Plum and posner’s diagnosis of stupor and coma fourth Edition series editor sid Gilman, md, frcp
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which, because of their diffuse involvement of brain, resemble the metabolic encephalopath- ies more than they do focal structural disease. Heading H lists a variety of miscellaneous dis- orders whose cause is unknown. Although they represent a heterogeneous group of disorders, the diseases listed in Table 5–1, when they cause stupor and coma, can usually be distinguished by clinical signs alone from supratentorial and infratentorial focal lesions and from psychologic disorders. One caveat: neither the neurologic exami- nation nor the examiner is infallible, and some patients have more than one cause for coma. Hence, even when the diagnosis of metabolic disease is absolutely unequivocal, unless the response to treatment is rapid and equally ro- bust, imaging is an essential part of a careful workup.
CLINICAL SIGNS OF METABOLIC ENCEPHALOPATHY Each patient with metabolic coma has a dis- tinctive clinical picture, depending on the par- ticular causative illness, the depth of coma, and the complications provided by comorbid ill- nesses or their treatment. Despite these indi- vidualities, however, specific illnesses often pro- duce certain clinical patterns that recur again and again, and once recognized, they betray the diagnosis. A careful evaluation of consciousness, respiration, pupillary reactions, ocular move- ments, motor function, and the electroenceph- alogram (EEG) may differentiate metabolic encephalopathy from psychiatric dysfunction (Chapter 6) on the one hand, and from supra- tentorial or infratentorial structural disease on the other (see Chapters 3 and 4). Because these general characteristics of metabolic coma are so important, they are discussed before the specific disease entities. CONSCIOUSNESS: CLINICAL ASPECTS In patients with metabolic encephalopathy, stupor or coma is usually preceded by delir- ium. Delirium is characterized by alterations of arousal (either increased or decreased), 1 dis- orientation, decreased short-term memory, re- duced ability to maintain and shift attention, disorganized thinking, perceptual disturbances, delusions and/or hallucinations, and disorders of sleep-wake cycle. 2 Some workers believe that Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma 181
Table 5–1 Some Diffuse, Multifocal, or Metabolic Causes of Delirium, Stupor, and Coma A. Deprivation of oxygen, substrate, or metabolic cofactors 1. Hypoxia* (interference with oxygen supply to the entire brain; cerebral blood flow [CBF] normal) a. Decreased blood PO 2 and O
2 content: pulmonary disease; alveolar hypoventilation; decreased atmospheric oxygen tension b. Decreased blood O 2 content, PO 2 normal: ‘‘anemic anoxia’’; anemia; carbon monoxide poisoning; methemoglobinemia 2. Ischemia* (diffuse or widespread multifocal interference with blood supply to brain) a. Decreased CBF resulting from decreased cardiac output: Stokes-Adams attack; cardiac arrest; cardiac arrhythmias; myocardial infarction; congestive heart failure; aortic stenosis; pulmonary embolism b. Decreased CBF resulting from decreased peripheral resistance in systemic circulation: syncope (see Table 5–8); carotid sinus hypersensitivity; low blood volume c. Decreased CBF associated with generalized or multifocal increased vas- cular resistance: hyperventilation syndrome; hyperviscosity (polycythemia, cryoglobulinemia or macroglobulinemia, sickle cell anemia); subarachnoid hemorrhage; bacterial meningitis; hypertensive encephalopathy d. Decreased CBF owing to widespread small-vessel occlusions: disseminated intravascular coagulation; systemic lupus erythematosus; subacute bacterial endocarditis; fat embolism; cerebral malaria; cardiopulmonary bypass 3. Hypoglycemia* resulting from exogenous insulin: spontaneous (endogenous insulin, liver disease, etc.) 4. Cofactor deficiency Thiamine (Wernicke’s encephalopathy) Niacin Pyridoxine Cyanocobalamin Folic acid B. Toxicity of endogenous products 1. Due to organ failure Liver (hepatic coma) Kidney (uremic coma) Lung (CO 2 narcosis) Pancreas (exocrine pancreatic encephalopathy) 2. Due to hyper- and/or hypofunction of endocrine organs: pituitary thyroid (myxedema-thyrotoxicosis); parathyroid (hypo- and hyperparathyroidism); adrenal (Addison’s disease, Cushing’s disease, pheochromocytoma); pancreas (diabetes, hypoglycemia) 3. Due to other systemic diseases: diabetes; cancer; porphyria; sepsis C. Toxicity of exogenous poisons 1. Sedative drugs*: hypnotics, tranquilizers, ethanol, opiates 2. Acid poisons or poisons with acidic breakdown products: paraldehyde; methyl alcohol; ethylene glycol; ammonium chloride 3. Psychotropic drugs: tricyclic antidepressants and anticholinergic drugs; amphetamines; lithium; phencyclidine; phenothiazines; LSD and mescaline; ponoamine oxidase inhibitors 4. Others: penicillin; anticonvulsants; steroids; cardiac glycosides; trace metals; organic phosphates; cyanide; salicylate D. Abnormalities of ionic or acid-base environment of central nervous system (CNS) Water and sodium (hyper- and hyponatremia) Acidosis (metabolic and respiratory) Alkalosis (metabolic and respiratory) Magnesium (hyper- and hypomagnesemia) Calcium (hyper- and hypocalcemia) Phosphorus (hypophosphatemia) 182
impairment of attention is the underlying ab- normality in all acute confusional states; others emphasize clouding of consciousness as the core symptom. 3 The importance of these early behavioral warnings is so great that we will re- view briefly some of the mental symptoms that often precede metabolic coma and, by their presence, suggest the diagnosis. The mental changes are best looked for in terms of arousal, attention, alertness, orientation and grasp, cog- nition, memory, affect, and perception. Tests of Mental Status Assessing cognitive function in patients with impairment of attention and alertness is often difficult. However, careful quantitative assess- ment of these functions is exceedingly impor- tant, because changes in cognition often indi- cate whether the physician’s therapeutic efforts are improving or worsening the patient’s con- dition. Several validated bedside tests that can be given in a few minutes, even to confused pa- tients, have been developed. These tests allow one to score cognitive functions and to follow the patient’s course in quantitative fashion. 4–6 One test is specifically designed for patients in intensive care units, even those on respirators. 7 Table 5–2 illustrates one such scale. Arousal can be defined as the degree of sen- sory stimulation required to keep the patient attending to the examiner’s question. Patients with metabolic encephalopathy always have ab- normalities of arousal. Some patients are hyper- vigilant, whereas in others arousal is decreased. In many delirious patients arousal alternates between hyper- and hypovigilance. 1 Hyperar-
oused patients are so distractible that they can- not maintain focus on relevant stimuli, whereas hypoaroused patients need constant sensory stimulation. In addition, most delirious patients have an altered sleep-wake cycle, often sleeping during the day but becoming more confused and hyperactive at night (‘‘sundowning’’). Ab- normalities of arousal can also be reflected in motor activity, with hyperaroused patients demonstrating increased but purposeless motor activity and hypoaroused patients being rela- tively immobile. Although certain clinical states (i.e., drug withdrawal and fever) are more likely to produce a hyperaroused state than are other E. Disordered temperature regulation Hypothermia Heat stroke, fever F. Infections or inflammation of CNS Leptomeningitis Encephalitis Acute ‘‘toxic’’ encephalopathy Parainfectious encephalomyelitis Cerebral vasculitis/vasculopathy Subarachnoid hemorrhage G. Primary neuronal or glial disorders Creutzfeldt-Jakob disease Marchiafava-Bignami disease Adrenoleukodystrophy Gliomatosis, lymphomatosis cerebri Progressive multifocal leukoencephalopathy H. Miscellaneous disorders of unknown cause Seizures and postictal states Concussion Acute delirious states*: sedative drugs and withdrawal; ‘‘postoperative’’ delirium; intensive care unit delirium; drug intoxications *Alone or in combination, the most common causes of delirium seen on medical or surgical wards. Table 5–1 (cont.) Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma 183
metabolic disorders such as drug intoxication and hypoxia/ischemia, in a given patient the state of arousal is not a reliable guide in diagnosis. In general, about one-quarter of patients with de- lirium are hyperaroused, one-quarter are hypo- aroused, and one-half fluctuate between the two states. Although hyperaroused patients are of- ten diagnosed earlier because of their florid behavior, their outcome appears no different from those patients who are hypoactive. 8,9 Table 5–2 The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) Delirium is diagnosed when both features 1 and 2 are positive, along with either feature 3 or feature 4. Feature 1. Acute Onset of Mental Status Changes or Fluctuating Course
Is there evidence of an acute change in mental status from the baseline? Did the (abnormal) behavior fluctuate during the past 24 hours, that is, tend to come and go or increase and decrease in severity? Sources of information: Serial Glasgow Coma Scale or sedation score ratings over 24 hours as well as readily available input from the patient’s bedside critical care nurse or family Feature 2: Inattention
Did the patient have difficulty focusing attention? Is there a reduced ability to maintain and shift attention? Sources of information: Attention screening examinations by using either picture recognition or Vigilance A random letter test (see Methods and Appendix 2 for description of attention screening examinations). Neither of these tests requires verbal response, and thus they are ideally suited for mechanically ventilated patients. Feature 3. Disorganized Thinking
Was the patient’s thinking disorganized or incoherent, such as rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject?
