephalopathy and those caused by drugs that have specific effects on the pupil, pupillary response to light is spared regardless of the rostral-caudal involvement. The clinical differentiation of structural from metabolic causes of coma pivots around a clearly progressive anatomic localization of the rostral-caudal syndrome. Intracranial mass lesions usually follow this syndrome exactly, whereas the signs of the toxic-metabolic encephalopathy may be much more patchy, such as pontine involvement without prior mesencephalic involvement and no clear-cut rostral-caudal progression.

Decerebration does occur in the toxic-metabolic encephalopathies and should not be considered diagnostic of structural brain disease. Metabolic encephalopathy is often accompanied by widespread, involuntary, small-amplitude myoclonic jerks. The patient should be examined with an oblique light for several minutes, since the muscle twitches are often not otherwise apparent.

Clearly, a full discussion of all the causes of coma is beyond the scope of this chapter, which serves only as a model for an approach to the comatose patient.

[edit] Outcome and Prognostication

A body of literature exists on the outcome of coma, but the most reliable data stem from studies of posttraumatic coma.^[7] The Glasgow Coma Scale and the Glasgow Outcome Scales are most helpful in the monitoring and prognostication of traumatic coma but are less reliable in other forms of coma. Only 10% of patients with nontraumatic coma, who do not demonstrate spontaneous eye movements at 6 hours, will make a moderate to good recovery.^[8] Eye opening to painful stimuli at 6 hours raises the chances of moderate to good recovery. Some 85% die, remain in a vegetative state, or recover to a state of significant dependency.^[9]

[edit] BRAIN DEATH

Guidelines for the determination of brain death recommended by the President's Commission in 1981 are now used widely; however, state and local laws or practices may modify their applications (Box 157-2).

Patients are not brain dead if they have reactive pupils, corneal or gag reflexes, or decerebrate or decorticate posturing (Box 157-3). The pupils are generally midposition and dilated in brain death. Small pupils are uncommon and should be checked for reactivity because of possible drug overdose. Spinal reflexes (deep tendon and Babinski's) may persist in the presence of brain death. And, in the 15-to 30-minute interval after ventilatory assistance is withdrawn, unusual movements of the extremities may occur, most likely resulting from terminal ischemia of the spinal cord.

Hypothermia, drug intoxication, and viral encephalitis may all produce an isoelectric EEG. Thus the presence of an isoelectric EEG alone is not sufficient to serve as a criterion for brain death.

[edit] ACUTE CONFUSIONAL STATES

Acute confusion, also known as acute encephalopathy, acute toxic psychosis, or delirium, can be thought of as an acquired incapacity to think with customary speed and clarity. The major feature of this syndrome is the failure to maintain normal, sequential thought, reflecting an inability to rank the priority of stimuli. Patients thus are unable to maintain a coherent stream of thought. The consequent failure in the designation of behavioral priorities causes an immediate and drastic disintegration of the adaptational interaction with the environment. Patients' general behavior and speech reflect an inappropriate sequencing of ideas, and patients exhibit a wide range of abnormal behaviors, including assaultiveness, motor hyperactivity, hallucinations, somnolence, and extreme states of panic or fear.^[10]

The diagnosis of an acute confusional syndrome is often not entirely objective, and most physicians rely to some degree on intuition. A clear definition has not been established, but the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) provides specific diagnostic criteria that may serve as a point of departure in defining the clinical features of this syndrome (Box 157-4).

[edit] Clinical Features

The diagnosis of confusion depends on the recognition of specific disturbances in the processes of attention, thought, and perception.

[edit] Attentional Deficits.

Disordered attention is a major feature of confusion.^[11] Disturbances include difficulties in attaining and maintaining attention. This disturbance is apparent in the evaluation of patients with confusion; it is often very difficult to attract the attention of these individuals, who may appear relatively unresponsive to external stimuli. Furthermore, maintaining their attention may also prove difficult. Patients respond equally to all auditory, visual, and kinesthetic stimuli and are unable to filter out irrelevant stimuli. They may be extremely distractible and thus unable to sustain any goal-directed behavior.

[edit] Thought Disorder.

