Книги по МРТ КТ на английском языке / PLUM AND POSNER S DIAGNOSIS OF STUPOR AND COM-1

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parieto-occipital cortex, with a relative increase in the basal ganglia, hippocampus, and cerebellum.235

Mild hepatic encephalopathy may fluctuate markedly in severity, and it is sometimes confused with psychiatric disturbances or acute alcoholism. Comatose patients in whom hepatic coma has developed rapidly often have motor signs (but not neuro-ophthalmologic changes) that may suggest structural disease of the brainstem. They are sometimes mistakenly believed to have subdural hematoma or basilar artery thrombosis. In anything short of preterminal hepatic coma, however, pupillary and caloric responses are normal, patients hyperventilate, and signs of rostral-caudal deterioration are absent, all of which rule out subdural hematoma. Subtentorial structural disease is ruled out by the normal pupillary and caloric responses as well as the fluctuating and inconstant quality of motor signs.

Renal Disease

Renal failure causes uremic encephalopathy. The treatment of uremia, in turn, potentially causes two additional disorders of cerebral function: the dialysis dysequilibrium syndrome and progressive dialysis encephalopathy. Confusion, delirium, stupor, and sometimes coma can occur with each of these conditions.

UREMIC ENCEPHALOPATHY

Before the widespread use of dialysis and renal transplantation, the uremic syndrome was common in North America and Western Europe. Today, the early correction of biochemical abnormalities in patients with known acute or chronic renal disease often prevents the development of cerebral symptoms. As a result, the physician more often encounters uremic encephalopathy as a problem of differential diagnosis in patients with a systemic disease causing multiorgan failure such as a collagen vascular disorder, malignant hypertension, the ingestion of a toxin, bacteremia, or disseminated anoxiaischemia. Most of these primary disorders themselves produce abnormalities of brain function, adding to the complexities of diagnosis.

Despite extensive investigations, the precise cause of the brain dysfunction in uremia eludes identification. However, certain notable asso-

ciations exist. Once azotemia develops, the uremic syndrome correlates only in a general way with biochemical changes in the blood. As with other metabolic encephalopathies, the more rapid the development of the toxic state, the less disturbed is the systemic chemical equilibrium. The level of the blood urea nitrogen (BUN) associated with uremic encephalopathy can vary widely. Urea itself cannot be the toxin, as urea infusions do not reproduce uremic symptoms and hemodialysis reverses the syndrome, even when urea is added to the dialyzing bath so as not to lower the blood level. Although it is rare to see uremic encephalopathy with a creatine lower than 7.0, levels of creatinine and other serum biochemical or electrolyte abnormalities do not correlate with the neurologic state. Serum sodium or potassium levels can be abnormally low or high in uremia, depending on its duration and treatment, but symptoms associated with these electrolyte changes are distinct from the typical panorama of uremic encephalopathy. Systemic acidosis is not the cause; the systemic acidosis does not involve the CNS, and treatment of the reduced blood pH has no effect on uremic cerebral symptoms.

Morphologically, the brains of patients dying of uremia show no consistent abnormality. Uremia uncomplicated by hypertensive encephalopathy does not cause cerebral edema. The cerebral oxygen consumption declines in uremic stupor, just as it does in most other metabolic encephalopathies, although perhaps not as much as might be expected from the degree of impaired alertness. Levels of cerebral high-energy phosphates remain high during experimental uremia, while rates of glycolysis and energy utilization are reduced below normal. Uremic brains show a decrease in sodium and potassium flux along with depressed sodiumstimulated, potassium-dependent ATPase activity. However, all the above changes appear to be effects rather than causes of the disorder.