Was the patient able to follow questions and commands throughout the assessment? 1. ‘‘Are you having any unclear thinking?’’ 2. ‘‘Hold up this many fingers.’’ (Examiner holds two fingers in front of the patient.) 3. ‘‘Now, do the same thing with the other hand.’’ (Not repeating the number of fingers) Feature 4. Altered Level of Consciousness
Any level of consciousness other than ‘‘alert.’’ Alert—normal, spontaneously fully aware of environment and interacts appropriately
Vigilant—hyperalert Lethargic—drowsy but easily aroused, unaware of some elements in the environment, or not spontaneously interacting appropriately with the interview; becomes fully aware and appropriately interactive when prodded minimally
Stupor—difficult to arouse, unaware of some or all elements in the environment, or not spontaneously interacting with the interviewer; becomes incompletely aware and inappropriately interactive when prodded strongly
Coma—unarousable, unaware of all elements in the environment, with no spontaneous interaction or awareness of the interviewer, so that the interview is difficult or impossible even with maximum prodding From Ely et al., 6 with permission. 184 Plum and Posner’s Diagnosis of Stupor and Coma ATTENTION AND ALERTNESS Attention is a process whereby one focuses on relevant stimuli from the environment and is able to shift focus to other stimuli as they become relevant. Most observers believe that the core of delirium as an altered state of con- sciousness is failure of attention. Attention is assessed by the examiner during the course of the clinical examination by determining whether a patient continues to respond in an appropriate fashion to the questions posed by the examiner. Attention is tested formally by having a patient perform a repetitive task that requires multiple iterations, such as naming the days of the week or months of the year, or a random list of numbers or serial subtractions, backwards. Failure to complete the task and even inability to name what the task was indi- cate inattention. Three different disorders of attention can be identified in delirious patients. The first disorder that usually occurs in patients who are hyper- aroused is distractibility. Patients shift attention from the examiner to noises in the hallway or other extraneous stimuli. A second abnormality of attention is perseveration. Patients answer a new question or respond to a new stimulus with the same response they gave to the previous stimulus, failing to redirect behavior toward the new stimulus. The third abnormality is failure to focus on an ongoing stimulus. After being dis- tracted by another stimulus, the patient will for- get to return to the activity in which he or she was engaged before distraction. Alterations of alertness preceding other changes are more characteristic of acute or subacutely developing metabolic encephalop- athy than of more slowly developing demen- tia; demented patients tend to lose orientation and cognition before displaying an alteration in alertness. Severe metabolic encephalopathy eventually leads to stupor and finally coma, and of course, when this point is reached, mental testing no longer helps to distinguish metabolic from other causes of brain dysfunction. ORIENTATION AND GRASP Although attention and arousal are the first faculties to be impaired by metabolic encepha- lopathies, they are difficult to quantify. As a re- sult, defects in orientation and immediate grasp of test situations often become the earliest unequivocal symptoms of brain dysfunction. When examining patients suspected of meta- bolic or cerebral disorders, one must ask spe- cifically the date, the time, the place, and how long it takes or the route one would take to reach home or some other well-defined place. Even uneducated patients or those with limited intellect should know the month and year, and most should know the day and date, particu- larly if there has been a recent holiday. Patients with early metabolic encephalopathy lose ori- entation for time and miss the year as frequently as the month or the day. Orientation for dis- tance is usually impaired next, and finally, the identification of persons and places becomes confused. Disorientation for person and place but not time is unusual in structural disease but sometimes is a psychologic symptom. Disori- entation for self is almost always a manifesta- tion of psychologically induced amnesia. COGNITION The content and progression of thought are always disturbed in delirium and dementia, sometimes as the incipient symptoms. To de- tect these changes requires asking specific questions employing abstract definitions and problems. As attention and concentration are nearly always impaired, patients with meta- bolic brain disease usually make errors in serial subtractions, and rarely can they repeat more than three or four numbers in reverse. Thus, difficulty with mental arithmetic is not a sign necessarily of impaired calculation ability; writ- ing the problem down, which eliminates the attentional component of the task, allows as- sessment of the underlying cognitive function. It is important to inventory language skills (in- cluding reading and writing), arithmetic skills, and visuospatial skills (including drawing), as well as to judge whether the patient is able to cooperate and to distinguish focal cognitive impairments (suggesting a focal lesion) from more global derangement that is seen in met- abolic encephalopathy. MEMORY
Loss of recent memory for recent events and inability to retain new memories for more than a few minutes is a hallmark of dementia and a frequent accompaniment of delirium. Most patients with metabolic brain disease have a Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma 185
memory loss that is proportional to other losses of cognitive functions. When the maximal path- ologic changes involve the medial temporal lobe, however, recent memory loss outstrips other intellectual impairments. Thus, memory loss and an inability to form new associations can be a sign of either diffuse or bilateral focal brain disease. AFFECT AND COMPORTMENT Patients may appear apathetic and withdrawn, in which case they are often believed by their relatives to be depressed, or they may be ebul- lient and outgoing, particularly when hyper- aroused. Inappropriate comments and behav- ior are common and often embarrassing to friends and relatives. Patients are usually un- aware that their behavior is inappropriate. PERCEPTION Patients with metabolic brain disease frequently make perceptual errors, mistaking the mem- bers of the hospital staff for old friends and relatives and granting vitality to inanimate ob- jects. Illusions are common and invariably in- volve stimuli from the immediate environment. Quiet and apathetic patients suffer illusory ex- periences, but these must be asked about since they are rarely volunteered. Anxious and fear- ful patients, on the other hand, frequently ex- press concern about their illusions and mis- perceptions to the accompaniment of loud and violent behavior. Unlike patients with psychi- atric disorders, visual or combined visual and auditory hallucinations are more common than pure auditory ones. 10,11 Pathogenesis of the Mental Changes Both global and focal cerebral functional ab- normalities can cause the mental symptoms of metabolic brain disease. The global symptoms result from alterations of arousal that in turn interfere with attention, comprehension, and cognitive synthesis. Well-recognized focal ce- rebral abnormalities include specific abnormal- ities in language recognition and synthesis, in recent memory storage and recall, in gnosis (recognition of persons and/or objects [from the Greek for knowledge]) and praxis (ability to preform an action [from the Greek for action]), and perhaps in the genesis of hallucinations. Focal lesions may mimic more diffuse causes of delirium. Perhaps the best example is the florid delirium that sometimes accompanies cerebral infarcts of the nondominant parietal lobe, 12
tion 13 that, as indicated above, may be the pri- mary abnormality in delirium. A combination of diffuse and focal dysfunc- tion probably underlies the cerebral symptoms of most patients with metabolic encephalopa- thy. The extensive corticocortical physiologic connectivity of the human brain discussed in Chapter 1 implies that large focal abnormali- ties inevitably will cause functional effects that extend well beyond their immediate confines. Furthermore, the more rapidly the lesion de- velops, the more extensive will be the acute functional loss. Thus, the general loss of highest integrative functions in metabolic diseases is compatible with a diffuse dysfunction of neu- rons and, as judged by measurements of ce- rebral metabolism, the severity of the clinical signs is directly related to the mass of neurons affected. However, certain distinctive clinical signs in different patients and in different dis- eases probably reflect damage to more discrete areas having to do with memory and other selective aspects of integrative behavior. An example is the encephalopathy resulting from thiamine deficiency (Wernicke-Korsakoff syn- drome; see page 223). In this illness, patients show acutely the clinical signs of delirium and, rarely, coma. 14 All neuronal areas are deprived of thiamine to the same extent, but certain cell groups such as the mamillary bodies, the me- diodorsal nucleus of the thalamus, the peria- queductal gray matter, and the oculomotor nuclei are pathologically more sensitive to the deficiency and show the greatest anatomic evidence of injury. The final common pathway to neuronal destruction, as in many other dis- orders, is probably glutamate-induced excito- toxicity. 15,16 Thus, a diffuse disease may have a focal maximum. Clinically, eye movements, balance, and recent memory are impaired more severely than are other mental functions, and indeed, memory loss may persist to produce a permanent Wernicke-Korsakoff syndrome af- ter other mental functions and overall cerebral metabolism have improved to a near-normal level.