Disordered thought is most frequently recognized as an incoherent stream of thought. The patient may be aware of this and complain of being “confused,” “unable to think straight,” or “unable to get it together.” Some patients, however, may be unaware of their deficit.

The term thought disorder is used here to encompass the various cognitive deficits that result in an incoherent stream of thought. Although memory disturbance and disorientation are invariably present, the patient may respond appropriately on formal memory and orientation testing. The patient does have significant difficulty in organizing recent and remote memories into an orderly sequence. Thus features of spatial disorientation may be expressed as symptoms of reduplicative paramnesia. This usually involves the reduplication of place; for example, the patient insists that the hospital room is duplicated and shifted in place so that “a branch of the main hospital is in my home.” Temporal disorientation is obvious when events from the past are directly related to the present. This association of unrelated events may lead to a diagnosis of confabulation. Indeed, the patient may exhibit frank confabulation; this may be concrete and obviously related to surrounding visual and auditory cues; alternatively, it may be quite bizarre, apparently generated from inner thought processes.

Thought content may have a dreamlike quality. The patient may find it difficult to separate fact from fantasy or dreams from reality. Delusions may occur, are usually fleeting, and may be modified by environmental stimuli. Vague feelings of apprehension are often crystallized into persecutory delusional beliefs. Delusions are often concrete; the classic schneiderian delusions of thought insertion, withdrawal, control, and broadcasting are only rarely seen.

[edit] Perceptual Disturbances.

Perceptual disturbances are perhaps the most dramatic manifestations of acute confusion. Illusions range from simple to more complex misinterpretations of environmental stimuli. For example, markings on the wall are interpreted as crawling insects, folds in the bedclothes as snakes or wild animals, and sounds as fire alarms or gunshots. In more complex illusions the hospital room might be mistaken for a prison or the door for a window. The patient may act on these misinterpretations, resulting in inadvertent accident or death.

Hallucinations may occur in all sensory modalities. Visual and auditory hallucinations are more frequent than tactile, kinesthetic, olfactory, and gustatory hallucinations. However, no characteristic type of hallucination exemplifies the acute confusional state. The content of these hallucinations varies greatly and is usually interpreted by the patient as real.

[edit] Language Disturbances.

Language is often vague, circumlocutory, and perseverative. Word-finding difficulty may take the form of approximations. A pitcher may be called a glass or a bedrail a gate. Reading is often preserved, whereas writing is very abnormal. The patient demonstrates poor penmanship, starting off well but ending with micrographia. The patient characteristically shows no regard for paper space or lines and neglects to dot the is and cross the ts (Fig. 157-3). Misspellings and perseverations or overdrawings on letters and words are common.

Figure 157-3 A, “It's a sunny day.” The down-slant of the sentence, the uncrossed t, and the perseveration of the n of sunny illustrate the dysgraphic features of the confusional state. B, “Hit the ball with the bat.” The up-slant of the sentence, the uncrossed t, and the generally sloppy orthography further illustrate the dysgraphic features of the confusional state.

[edit] Disturbance in the Sleep-Wake Cycle.

Disturbance in the sleep-walk cycle is an invariable feature of confusional states. Some patients are hypersomnolent, whereas others remain awake for days at a time. The patient may not offer this information, but it is the most common complaint of family or friends.

[edit] Fluctuations in Symptomatology.

The patient shows fluctuations in cognitive function over a 24-hour cycle and also from day to day. The patient usually functions worse in the early morning, after a nap, or at sundown. However, the patient has periods of surprising lucidity. Such fluctuation is rarely seen in any other disorder of the mental status.

[edit] Arousal: Psychomotor and Autonomic Activity.

The degree of psychomotor activity in acute confusion varies. Two distinct syndromes have been described. In the hypoactive syndrome, patients have diminished psychomotor activity and are generally quiet and withdrawn. Verbal output is restricted, varying from complete mutism to empty, vague speech. In the hyperactive syndrome, on the other hand, patients appear to be hyperaroused, and there is psychomotor and autonomic overactivity. These patients tend to require minimal sleep and constantly thrash about in bed or pace the halls. Speech output is increased and emotional tone heightened. Most often, however, the physician encounters a clinical syndrome that contains elements of both the hyperactive and the hypoactive variants, with unpredictable changes over the course of the day. No evidence indicates that the hypoactive syndrome is a milder form of, and will progress to, the hyperactive variant, and no obvious relationship exists between the specific cause of acute confusion and a particular variant of this syndrome.