Calcium concentration in the brain is elevated,236 and in humans with uremia both cognitive function and the EEG may be improved by parathyroidectomy,237 suggesting that calcium plays a role. In addition, 1-guanidino compounds are elevated in uremia, and this may affect the release of gamma-aminobutyric acid.238 In uremic experimental animals, tryptophan is diminished both in plasma and brain, but levels of its metabolic product, 3-hydroxykinurine, a

known neurotoxin, are elevated in the brain, particularly in the striatum and the medulla.239 Also in uremic animals, up-regulation of the superoxide-producing enzyme nicotinamide adenine dinucleotide phosphate oxidase and down-regulation of supraoxide dismutase cause oxidative stress in the brain via the nitration of brain proteins and the oxidation of myelin. Oxidative stress is also caused during dialysis treatment by interaction of the patient’s blood with both the dialysis membrane and dialysate impurities.240 Turnover of dopamine in the striatum, mesencephalon, and hypothalamus is decreased in uremic animals, whereas turnover of norepinephrine and 5-hydroxytriptomine is unchanged. Whether suppression of central dopamine turnover contributes to motor impairment in uremic animals is not clear.241

The clinical picture of uremic encephalopathy is nonspecific in most instances, although the characteristic combination of dulled consciousness, hyperpnea, and motor hyperactivity should immediately give high suspicion to the diagnosis. Untreated patients with uremic encephalopathy have metabolic acidosis, generally with respiratory compensation. Like many other metabolic encephalopathies, uremia, particularly when it develops rapidly, can produce a florid delirium marked by noisy agitation, delusions, and hallucinations. More often, however, progressive apathetic, dull, quiet confusion with inappropriate behavior blends slowly into stupor or coma accompanied by characteristic respiratory changes, focal neurologic signs, tremor, asterixis, muscle paratonia, and convulsions or, more rarely, nonconvulsive status epilepticus.242 In uremic patients, both generalized convulsions and nonconvulsive status epilepticus may be caused by antibiotics, particularly cephalosporins.243 Untreated patients with uremic encephalopathy all have serum acidosis. Pupillary and oculomotor functions are seldom disturbed in uremia, certainly not in any diagnostic way. On the other hand, motor changes are rarely absent. Patients with chronic renal disease are weak and unsteady in their movements. As uremia evolves, many of them develop diffuse tremulousness, intense asterixis, and, often, so much multifocal myoclonus that the muscles can appear to fasciculate. Ac-

tion myoclonus (see page 195) has also been reported.244,245 Tetany is frequent. Stretch re-

flex asymmetries are common, as are focal neurologic weaknesses; 10 of our 45 patients with

uremia had a hemiparesis that cleared rapidly after hemodialysis or shifted from side to side during the course of the illness.

Laboratory determinations tell one only that patients have uremia, but do not delineate this as the cause of coma. Renal failure is accompanied by complex biochemical, osmotic, and vascular abnormalities, and the degree of azotemia varies widely in patients with equally serious symptoms. One of our patients, a child with nephritis, had severe delirium proceeding to stupor despite a BUN of only 48 mg/dL. Other patients were free of cerebral symptoms with BUN values over 200 mg/dL. Uremia also causes aseptic meningitis accompanied by stiff neck with as many as 250 lymphocytes and polymorphonuclear leukocytes/mm3 in the CSF. The spinal fluid protein often rises as high as 100 mg/dL and the CSF pressure can be abnormally elevated to over 160 to 180 mm in some patients. EEG slowing correlates with increasing degrees of azotemia, but many patients with slow records have little or no accompanying mental changes.246 The electrophysiologic changes are nonspecific and of no help in establishing the diagnosis.

In differential diagnosis, uremia must be distinguished from other causes of acute metabolic acidosis, from acute water intoxication, and from hypertensive encephalopathy. Penicillin and its analogs can be a diagnostic problem when given to uremic patients, as these drugs can cause delirium, asterixis, myoclonus, convulsions, and nonconvulsive status epilepticus.243 Laboratory studies distinguish uremia from other causes of metabolic acidosis causing the triad of clouded consciousness, hyperpnea, and a low serum bicarbonate (uremia, diabetes, lactic acidosis, ingestion of exogenous poisons), but only uremia is likely to cause multifocal myoclonus, tetany, and generalized convulsions, and the others do not cause azotemia during their early stages.