186 Plum and Posner’s Diagnosis of Stupor and Coma RESPIRATION Sooner or later, metabolic brain disease nearly always results in an abnormality of either the depth or rhythm of breathing. Most of the time, this is a nonspecific alteration and simply a part of a more widespread brainstem de- pression. Sometimes, however, the respiratory changes stand out separately from the rest of the neurologic defects and are more or less specific to the disease in question. Some of these specific respiratory responses are homeostatic adjustments to the metabolic process causing encephalopathy. The others occur in illnesses that particularly affect the respiratory mecha- nisms. Either way, proper evaluation and in- terpretation of the specific respiratory changes facilitate diagnosis and often suggest an urgent need for treatment. As a first step in appraising the breathing of patients with metabolically caused coma, in- creased or decreased respiratory efforts must be confirmed as truly reflecting hyperventila- tion or hypoventilation. Increased chest efforts do not indicate hyperventilation if they merely overcome obstruction or pneumonitis, and con- versely, seemingly shallow breathing can ful- fill the reduced metabolic needs of subjects in deep coma. Although careful clinical evaluation usually avoids those potential deceptions, the bedside observations are most helpful when anchored by direct determinations of the ar- terial blood gases. Neurologic Respiratory Changes Accompanying Metabolic Encephalopathy Lethargic or slightly obtunded patients have posthyperventilation apnea, probably resulting from loss of the influence of the frontal lobes in causing continual if low-volume ventila- tion, even when there is no metabolic need to breathe. 17 Those in stupor or light coma com- monly exhibit Cheyne-Stokes respiration. With more profound brainstem depression, tran- sient neurogenic hyperventilation can ensue either from suppression of brainstem inhibi- tory regions or from development of neuro- genic pulmonary edema. 18,19 As an illustration, poisoning with short- or intermediate-acting barbiturate preparations often induces brief episodes of hyperventilation and motor hy- pertonus, either during the stage of deepening coma or as patients reawaken. Hypoglycemia and anoxic damage are even more frequent causes of transient hyperpnea. Diabetic keto- acidosis and other causes of coma that cause a metabolic acidosis may produce slow, deep (Kussmaul) respirations. Both hepatic enceph- alopathy and systemic inflammatory states cause persistent hyperventilation, resulting in a primary respiratory alkalosis. In these in- stances, the increased breathing sometimes outlasts the immediate metabolic perturba- tion, and if the subject also has extensor rigid- ity, the clinical picture may superficially re- semble structural disease or severe metabolic acidosis. However, attention to other neuro- logic details usually leads to the proper diag- nosis, as the following case illustrates. Patient 5–1 A 28-year-old man was brought unconscious to the emergency department. Fifteen minutes ear- lier, with slurred speech, he had instructed a taxi driver to take him to the hospital, then ‘‘passed out.’’ His pulse was 100 per minute, and his blood pressure was 130/90 mm Hg. His respirations were 40 per minute and deep. The pupils were small (2 mm), but the light and ciliospinal reflexes were preserved. Oculocephalic reflexes were present. Deep tendon reflexes were hyperactive; there were bilateral extensor plantar responses, and he peri- odically had bilateral extensor spasms of the arms and legs. His blood glucose was 20 mg/dL. After 25 g of glucose was given intravenously, respira- tions quieted, the extensor spasms ceased, and he withdrew appropriately from noxious stimuli. Af- ter 75 g of glucose, he awoke and disclosed that he was diabetic, taking insulin, and had neglected to eat that day. Comment: This man’s hyperpnea and decere- brate rigidity initially suggested structural brainstem disease to the emergency department physicians. Normal oculocephalic responses, normal pupillary reactions, and the absence of other focal signs made metabolic coma more likely, and the diagnosis was confirmed by the subsequent findings. The effectiveness of respiration must be evaluated repeatedly when metabolic disease depresses the brain, because the brainstem Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma 187
reticular formation is especially vulnerable to chemical depression. Anoxia, hypoglycemia, and drugs all are capable of selectively induc- ing hypoventilation or apnea while concurrently sparing other brainstem functions such as pu- pillary responses and blood pressure control. Acid-Base Changes Accompanying Hyperventilation During Metabolic Encephalopathy Respiration is the first and most rapid defense against systemic acid-base imbalance. Chemo- receptors located in the carotid body and aortic arterial wall, as well as in the lower brainstem, quickly respond to alterations in the blood of either hydrogen ion concentration or PCO 2 . Hypoxia sensitizes peripheral chemoreceptors and activates central chemoreceptors, but un- der most circumstances carbon dioxide levels, which are linked to blood pH, are more im- portant in determining respiration (see Chap- ter 2). Table 5–3 lists some causes of abnormal ventilation in unresponsive patients. HYPERVENTILATION In a stuporous or comatose patient, hyper- ventilation is a danger sign meaning one of two things: either compensation for metabolic acidosis or a response to primary respiratory stimulation (respiratory alkalosis). Metabolic acidosis and respiratory alkalosis are differen- tiated by blood biochemical analyses. In the first instance, the arterial blood pH is low (less than 7.30 if hyperpnea is to be attributed to acidosis) and the serum bicarbonate is also low (usually below 10 mEq/L). In the second case, the arterial pH is high (over 7.45) and the se- rum bicarbonate is normal or reduced. In both primary respiratory alkalosis and metabolic ac- idosis with respiratory compensation, the ar- terial carbon dioxide tension (PaCO 2 ) is re-
duced, usually below 30 mm Hg. Respiratory compensation for metabolic acidosis is a nor- mal brainstem reflex response and, hence, oc- curs in most cases of metabolic acidosis. Mixed primary metabolic acidosis and primary respi- ratory alkalosis (which persists after the aci- dotic load is removed) also occurs in several conditions, particularly salicylate toxicity and hepatic coma. A diagnosis of mixed metabolic abnormality can be made when the degree of respiratory or metabolic compensation is ex- cessive. Table 5–4 lists some of the causes of hyperventilation in patients with metabolic en- cephalopathy. Table 5–3 Some Causes of Abnormal Ventilation in Unresponsive Patients I. Hyperventilation A. Metabolic acidosis 1. Anion gap Diabetic ketoacidosis* Diabetic hyperosmolar coma* Lactic acidosis Uremia* Alcoholic ketoacidosis Acidic poisons* Ethylene glycol Propylene glycol Methyl alcohol Paraldehyde Salicylism (primarily in children) 2. No anion gap Diarrhea
Pancreatic drainage Carbonic anhydrase inhibitors NH 4
Renal tubular acidosis Ureteroenterostomy B. Respiratory alkalosis Hepatic failure* Sepsis* Pneumonia Anxiety (hyperventilation syndrome) C. Mixed acid-base disorders (metabolic acidosis and respiratory alkalosis) Salicylism Sepsis* Hepatic failure* II. Hypoventilation A. Respiratory acidosis 1. Acute (uncompensated) Sedative drugs* Brainstem injury Neuromuscular disorders Chest injury Acute pulmonary disease 2. Chronic pulmonary disease* B. Metabolic alkalosis Vomiting or gastric drainage Diuretic therapy Adrenal steroid excess (Cushing’s syndrome) Primary aldosteronism Bartter’s syndrome *Common causes of stupor or coma. 188