[edit] Pathophysiology

The pathophysiologic mechanisms underlying the confusional states remain to be established. Some researchers have suggested that acute confusional states may result from decreased cerebral metabolism. However, in studies of patients with delirium tremens and delirium associated with hyperthermia, the cerebral metabolic rate is normal. Likewise, regional cerebral blood flow studies have thus far been inconclusive.^[11]

Studies of endocrine function and delirium tremens have shown abnormalities of thyroxine (T₄), ACTH, and growth hormone; however, these disturbances are not considered to be of clinical significance.^[11] Similarly, EEG and polygraphic sleep studies have not been helpful in understanding the pathophysiology of acute confusional states. The most common EEG abnormality is general slowing with activity in the theta and delta ranges. Bifrontal delta activity and triphasic waves have also occasionally been noted. However, the EEG is not invariably abnormal in confusion and is not directly correlated to mental status or behavior abnormalities.

In studies of the CSF metabolites of confused patients, abnormalities of 5-hydroxyindoleacetic acid, homovanillic acid, serotonin, and dopamine breakdown products have been documented.^[12]

An acute confusional state associated with infarction in the area of the right middle cerebral artery involving the parietal and frontal lobes has been reported. Similarly, other case reports have demonstrated lesions associated with confusion in the right fusiform and calcarine regions, the fusiform and lingual gyri, and the hippocampal formation.^[13]

No unified hypothesis for the pathophysiology of confusional states has yet emerged from these diverse observations. However, a discussion on consciousness and selective attention postulated a central nervous system (CNS) network, involving a disturbance in the integration of stimuli at one or more of several specific sites, the RAS, the limbic system, and the polymodal association areas of the cortex.^[14] Such an elaborate network might be vulnerable to the wide range of etiologic agents reported to result in acute confusional states. The biochemical disturbances that are by far the most common causes of confusional states would probably act at the RAS level. This hypothesis would also encompass the less common focal cortical lesions associated with this disorder. This theory could explain various issues concerning the etiology, clinical signs, treatment, and outcome of confusional states.

[edit] Etiology

Acute confusional states can be divided into those of CNS origin and those caused by toxic-metabolic disorders. The common CNS disorders are trauma, seizures, infections, dementing diseases, nutritional problems, and mass lesions.

In head trauma a period of loss of consciousness may be followed by an agitated confusional state, even in the absence of obvious focal deficit.

A variable period of confusion may follow a seizure. In most instances, however, the duration of this confusional state is short. Occasionally, continuous psychomotor seizures manifest as an acute behavioral syndrome with profound confusion. Close observation of the patient may reveal clonic twitches, mouthing, or lip-smacking movements; an EEG may be needed to elucidate the diagnosis.

Encephalitis, especially when caused by herpes simplex and purulent meningitis, is an important infectious cause of the acute confusional syndrome and is one reason for performing a lumbar puncture in all patients with acute confusion in whom no clear contraindication exists.

Elderly patients or patients with dementia seem particularly prone to episodes of acute confusion. Acute confusion occurs in elderly patients most often when they develop congestive heart failure, a slight electrolyte imbalance, mild carbon dioxide retention, or constipation with fecal impaction. A relatively asymptomatic pyelonephritis or pneumonia may also manifest with acute confusion as the presenting problem.

Nutritional disorders such as Wernicke-Korsakoff syndrome (encephalopathy) are not rare. Patients with this syndrome have acute confusion, ataxia, bilateral sixth nerve palsies, and nystagmus. The disorder is most common in alcoholics, but food faddists and recluses may also develop thiamine deficiency. The policy of discharging increasing numbers of patients from state mental institutions has resulted in an increased incidence of Wernicke-Korsakoff encephalopathy in nonalcoholic patients. Some of these patients become recluses and severely neglect their nutrition. Pellagra caused by niacin deficiency is much rarer in Western society; confusion, irritability, insomnia, and photosensitive rash with diarrhea suggest this diagnosis.