Hyponatremia is common in uremia and can be difficult to dissociate from the underlying uremia as a cause of symptoms. Patients with azotemia are nearly always thirsty, and they have multiple electrolyte abnormalities. Excessive water ingestion, inappropriate fluid therapy, and hemodialysis all potentially reduce the serum osmolarity in uremia and thereby risk inducing or accentuating delirium and convulsions. The presence of water intoxication is

confirmed by measuring a low serum osmolarity (less than 260 mOsm/L), but the disorder can be suspected when the serum sodium concentration falls below 120 mEq/L (see page 253). Interestingly, rapid correction of hyponatremia does not seem to be associated with pontine myelinolysis (see page 171) when it occurs in uremic patients. The osmotic pressure of urea in the brain that is eliminated more slowly than in the blood appears to protect the brain against the sudden shifts in brain osmolality, although such shifts may emerge during treatment unless special precautions are taken (see below).247 Patients with uremia are often deficient in thiamine, which may cause neurologic manifestations that mimic uremia.248

It may be difficult to separate the symptoms of uremia from those of hypertensive encephalopathy if both azotemia and advanced hypertension plague the same patient. Each condition can cause seizures, focal neurologic signs, increased ICP, and delirium or stupor. The MRI of typical posterior leukoencephalopathy (see page 215) establishes the diagnosis of hypertensive encephalopathy.

The treatment of uremia by hemodialysis sometimes adds to the neurologic complexity of the syndrome. Neurologic recovery does not always immediately follow effective dialysis, and patients often continue temporarily in coma or stupor. One of our own patients remained comatose for 5 days after his blood nitrogen and electrolytes returned to normal. Such a delayed recovery did not imply permanent brain damage, as this man, like others with similar but less protracted delays, enjoyed normal neurologic function on chronic hemodialysis.

DIALYSIS DYSEQUILIBRIUM

SYNDROME

Some patients undergoing dialysis, particularly during the first treatment, develop headache, nausea, muscle weakness, cramps, and fatigue. At one time, occasional patients had more serious symptoms caused by a sudden osmolar gradient shifting of water into the brain, including asterixis, myoclonus, delirium, convulsions, stupor, coma, and very rarely death,249 but these are now prevented by slower dialysis and the addition of osmotically reactive solutes such as urea, glycerol, mannitol, or sodium to the dialysate.238 An occasional patient will de-

velop a subdural hematoma, probably resulting from a combination of anticoagulants used for dialysis and the coagulopathy that often accompanies uremia. Wernicke’s encephalopathy with its attendant confusional state (page 223) has developed in patients receiving chronic dialysis who were not being given vitamin supplements.248

All agree on the general mechanism of the dialysis dysequilibrium syndrome, although not on the details.250 The blood-brain barrier is only slowly permeable to urea as well as to a number of other biologic molecules, including electrolytes and idiogenic osmols251 (molecules, e.g., organic acids, amino acids, that form during pathologic processes and increase tissue osmolality), that form in brain during serum hyperosmolarity. The brain and blood are in osmotic equilibrium in steady states such as uremia; electrolytes and other osmols are adjusted so that brain concentrations of many biologically active substances (e.g., Hþ, Naþ, C1 ) remain more normal than those in blood. A rapid lowering of the blood urea by hemodialysis is not paralleled by equally rapid reductions in brain osmols. As a result, during dialysis the brain becomes hyperosmolar relative to blood and probably loses sodium, the result being that water shifts from plasma to brain, potentially resulting in water intoxication. Concurrently, rapid correction of blood metabolic acidosis can induce brain tissue acidosis because the increased PCO2 in the blood rapidly diffuses into the brain, whereas the bicarbonate moves much more slowly because of the slow movement of bicarbonate into the brain. Symptoms of water intoxication can be prevented by slower dialysis and by adding agents to maintain blood osmolarity.

RENAL TRANSPLANT

Immunosuppression accompanying renal

transplant can lead to a variety of neurologic disorders.246,252 As indicated on page 215, cy-

closporin and taxolimus can cause posterior leukoencephalopathy and the anti-CD3 murine monoclonal antibody, muromonab-CD3, can be neurotoxic, causing aseptic meningitis with headache and blurred vision and sometimes encephalopathy and seizures.252,253 MRI shows patchy enhancement in the corticomedullary junction, indicating blood-brain barrier

dysfunction. The pathogenesis of the encephalopathy is believed to be cerebral edema from a capillary leak syndrome.254