Plum and Posner’s Diagnosis of Stupor and Coma Metabolic acidosis sufficient to produce coma and hyperpnea has four important causes: uremia, diabetes, lactic acidosis (anoxic or spontaneous), and the ingestion of poisons that are acidic or have acidic breakdown prod- ucts (Table 5–4). In any given patient, a quick and accurate selection can and must be made from among these disorders. Diabetes and uremia are di- agnosed by appropriate laboratory tests, and di- abetic acidosis is confirmed by identifying se- rum ketonemia. It is important to remember that severe alcoholics without diabetes occa- sionally can develop ketoacidosis after pro- longed drinking bouts. 21 An important obser- vation is that diabetics, especially those who have been treated with the oral hypoglycemic agent metformin, are subject to lactic acidosis as well as to diabetic ketoacidosis, but in the former condition ketonemia is lacking. 22 If di- abetes and uremia are eliminated in a patient as causes of acidosis, it can be inferred either that he or she has spontaneous lactic acidosis or has been poisoned with an exogenous toxin such as ethylene glycol, propylene glycol (which is metabolized to a racemic mixture of lactate), methyl alcohol, or decomposed paraldehyde. Anoxic lactic acidosis would be suspected only if anoxia or shock was present, and even then severe anoxic acidosis is relatively uncom- mon. Although laboratory tests can identify and quantify the ingested agents, these tests are not usually immediately available (see Chapter 7). However, the toxins are osmotically active and measurement of serum osmolality can de- tect the presence of an osmotically active sub- stance, indicating exposure to a toxic agent. 23 Severe toxic alcohol poisonings can be treated with fomepizole and, if necessary in patients with renal failure, hemodialysis. 24 One report suggests that diethylene glycol poisoning can cause delayed neurologic sequelae including cranial neuropathies and bulbar palsy. 25 The treatment of metabolic acidosis depends first on treating the inciting factor. Intravenous bicarbonate is indicated to treat hyperkalemia and to help clear acidic toxins from cells. Bicar- bonate does not appear helpful in treating dia- betic ketoacidosis. 20 Sustained respiratory alkalosis has five im- portant causes among disorders producing the picture of metabolic stupor or coma: salicy- lism, hepatic coma, pulmonary disease, sepsis, and psychogenic hyperventilation (Table 5–5). Table 5–4 Pathophysiology of Metabolic Acidosis Cause Rate of Acid Accumulation Failure of renal acid excretion 2–4 mEq/hour Decreased H þ secretion Distal renal tubular acidosis
Decreased NH 4 þ production Generalized renal failure Adrenal insufficiency/ hypoaldosteronism Loss of bicarbonate and alkaline equivalents 1–20 mEq/hour Gastrointestinal Diarrhea
Pancreatic, biliary, and enteric drainage Urinary diversion Renal
Carbonic anhydrase inhibitors Proximal renal tubular acidosis
Posthypocapnic state Dilutional acidosis Addition and/or overproduction of acid 2–500 mEq/hour Endogenous Lactic acidosis Ketoacidosis Alcoholic Starvation Diabetes Hereditary metabolic enzyme disorders Exogenous Acid administration Hydrochloric acid Ammonium chloride Cationic amino acids in total parenteral nutrition Toxins converted to acid Methanol
Ethylene glycol, propylene glycol Paraldehyde Salicylate From Swenson, 20 with permission. Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma 189
Neurogenic pulmonary edema and central neurogenic hyperventilation may also cause re- spiratory alkalosis in patients with metabolic stupor or coma. As is true with metabolic aci- dosis, these usually can be at least partially separated by clinical examination and simple laboratory measures. Salicylate poisoning causes a combined re- spiratory alkalosis and metabolic acidosis that lowers the serum bicarbonate disproportion- ately to the degree of serum pH elevation. Salicylism should be suspected in a stuporous hyperpneic adult if the serum pH is normal or alkaline, there is an anion gap, and the se- rum bicarbonate is between 10 and 14 mEq/L. Salicylism in children lowers serum bicarbon- ate still more and produces serum acidosis. A bedside laboratory test can rapidly establish a diagnosis of salicylate intoxication, 27 although usually in an awake patient the positive history and the presence of respiratory alkalosis are suf- ficient. A single serum salicylate measurement may be somewhat misleading, particularly if the patient has taken enteric-coated tablets that may delay absorption. Therefore, in a pa- tient with a suspected salicylate overdose, care- ful measurements should be done every 3 hours until levels have peaked. The ingestion of sed- ative drugs in addition to salicylates may blunt the hyperpnea and lead to metabolic acidosis, a picture that may mislead the examiner. Salicylates directly activate the respiratory centers of the brainstem, although the mecha- nism is not known. Acetaminophen poisoning, more common than salicylate poisoning, may cause either metabolic acidosis (lactic acidosis) or respiratory alkalosis resulting from its hepatic toxicity (see below). 28,29
The treatment includes, where appropriate, gastric lavage and activated charcoal. Urinary alkalization helps promote excretion of the drug; hemodialysis may be necessary if there is renal failure. 30 Acetylcysteine may limit the degree of hepatic toxicity by acetaminophen (see Chap- ter 7).
Hepatic coma, producing respiratory alka- losis, rarely depresses the serum bicarbonate below 16 mEq/L, and the diagnosis usually is betrayed by other signs of liver dysfunction. The associated clinical abnormalities of liver disease are sometimes minimal, particularly with fulminating acute liver failure or when gastrointestinal hemorrhage precipitates coma in a chronic cirrhotic patient. Liver function tests and measurement of arterial ammonia must be relied upon in such instances. Sepsis is always associated with hyperventi- lation, probably a direct central effect of the cascade of cytokines and prostaglandins initi- ated by endotoxinemia. In fact, a respiratory rate of more than 20 breaths per minute, or a PCO 2
tion of sepsis. 31 Early in the course of the illness the acid-base defect is that of a pure respiratory alkalosis (HCO 3 greater than 15 mEq/L), but in critically ill patients, lactic acid later accumu- lates in the blood and the stuporous patient usually presents a combined acid-base defect of respiratory alkalosis and metabolic acidosis (HCO 3
cases hypothermia and hypotension, may ac- company the neurologic signs and suggest the diagnosis. Respiratory alkalosis caused by pulmonary congestion, fibrosis, or pneumonia rarely de- presses the serum bicarbonate significantly. This diagnosis should be considered in hyp- Table 5–5 Pathophysiology of Respiratory Alkalosis Hypoxia
Parenchymal lung disease Pneumonia Bronchial asthma Diffuse interstitial fibrosis Pulmonary embolism Pulmonary edema Medications and mechanical ventilation Medications Salicylate Nicotine
Xanthine Catecholamines Analeptics Mechanical ventilation Central nervous system disorders Meningitis, encephalitis Cerebrovascular disease Head trauma Space-occupying lesion Anxiety
Metabolic Sepsis
Hormonal Pyrexia
Hepatic disease Hyperventilation syndrome From Foster et al., 26 with permission. 190 Plum and Posner’s Diagnosis of Stupor and Coma oxic, hyperpneic comatose patients who have normal or slightly lowered serum bicarbonate levels and no evidence of liver disease. Psychogenic hyperventilation does not cause coma, but may cause delirium, and may be pres- ent as an additional symptom in a patient with psychogenic ‘‘coma.’’ Severe alkalosis, by itself, has been reported to cause seizures and coma. The decreased ionizable calcium complicating alkalosis may lead to muscle twitching, muscle spasms, and tetany, as well as positive Chvos- tek and Trousseau’s signs. 32 Acid-Base Changes Accompanying Hypoventilation During Metabolic Encephalopathy In an unconscious patient, hypoventilation means either respiratory compensation for met- abolic alkalosis or respiratory depression with consequent acidosis. The differential diagnosis is outlined in Table 5–3. In metabolic alkalosis the arterial blood pH is elevated (greater than 7.45), as is the serum bicarbonate (greater than 35 mEq/L). In untreated respiratory acidosis with coma, the serum pH is low (less than 7.35) and the serum bicarbonate is either normal or high, depending on prior treatment and how rapidly the respiratory failure has developed. The PaCO 2 is always elevated in respiratory acidosis (usually greater than 55 mm Hg) and is often elevated in metabolic alkalosis as well because of respiratory compensation in meta- bolic alkalosis. In respiratory acidosis, the pH of the cerebrospinal fluid (CSF) is always low if artificial ventilation has not been used. 33,34 The
PCO 2 is elevated in respiratory acidosis, and in metabolic alkalosis with respiratory compen- sation, but is usually less than 50 mm Hg in primary metabolic alkalosis and almost invari- ably rises considerably higher than this when primary respiratory acidosis causes stupor or coma. In both disorders, the oxygen tension is reduced due to hypoventilation. A normal se- rum bicarbonate level is consistent with un- treated respiratory acidosis of short duration but not with metabolic alkalosis. Metabolic alkalosis results from (1) excessive loss of acid via gastrointestinal or renal routes, (2) excessive bicarbonate load, or (3) failure to fully correct the posthypocapnic state (Table 5–6). 32 To find the specific cause often requires ex- haustive laboratory analyses, but delirium and obtundation owing to metabolic alkalosis are rarely severe and never life threatening, so that Table 5–6 Pathophysiology of Metabolic Alkalosis Generation Examples