Intracranial space-occupying lesions may cause confusional states as a nonfocal manifestation of distortion of the intracranial contents. The mass may be a neoplasm, hematoma, cyst, or granuloma. In all these instances, gadolinium-enhanced MRI or contrast CT is the major diagnostic test for sorting out these possibilities.

As previously discussed, occasionally, a patient with an acute, agitated confusional state may have only a small area of infarction, presumably in one of the multimodal cortical areas.

Drug intoxication is the most common cause of the acute confusional state in older adolescents and young adults. Amphetamines, lysergic acid, cocaine, and phencyclidine (angel dust) often produce an excited, hyperalert confusion with hallucinations (see Chapter 52 ). The belladonna alkaloids can cause a dramatic acute confusion in the elderly patient being treated for Parkinson's disease. Many prescription drugs in common use can cause acute confusional states, and this should be a prime consideration in any individual recently beginning medical treatment. Cimetidine has been found to be a fairly common cause of confusion in recent years, but many other frequently used drugs also seem capable of producing acute confusion.

The paradigm of the hyperalert, acute confusional state is that associated with alcohol withdrawal. In this condition, confusion, tremulousness, illusions, and hallucinations with restlessness appear within 10 to 72 hours after the cessation of drinking (see Chapter 51 ). Withdrawal seizures consistently occur before the onset of mental symptoms.

The range of alcohol-withdrawal syndromes is wide. The most severe form is delirium tremens, in which simultaneous mental, motor, and autonomic abnormalities occur. It is a life-threatening disorder with a significant mortality rate. Major withdrawal syndromes and seizures with confusion may also develop 2 to 8 days after withdrawal from chronic use of many sedatives and tranquilizers, including the barbiturates, glutethimide, and paraldehyde.

The metabolic encephalopathies are partially listed (Box 157-5). The clinical appearances of the mental syndrome in almost all disorders may be indistinguishable from one another. The distinction must be based on a careful, general medical evaluation and appropriate laboratory investigations for these disorders. The encephalopathy caused by endogenous derangements in metabolism usually causes a hypoalert or sleepy confusion with progression to coma. Some interesting exceptions to this rule include the hyperalert, agitated mental syndromes that may be seen in acute porphyria and hyperthyroidism. The finding of asterixis (metabolic flaps) or widespread, small-amplitude myoclonic jerks is characteristic of metabolic encephalopathies.

A full discussion of the psychiatric disorders that may be associated with acute confusional states is beyond the scope of this chapter. Acute schizophrenia and manic-depressive illness in the manic phase are the two most common problems. Physicians should be very wary of making the diagnosis of a psychiatric disorder in a somnolent or obtunded, confused patient.

The cause of confusional states appears to be nonspecific. Almost any disturbance of body function may result in this syndrome. Box 157-5 presents an etiologic classification as an example of the long list of agents associated with confusional states.

[edit] Differential Diagnosis

The differential diagnosis of acute confusional states includes both “organic” and “functional” disorders. Although acute confusion is a distinctive syndrome, the varied symptomatology may cause difficulty in differentiating acute confusion from closely related disturbances.

[edit] Dementia.

Dementia is an important consideration in the differential diagnosis of confusional states (see Chapter 158 ). The two conditions are similar in that they both involve a diffuse impairment of intellectual functioning. The confused patient, however, has what appears to be a specific disturbance of consciousness, whereas dementia occurs in the context of a “clear sensorium.” The nature of onset and course of the illness are most valuable in separating these two conditions. Dementia is usually insidious in onset with a progressive deterioration, whereas confusion usually begins abruptly and shows little progression. Confusional states are relatively short-lived. If treated appropriately, and in some patients even if left untreated appropriately, spontaneous clearing may occur. Most cases of dementia, on the other hand, do not improve unless a specific treatable cause exists. Other features that help differentiate the two conditions are (1) fluctuation in symptoms, (2) disruption of the sleep-wake cycle, and (3) autonomic overactivity. These features, if present, usually favor a diagnosis of acute confusion. Periods of acute confusion, however, may be noted in the course of dementia. Dementia sometimes becomes much worse, and a stable dementia may exhibit a sudden deterioration. Frequently, this deterioration in the mental status is the result of a superimposed confusional state for which a reversible cause may be identified and corrected.

[edit] Korsakoff's Psychosis.

Korsakoff's psychosis is an amnesic syndrome associated with features of disorientation and confabulation and dominated by memory disturbance. Confusional states should be easily differentiated, since Korsakoff's psychosis occurs in the setting of a clear sensorium.

[edit] Psychiatric Disorders.

If the criteria in the DSM-IV are followed, the physician should have no difficulty in differentiating delirium from illnesses such as schizophrenia, mania, and depression.

[edit] Laboratory Investigations

The workup of the acutely confused patient is similar to that of the patient in coma: routine chest x-ray study; complete blood count; sedimentation rate, along with determination of serum glucose, electrolyte, calcium, and blood urea nitrogen levels and a toxic screen. Arterial blood gas values, serum ammonia tests, liver function studies, serum cortisol and T₄ levels, antinuclear antibodies, serum protein electrophoresis, and a urine test for porphyrins and heavy metals may be required in certain patients. An EEG may offer important evidence of a continuous complex partial seizure disorder or demonstrate the widespread symmetric slowing with triphasic activity that characterizes metabolic encephalopathies (e.g., hepatic encephalopathies). Rapid, frontally distributed EEG activity may signify the presence of sedative drugs.

A lumbar puncture should be performed on every patient who is acutely confused unless a distinct contraindication exists. Contraindications consist of two possibilities: (1) the patient may be seen in a phase marked by extremely rapid, ongoing improvement, as in the treatment of a bout of hypoglycemia, or (2) a lumbar puncture may be deferred, a circumstance that arises in a patient with signs of increased intracranial pressure from a mass lesion. In this second situation, it is not satisfactory simply to defer a lumbar puncture; urgent alternative diagnostic measures, usually neuroimaging, should be performed.

Neurologic and neurosurgical consultation should be obtained for advice and guidance regarding the selection of procedures or further diagnostic tests. The role of other noninvasive examinations, such as isotope brain scanning, flow scans, and the EEG, remains a matter of judgment that must take into account both the rate of progression of the patient's clinical status and the likelihood of diagnostic yield. Both EEG and neuroimaging may be difficult if the patient is restless or combative.

[edit] Management

Treatment largely depends on correcting the specific underlying abnormality. Since medication is frequently a cause of confusional states, the most effective approach is to discontinue the medication whenever possible while correcting any underlying metabolic disturbance. In most instances the etiology is clear, but in the more difficult cases a full workup is essential because attempts at simply controlling the behavior may result, for example, in not recognizing a case of fatal meningitis.

The management of the behavior disturbance could be accomplished by pharmacotherapy; however, most confused patients benefit more from specialized nursing care. For the more belligerent patients, it is often necessary to use geriatric chairs or padded bedrails or to glove and partially restrain the patient limbs. Generally, however, patients do best unrestrained but contained in an environment where strict limits are set. Large calendars, constant reassurance, and positive reinforcement from the staff are invaluable orienting stimuli and often improve behavior. The bedside lamp and radio are helpful aids when the patient awakens at night. Only when these measures have failed should pharmacotherapy be used.

Antipsychotics are the most popular drugs in the treatment of confusional states. No evidence has shown that one is superior to any other. Haloperidol is frequently used. Loxapine is more sedating and in some patients might be preferable. Most of the sedative-hypnotic agents, such as barbiturates, chloral hydrate, and flurazepam, are less helpful and may even exacerbate the confusional state. The anxiolytics are sometimes effective. Chlorazepam and oxazepam have relatively short half-lives with little buildup of active metabolites. β-Adrenergic blockers such as propranolol have been reported to be effective in agitated and belligerent patients and may be particularly effective in elderly patients. Antihistamines are sedating and sometimes useful. Initial dosages of all drugs should be low and should increase only in gradual increments, since all these medications may precipitate a paradoxical reaction with greatly increased behavioral disturbances. Disturbances in the sleep-wake cycle are often difficult to correct. Prevention of “catnaps” during the day may help promote a full night of sleep. Sedation, however, is rarely effective; the sleep-wake cycle usually normalizes only as the confusional state clears.

[edit] REFERENCES