1. Loss of acid from extracellular space Vomiting
A. Loss of gastric fluid (HCI) Primary aldosteronism and diuretic administration B. Acid loss in the urine: increased distal Na þ delivery in presence of hyperaldosteronism C. Acid shifts into cells Potassium deficiency D. Loss of acid into stool Congenital chloride-losing diarrhea 2. Excessive HCO 3 loads
A. Absolute 1. Oral or parenteral HCO 3 Milk alkali syndrome 2. Metabolic conversion of the salts of organic acids in HCO 3 1
administration (especially in conditions with underlying liver disease) B. Relative NaHCO 3
3. Posthypercapnic states Correction of chronic hypercapnia in presence of low-salt diet or in a patient with congestive heart failure From Khanna and Kurtzman, 32 with permission Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma 191
time exists for careful diagnostic considerations. Respiratory compensation from metabolic al- kalosis leads to hypocapnia, but the PCO 2 rarely is higher than 50 torr. Higher levels suggest coexistent pulmonary disease. 35 Respiratory acidosis is a more pressing prob- lem, 36 caused by either severe pulmonary or neuromuscular disease (peripheral respiratory failure) or by depression of the respiratory cen- ter (central respiratory failure) (Table 5–7). Both causes induce hypoxia as well as CO 2 retention. Chest examinations almost always can differentiate neuromuscular from pulmo- nary disease, and the presence of tachypnea distinguishes pulmonary or peripheral neuro- muscular failure from central failure with its irregular or slow respiratory patterns. Severe respiratory acidosis of any origin is best treated by artificial ventilation. Acute respiratory aci- dosis causes encephalopathy, sometimes asso- ciated with headache, which may reflect intra- cranial vasodilation. If the PCO 2 exceeds 70 torr, the patient may become stuporous or comatose. If awake, there may be asterixis, myoclonus, and sometimes papilledema, the last resulting from increased intracranial pres- sure (ICP) due to the carbon dioxide-induced cerebral vasodilation. PUPILS Among patients in deep coma, the state of the pupils becomes the single most important cri- terion that clinically distinguishes between metabolic and structural disease. The presence Table 5–7 Pathophysiology of Respiratory Acidosis Acute Chronic
Acute central nervous system depression Central sleep apnea Drug overdose (benzodiazepines, narcotics, barbiturates, Primary alveolar hypoventilation propofol, major tranquilizers) Obesity hypoventilation Head trauma syndrome
Cerebrovascular accident Spinal cord injury Central nervous system infection (encephalitis) Diaphragmatic paralysis Acute neuromuscular disease Amyotrophic lateral sclerosis Guillain-Barre´ syndrome Myasthenia gravis Spinal cord injury Muscular dystrophy Myasthenic crisis Multiple sclerosis Botulism
Poliomyelitis Organophosphate poisoning Hypothyroidism Acute airways disease Kyphoscoliosis Status asthmaticus Thoracic cage disease Upper airway obstruction (laryngospasm, angioedema, foreign body aspiration Chronic obstructive pulmonary disease Exacerbation of chronic obstructive pulmonary disease Severe chronic interstitial lung disease Acute parenchymal and vascular disease Cardiogenic pulmonary edema Acute lung injury Multilobular pneumonia Massive pulmonary embolism Acute pleural or chest wall disease Pneumothorax Hemothorax Flail chest From Epstein and Singh, 36 with permission. 192 Plum and Posner’s Diagnosis of Stupor and Coma of preserved pupillary light reflexes, despite concomitant respiratory depression, vestibulo- ocular caloric unresponsiveness, decerebrate rigidity, or motor flaccidity, suggests metabolic coma. Conversely, if asphyxia, anticholinergic or glutethimide ingestion, or pre-existing pu- pillary disease can be ruled out, the absence of pupillary light reflexes strongly implies that the disease is structural rather than metabolic. Pupils cannot be considered conclusively nonreactive to a light stimulus unless care has been taken to examine them with magnifica- tion using a very bright light and maintaining the stimulus for several seconds. Infrared pu- pillometry is more reliable than the flash- light.
38 Ciliospinal reflexes are less reliable than light reflexes but, like them, are usually pre- served in metabolic coma even when motor and respiratory signs signify lower brainstem dys- function. 37 OCULAR MOTILITY The eyes usually rove randomly with mild met- abolic coma and come to rest in the forward position as coma deepens. Although almost any eye position or random movement can be ob- served transiently when brainstem function is changing rapidly, a maintained conjugate lat- eral deviation or dysconjugate positioning of the eyes at rest suggests structural disease. Conju- gate downward gaze, or occasionally upward gaze, can occur in metabolic as well as in struc- tural disease and by itself is not helpful in the differential diagnosis. 39 HISTORICAL VIGNETTE Patient 5–2 A 63-year-old woman with severe hepatic cir- rhosis and a portacaval shunt was found in coma. She groaned spontaneously but otherwise was un- responsive. Her respirations were 18 per minute and deep. The pupillary diameters were 4 mm on the right and 3 mm on the left, and both reacted to light. Her eyes were deviated conjugately down- ward and slightly to the right. Oculocephalic re- sponses were conjugate in all directions. Her mus- cles were flaccid, but her stretch reflexes were brisk and more active on the right with bilateral extensor plantar responses. No decorticate or decerebrate responses could be elicited. Her arterial blood pH was 7.58, and her PaCO 2 was 21 mm Hg. Two days later she awoke, at which time her eye movements were normal. Four days later she again drifted into coma, this time with the eyes in the physiologic position and with sluggish but full oculocephalic responses. She died on the sixth hospital day with severe hepatic cirrhosis. No structural central ner- vous system (CNS) lesion was found at autopsy. Comment: This patient was seen prior to the availability of computed tomography (CT) scan- ning, but the later autopsy confirmed the clinical impression that these focal abnormalities were due to her liver failure, not a structural lesion. The initial conjugate deviation of the eyes downward and slightly to the right had suggested a deep, right-sided cerebral hemispheric mass lesion. But the return of gaze to normal with awakening within 24 hours and nonrepetition of the downward de- viation when coma recurred ruled out a structural lesion. At autopsy, no intrinsic cerebral pathologic lesion was found to explain the abnormal eye movements. We have observed transient down- ward as well as transient upward deviation of the eyes in other patients in metabolic coma. Because reflex eye movements are particu- larly sensitive to depressant drugs, cold caloric stimulation often provides valuable informa- tion about the depth of coma in patients with metabolic disease. The ocular response to pas- sive head movement is less reliable than the caloric test, as absence of oculocephalic re- sponses may imply purposeful inhibition of the reflex and does not dependably distinguish psychogenic unresponsiveness from brainstem depression. Cold caloric stimulation produces tonic conjugate deviation toward the irrigated ear in patients in light coma and little or no response in those in deep coma. If caloric stim- ulation evokes nystagmus, cerebral regulation of eye movements is intact and the impair- ment of consciousness is either very mild or the ‘‘coma’’ is psychogenic. If the eyes spontane- ously deviate downward following lateral devia- tion, one should suspect drug-induced coma. 39 Finally, if caloric stimulation repeatedly pro- duces dysconjugate eye movements, structural brainstem disease should be suspected (but see Chapter 2). Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma 193
Patient 5–3 A 20-year-old woman became unresponsive while riding in the back seat of her parents’ car. There was no history of previous illness, but her parents stated that she had severe emotional problems. On examination, her vital signs and general physical examination were normal. She appeared to be asleep when left alone, with quiet shallow respi- ration and no spontaneous movements. Her pupils were 3 mm and reactive. Oculocephalic responses were absent. She lay motionless to noxious stimuli but appeared to resist passive elevation of her eyelids. Cold caloric testing elicited tonic devia- tion of the eyes with no nystagmus. Blood and urine toxicology screens were positive for barbi- turates, and she awoke the next morning and ad- mitted ingesting a mixture of sedative drugs to frighten her mother. Comment: The coma in this patient initially appeared light or even simulated. However, tonic deviation of the eyes in response to cold caloric irrigation signified that normal cerebral control of eye movements was impaired and indicated that her unresponsiveness was the result of organic, but probably toxic or metabolic, and not structural brain dysfunction. Toxicology screening discov- ered at least one cause, but drug overdosages are often mixed, and not all of the components may be picked up on screening. MOTOR ACTIVITY Patients with metabolic brain disease generally present two types of motor abnormalities: (1) nonspecific disorders of strength, tone, and re- flexes, as well as focal or generalized seizures, and (2)certain characteristic adventitious move- ments that are almost diagnostic of metabolic brain disease. ‘‘Nonspecific’’ Motor Abnormalities Diffuse motor abnormalities are frequent in metabolic coma and reflect the degree and distribution of CNS depression (Chapter 1). Paratonia and snout, suck, or grasp reflexes may be seen in dementia, as well as in patients in light coma. With increasing brainstem depres- sion, flexor and extensor rigidity and sometimes flaccidity appear. The rigid states are sometimes asymmetric. Patient 5–4 A 60-year-old man was found in the street, stu- porous, with an odor of wine on his breath. No other history was obtainable. His blood pressure was 120/80 mm Hg, pulse rate 100 per minute, and respirations 26 per minute and deep. After assessing radiographically for cervical spine in- jury, his neck was found to be supple. There was fetor hepaticus and the skin was jaundiced. The liver was palpably enlarged. He responded to noxious stimuli only by groaning. There was no response to visual threat. His left pupil was 5 mm, the right pupil was 3 mm, and both reacted to light. The eyes diverged at rest, but passive head movement elicited full conjugate ocular move- ments. The corneal reflexes were decreased but present bilaterally. There was a left facial droop. The gag reflex was present. He did not move spontaneously, but grimaced and demonstrated extensor responses to noxious stimuli. The limb muscles were symmetrically rigid and stretch re- flexes were hyperactive. The plantar responses were extensor. An emergency CT scan was nor- mal. The lumbar spinal fluid pressure was 120 mm/CSF and the CSF contained 30 mg/dL protein and one white blood cell. The serum bicarbonate was 16 mEq/L, chloride 104 mEq/L, sodium 147 mEq/L, and potassium 3.9 mEq/L. Liver function studies were grossly abnormal. The following morning he responded appropri- ately to noxious stimulation. Hyperventilation had decreased, and the extensor posturing had dis- appeared. Diffuse rigidity, increased deep tendon reflexes, and bilateral extensor plantar responses remained. Improvement was rapid, and by the fourth hospital day he was awake and had normal findings on neurologic examination. However, on the seventh hospital day his blood pressure de- clined and his jaundice increased. He became hypotensive on the ninth hospital day and died. The general autopsy disclosed severe hepatic cir- rhosis. An examination of the brain revealed old infarcts in the frontal lobes and the left inferior cerebellum. There were no other lesions. Comment: In this patient, the signs of liver dis- ease suggested the diagnosis of hepatic coma. At first, however, anisocoria and decerebrate rigidity 194
Plum and Posner’s Diagnosis of Stupor and Coma hinted at a supratentorial mass lesion such as a subdural hematoma. The normal pupillary and oculocephalic reactions favored metabolic disease and the subsequent CT scan and absence of signs of rostral-caudal deterioration supported that di- agnosis.
Focal weakness is surprisingly common with metabolic brain disease. Several of our patients with hypoglycemia or hepatic coma were tran- siently hemiplegic, and several patients with uremia or hyponatremia had focal weakness of upper motor neuron origin. Others have re- ported similar findings. 40,41
HISTORICAL VIGNETTE Patient 5–5 A 37-year-old man had been diabetic for 8 years. He received 35 units of protamine zinc insulin each morning in addition to 5 units of regular in- sulin when he believed he needed it. One week before admission he lost consciousness transiently upon arising, and when he awoke, he had a left hemiparesis, which disappeared within seconds. The evening before admission the patient had re- ceived 35 units of protamine zinc and 5 units of regular insulin. He awoke at 6 a.m. on the floor and was soiled with feces. His entire left side was numb and paralyzed. His pulse was 80 per min- ute, respirations 12, and blood pressure 130/80 mm Hg. The general physical examination was unremarkable. He was lethargic but oriented. His speech was slurred. There was supranuclear left facial paralysis and left flaccid hemiplegia with weakness of the tongue and the trapezius muscles. There was a left extensor plantar response but no sensory impairment. The blood sugar was 31 mg/ dL. EEG was normal with no slow-wave focus. He was given 25 g of glucose intravenously and re- covered fully in 3 minutes. Comment: This patient, who was seen prior to the availability of CT scanning, provides a closer look at the range of physical signs and EEG phe- nomena that may occur in hypoglycemia. Today, fingerstick glucose testing would have occurred much earlier, often before reaching the hospital, and the physician rarely gets to see such cases. In this man, the occurrence of a similar brief attack of left hemiparesis a week previously suggested right carotid distribution infarction initially. 41 How- ever, the patient was a little drowsier than expected with an uncomplicated unilateral carotid stroke in which the damage was apparently rather limited. The fact that his attack might have begun with unconsciousness and the fecal staining made his physicians suspect a seizure. However, hypogly- cemia also can cause unconsciousness as well as focal signs in conscious patients. After treatment of the low glucose, the hemiplegia cleared rapidly. Patients with metabolic brain disease may have either focal or generalized seizures that can be indistinguishable from the seizures of structural brain disease. However, when met- abolic encephalopathy causes focal seizures, the focus tends to shift from attack to attack, something that rarely happens with structural seizures. Such migratory seizures are espe- cially common and hard to control in uremia. Motor Abnormalities Characteristic of Metabolic Coma Tremor, asterixis, and multifocal myoclonus are prominent manifestations of metabolic brain disease; they are less commonly seen with focal structural lesions unless these latter have a toxic or infectious component. The tremor of metabolic encephalopathy is coarse and irregular and has a rate of 8 to 10 per second. Usually these tremors are absent at rest and, when present, are most evident in the fingers of the outstretched hands. Severe trem- ors may spread to the face, tongue, and lower extremities, and frequently interfere with pur- poseful movements in agitated patients such as those with delirium tremens. The physiologic mechanism responsible for this type of tremor is unknown. It is not seen in patients with uni- lateral hemispheric or focal brainstem lesions. First described by Adams and Foley 42 in pa-
tients with hepatic coma, asterixis is now known to accompany a wide variety of metabolic brain diseases and even some structural lesions. 43 Asterixis was originally described as a sudden palmar flapping movement of the outstretched hands at the wrists. 44 It is most easily elicited in lethargic but awake patients by directing them to hold their arms outstretched with hands dorsiflexed at the wrist and fingers extended Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma 195
and abducted (i.e., ‘‘stopping traffic’’). Incipi- ent asterixis comprises a slight irregular tremor of the fingers, beginning after a latent period of 2 to 30 seconds that is difficult to distinguish from the tremor of metabolic encephalopathy. Leavitt and Tyler 45 have described the two sep- arate components of this tremulousness. One is an irregular oscillation of the fingers, usually in the anterior-posterior direction but with a ro- tary component at the wrist. The second con- sists of random movements of the fingers at the metacarpal-phalangeal joints. This second pat- tern becomes more and more marked as the pa- tient holds his or her wrist dorsiflexed until fi- nally the fingers lead the hand into a sudden downward jerk followed by a slower return to the original dorsiflexed position. Both hands are affected, but asynchronously, and as the abnormal movement intensifies, it spreads to the feet, tongue, and face (dorsiflexion of the feet is often an easier posture for obtunded patients to maintain). Indeed, with severe met- abolic tremors it sometimes becomes difficult to distinguish between intense asterixis and myoclonus, and there is some evidence that the two types of movements represent the same underlying phenomena (sudden and transient loss of muscle tone followed by sudden com- pensation). Asterixis is generally seen in awake but lethargic patients and generally disappears with the advent of stupor or coma, although occasionally one can evoke the arrhythmic con- traction in such subjects by passively dorsi- flexing the wrist. Asterixis can also be elicited in stuporous patients by passively flexing and abducting the hips. 46 Flapping abduction- adduction movements occurring either syn- chronously or asynchronously suggest meta- bolic brain disease (Figure 5–1). Unilateral, or less commonly bilateral, aster- ixis has been described in patients with focal brain lesions. 43 Electromyograms recorded dur- ing asterixis show a brief absence of muscular activity during the downward jerk followed by Figure 5–1. (A) Technique of hip flexion-abduction. (B) Electromyographic (EMG) recording from the hip adductors (upper trace) and accelerometric recording from the patella (lower trace). Brief periods of EMG silence (black dots) are followed by a burst of high-voltage electrical activity and a striking change in acceleration. (From Noda et al., 46 with permission.) 196 Plum and Posner’s Diagnosis of Stupor and Coma a sudden muscular compensatory contraction, much like the sudden bobbing of the head that normally accompanies drowsiness. The sudden electrical silence is unexplained and not ac- companied by EEG changes. 42,45,47
Multifocal myoclonus consists of sudden, nonrhythmic, nonpatterned gross twitching in- volving parts of muscles or groups of muscles first in one part of the body, then another, and particularly affecting the face and proximal limb musculature. Multifocal myoclonus most com- monly accompanies uremic encephalopathy, a large dose of intravenous penicillin, CO 2 nar-
cosis, and hyperosmotic-hyperglycemic en- cephalopathy. Multifocal myoclonus, in a pa- tient who is stuporous or in coma, is indicative of severe metabolic disturbance. However, it may be seen in some waking patients with neu- rodegenerative disorders (e.g., Lewy body de- mentia or Alzheimer’s disease) or prion dis- orders (Creutzfeldt-Jakob disease and related disorders). Its physiology is unknown; the mo- tor twitchings are not always reflected by a specific EEG abnormality and have, in fact, been reported in a patient with electrocerebral silence. 48 DIFFERENTIAL DIAGNOSIS Distinction Between Metabolic and Psychogenic Unresponsiveness In awake patients, differences in the mental state, the EEG, the motor signs, and, occasion- ally, the breathing pattern distinguish meta- bolic from psychiatric disease. Most conscious patients with metabolic brain disease are con- fused and many are disoriented, especially for time. Their abstract thinking is defective; they cannot concentrate well and cannot easily re- tain new information. Early during the illness, the outstretched dorsiflexed hands show irreg- ular tremulousness and, frequently, asterixis. Snout, suck, and grasp reflexes are seen. The EEG is generally slow. Posthyperventilation apnea may be elicited and there may be hy- poventilation or hyperventilation, depending on the specific metabolic illness. By contrast, awake patients with psychogenic illness, if they will cooperate, are not disoriented and can re- tain new information. If they seem disoriented, they are disoriented to self (i.e., they report that they don’t know who they are) as well as to time and place; disorientation to self almost never occurs in delirious patients. They also lack abnormal reflexes or adventitious movements, although they may have irregular tremor, and they have normal EEG frequencies. Ventila- tory patterns, with the exception of psychogenic hyperventilation, are normal. Unresponsive patients with metabolic dis- ease have even slower activity in their EEGs than responsive patients with metabolic disease, and caloric vestibulo-ocular stimulation elicits either tonic deviation of the eyes or, if the pa- tient is deeply comatose, no response. Psycho- genically unresponsive patients have normal EEGs and a normal response to caloric irriga- tion, with nystagmus having a quick phase away from the side of ice water irrigation; there is little or no tonic deviation of the eyes (see page 65). In some patients with psychogenic coma, the eyes deviate toward the ground when the patient is placed on his or her side. 49 Forced
downward deviation of the eyes has been de- scribed in patients with psychogenic seizures. 50 Distinction Between Coma of Metabolic and Structural Origin As discussed in Chapter 2, the key to distin- guishing coma of metabolic versus structural origin is to identify focal neurologic signs that distinguish structural coma. On the other hand, certain characteristic motor and EEG findings can help confirm the diagnosis of a metabolic encephalopathy when patients are merely ob- tunded or lethargic. Most patients with meta- bolic brain disease have diffusely abnormal motor signs including tremor, myoclonus, and, especially, bilateral asterixis. The EEG is dif- fusely, but not focally, slow. The patient with gross structural disease, on the other hand, generally has abnormal focal motor signs and if asterixis is present, it is unilateral. The EEG may be slow, but in addition with supraten- torial lesions, a focal abnormality will usually be present. Finally, metabolic and structural brain dis- eases are distinguished from each other by a combination of signs and their evolution. Co- matose patients with metabolic brain disease usually suffer from partial dysfunction affect- ing many levels of the neuraxis simultaneously, yet concurrently retain the integrity of other Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma 197
functions originating at the same levels. The or- derly rostral-caudal deterioration that is char- acteristic of supratentorial mass lesions does not occur in metabolic brain disease, nor is the an- atomic defect regionally restricted as it is with subtentorial damage. ASPECTS OF CEREBRAL METABOLISM PERTINENT TO COMA Earlier chapters of this book have described the physiologic relationships among the brainstem, the diencephalon, and the cerebral hemispheres that underlie the wakeful state and normally generate the psychologic activities that consti- tute full consciousness. The brain’s sensori- motor and mental activities are closely coupled to cerebral metabolism so that neurochemical impairment or failure from any cause is likely to produce rapidly evolving neurologic abnor- malities. Neurons and glial cells undergo many che- mical processes in fulfilling their specialized functions. The nerve cells must continuously maintain their membrane potentials, synthe- size and store transmitters, manufacture axo- plasm, and replace their always decaying struc- tural components (Figure 5–2). Glia, which constitute 90% of the brain’s cells, have several functions, some of which have been recently recognized. 51,52 The oligodendroglial cells have as their major role the generation and main- tenance of myelin. Microglia (macrophages) are the brain’s immune cells. Astrocytes reg- ulate much of the ion homeostasis of the brain’s extracellular fluid. In addition, they may aid neuronal function by supplying substrate (lac- tate) 51
neurons metabolize lactate in vivo is contro- versial
53 ). Astrocytes also participate in con- trolling blood flow 52 and in maintaining the blood-brain barrier. 54 All of these complex ac- tivities require energy, in fact, more of it per kilogram weight of cells than in any other or- gan in the body. Furthermore, many of the enzymatic reactions of both neurons and glial cells, as well as of the specialized cerebral cap- illary endothelium, must be catalyzed at some point by the energy-yielding hydrolysis of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and inorganic phosphate. Without a constant and generous supply of ATP, cellular synthesis slows or halts, neuro- nal functions decline or cease, and cell struc- tures quickly crumble. Oxygen, glucose, and cerebral blood flow (CBF) operate interdependently to supply the brain with the substrate and cofactors it re- quires to carry out the chemical reactions that generate its energy and synthesize its structural components. Awake or asleep, the brain metab- olizes at one of the highest rates of any organ in the body. However, although the overall me- tabolism of the brain is relatively constant, dif- ferent areas of the brain metabolize at differ- ent rates, depending on how active an area is. 55 For example, during exercise, the activity of the motor cortex increases dramatically, compen- sated for by decreased metabolism elsewhere in the brain. 56 Changes in regional metabolism are best demonstrated by functional magnetic resonance imaging (MRI) or positron emission tomography (PET) imaging (Figure 5–3). The brain suffers a special vulnerability in that it possesses almost no reserves of its critical nu- trients, so that even a brief interruption of blood flow or oxygen supply threatens the tissue’s vi- tality. These considerations are central to an understanding of many of the metabolic en- cephalopathies, and the following paragraphs discuss them in some detail. CEREBRAL BLOOD FLOW Under normal resting conditions, the total CBF in man is about 55 mL/100 g/minute, an amount that equals 15% to 20% of the resting cardiac output. A number of studies have found that the overall CBF remains relatively constant during the states of wakefulness or slow-wave sleep as well as in the course of various mental and physical activities. PET and functional MRI scanning reveal that this apparent uniformity masks a regionally varying and dynamically fluc- tuating CBF, which is closely adjusted to meet the metabolic requirements posed by local phys- iologic changes in the brain. Overall flow in gray matter, for example, is normally three to four times higher than in white matter. 55 When neural activity increases within a re- gion, cerebral metabolism increases to meet the increased demand. 57 Cerebral metabolic rate for glucose and CBF each increase about 50% in the active area, whereas the metabolic rate for oxygen increases only about 5%. 57 198 Plum and Posner’s Diagnosis of Stupor and Coma glutamate GLUTAMATE GLUCOSE 2 LACTATE GLUTAMINE Vm A B glutamatergic synapse PYRUVATE PYRUVATE
LACTATE GLUCOSE
LACTATE LACTATE
astrocyte capillary glutamate receptors neuron
astrocyte EAAT 1 & 2 capillary glutamate aspartale GABA
TCA cycle
LDH 1 Na + /K + ATPase ATP
ADP 2 K
+ ATP
ADP PGK
3 Na + Na + Ca 2+ G G glycolysis GLUCOSE glycolysis LDH 5
MCT 1 & 2
energy Figure 5–2. (A) Schematic representation of the mechanism for glutamate-induced glycolysis in astrocytes during physiologic activation. At glutamatergic synapses, presynaptically released glutamate depolarizes postsynaptic neurons by acting at specific receptor subtypes. The action of glutamate is terminated by an efficient glutamate uptake system located primarily in astrocytes. Glutamate is cotransported with Na þ , resulting in an increase in the intra-astrocytic concentration of Na þ , leading to an activation of the astrocyte Na þ /K þ -ATPase. Activation of the Na þ /K þ -ATPase stimulates glycolysis (i.e., glucose use and lactate production). Lactate, once released by astrocytes, can be taken up by neurons and serves them as an adequate energy substrate. (For graphic clarity, only lactate uptake into presynaptic terminals is indicated. However, this process could also occur at the postsynaptic neuron.) This model, which summarizes in vitro experimental evidence indicating glutamate-induced glycolysis, is taken to reflect cellular and molecular events occurring during activation of a given cortical area. (B) Schematic representation of the proposed astrocyte-neuron lactate shuttle. Fol- lowing neuronal activation and synaptic glutamate release, glutamate reuptake into astrocytes triggers increased glucose uptake from capillaries via activation of an isoform of the Na þ /K þ -ATPase, which is highly sensitive to ouabain, possibly the alpha-2 isoform (Pellerin and Magistretti 1994, 1997). Glucose is then processed glycolytically to lactate by astrocytes that are enriched in the muscle form of lactate dehydrogenase (LDH 5 ). The exchange of lactate between astrocytes and neurons is operated by monocarboxylate transporters (MCTs). Lactate is then converted to pyruvate since neurons contain the heart form of LDH (LDH 1 ). Pyruvate, via the formation of acetyl-CoA by pyruvate dehydrogenase (PDH), enters the tricarboxylic acid (TCA) cycle, thus generating 17 adenosine triphosphate (ATP) molecules per lactate molecule. ADP, adenosine diphosphate. (From Magistretti and Pellerin, 58 with permission.) 199 Thus, the oxygen extraction falls, increasing the concentration of oxyhemoglobin in venous blood. This is the basis for the blood oxygena- tion level dependent (BOLD) signal obtained using functional MRI. The increase in glucose metabolism over oxygen metabolism results in increased lactate production, possibly the sub- strate for the increased demand of neurons 58 (Figure 5–4). The stimulus for the increase in regional CBF is complex. 59 A number of vaso- active substances are released by neurons and glia during increased neural activity. Important among these are adenosine, nitric oxide, dopa- mine, acetylcholine, vasoactive intestinal poly- peptide, and arachidonic acid metabolites. 59 Several pathologic states of brain are marked by a disproportionately high rate of local blood flow in relation to metabolism. Examples of such reactive hyperemia or ‘‘uncoupling’’ of flow and metabolism occur in areas of trau- matic or postischemic tissue injury, as well as in regions of inflammation or in the regions sur- rounding certain brain tumors. So far, the na- ture of the local stimulus to such pathologic vasodilation also has eluded investigators. The effects of the process, however, can act to in- crease the bulk of the involved tissue and thereby accentuate the pathologic effects of compartmental swelling in the brain, as dis- cussed in Chapter 2. Reduced CBF has several causes. As de- scribed in Chapter 3, the cerebral vasculature’s capacity for autoregulation protects the CBF against all but the most profound drops in systemic blood pressure. The process of auto- regulation also means that conditions causing a lowered cerebral metabolism are usually accompanied by a secondary fall in CBF, al- though in many such cases the initial decline in CBF is less than the metabolic reduction. 60 This delayed response may reflect the rela- tively slow adaptation of the tonic contractile state of vascular smooth muscle rather than a true uncoupling of flow and metabolism. In- trinsic arterial spasm in cerebral vessels, which reduces tissue flow below metabolic needs, is an uncommon phenomenon limited largely to arteries at the base of the brain (e.g., with lo- cal surgical trauma as well as with subarach- noid bleeding and sometimes with meningitis [see Chapter 4]). Multifocal cerebral arteriolar spasm had been invoked to explain the re- gional cerebral vascular injury of malignant hypertension; recent work, however, offers a different interpretation of the pathogenesis of that disorder (see page 168). Primary reductions in CBF can be regional or general (global). Regional impairments of CBF results from intrinsic diseases of the cervical and cerebral arteries (atherosclerosis, throm- bosis, and, rarely, inflammation), from arterial embolism, and from the extrinsic pressure on individual cerebral arteries produced by com- partmental herniation. General or global reduc- tions in CBF result from systemic hypotension, complete or functional cardiac arrest (e.g., ven- tricular arrhythmias in which output falls below requirements of brain perfusion), and increased ICP. As noted earlier in this volume, however, unless some primary abnormality of brain tissue acts to increase regional vascular resistance, an increase in the ICP must approach the systemic systolic pressure before the CBF declines suf- ficiently to cause recognizable changes in neu- rologic functions. Figure 5–3. A functional magnetic resonance imaging scan of the normal individual flexing and extending his fingers. Blood flow increases to a greater degree than oxygen consumption in the motor areas, leading to an increase in oxyhemoglobin. The paramagnetic oxyhemo- globin causes an increased blood oxygen level-dependent signal in the motor cortex bilaterally. (Image courtesy Dr. Andrei Holodny.) 200 Plum and Posner’s Diagnosis of Stupor and Coma Cessation of blood flow to the brain (ische- mia), as discussed in subsequent paragraphs, appears to cause a greater risk of irreversible tissue damage than does even a profound re- duction in the arterial oxygen tension (anox- emia). The precise lower level of arterial per- fusion required to maintain the vitality of the tissue in man is not known. Extrapolations based on animal experiments suggest that the CBF of 20 mL/100 g of brain per minute causes loss of consciousness but not permanent damage. If the flow falls to 10 mL/100 g/minute, mem- brane integrity is lost and calcium influx into the cells leads to irreversible damage. Time is also an important factor. Flows of 18 mL can be tolerated for several hours without leading to infarction, whereas flows of 5 mL lasting for more than 30 minutes will cause infarction. 61 K
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