Renal transplant patients also are at risk for a variety of opportunistic infections and tumors similar to other immune-suppressed patients, such as those with HIV infection. These include lymphomas, which may occur primarily in the CNS, as the patient description indicates on page 362, and lead to stupor or coma. Opportunistic infections include fungi, such as Aspergillus, Cryptococcus, or Candida, and viruses, including cytomegalovirus, varicella-zoster, papova virus (JC virus), or progressive multifocal leukoencephalopathy. On rare occasions, the transplanted kidney carries a virus and may cause encephalitis within a few days of the transplant.252

Pulmonary Disease

Hypoventilation owing to advanced lung failure or neurologic causes can lead to a severe encephalopathy or coma.255 The mechanistic basis for the neurologic changes has not been fully explained, and in most instances the encephalopathy probably depends on a variable interaction of hypoxemia, hypercapnia, congestive heart failure, and other factors such as systemic infection and the fatigue of prolonged, ineffective respiratory efforts. Airway obstruction due to obstructive sleep apnea may awaken patients at night, adding to their daytime lethargy.256 However, unless some complication such as respiratory arrest occurs leading to prolonged hypoxia, permanent changes in the brain are lacking and the encephalopathy is fully reversible. Serum acidosis per se is probably not an important factor, as alkali infusions unaccompanied by ventilatory therapy fail to improve the neurologic status of these patients. Also, although hypoxia may potentiate the illness, it is unlikely that it is the sole cause of the cerebral symptoms, as patients with congestive heart failure commonly tolerate equal degrees of hypoxemia with no encephalopathy. Of all the variables, the degree of carbon dioxide retention correlates most closely with the neurologic symptoms. The development of cerebral symptoms also depends in part on the duration of the condition. For example, some subjects with chronic hypercarbia have no cerebral symptoms despite

PaCO2 levels of 55 to 60 mm Hg, whereas patients with previously compensated, but marginal, pulmonary function suddenly become hypoxic and hypercapnic because of an infection or excess sedation. Such patients may be erroneously suspected of having sedative poisoning or other causes of coma, but as in the following example, blood gas measurements make the diagnosis.

Patient 5–14

A 60-year-old woman with severe chronic pulmonary disease went to a physician complaining of nervousness and insomnia. An examination disclosed no change in her pulmonary function, and she was given a sedative to help her sleep. Her daughter found her unconscious the following morning and brought her to the hospital. She was comatose but withdrew appropriately from noxious stimuli. She was cyanotic, and her respirations were labored at 40 per minute. Her pupils were 3 mm in diameter and reacted to light. There was a full range of extraocular movements on passive head turning. No evidence of asterixis or multifocal myoclonus was encountered, and her extremities were flaccid with slightly depressed tendon reflexes and bilateral extensor plantar responses. The arterial blood pH was 7.17, the PaCO2 was 70 mm Hg, the serum bicarbonate was 25 mEq/L, and the PaO2 was 40 mm Hg. She was intubated and received artificial ventilation with a respirator for several days before she awakened and was able by her own efforts to maintain her arterial PaCO2 at its normal level of 45 mm Hg.

Comment: This is not an unusual history. It is possible that the increased nervousness and insomnia were symptoms of increasing respiratory difficulty. The sedative hastened the impending decompensation and induced severe respiratory insufficiency as sleep stilled voluntary respiratory efforts. The rapidity with which her PaCO2 rose from 45 to 70 mm Hg is indicated by her normal serum bicarbonate, there having been no time for the development of the renal compensation that usually accompanies respiratory acidosis.

When CO2 accumulates slowly, the complaints of insidiously appearing headache, somnolence, and confusion may occasionally attract

more attention than the more direct signs of respiratory failure. The headache, like other headaches associated with increased ICP, may be maximal when the patient first awakens from sleep and disappears when activity increases respiration, lowering the PCO2 and, thus, the ICP.

In its most severe form, pulmonary encephalopathy may cause increased ICP, papilledema,257 and bilateral extensor plantar responses, symptoms that may at first raise the question of a brain tumor or some other expanding mass. The important differential features are that in CO2 retention focal signs are rare, blood gases are always abnormal, and the encephalopathy usually improves promptly if artificial ventilation is effectively administered.

Two associated conditions are closely related to CO2 narcosis and often accentuate its neurologic effects. One is hypoxemia and the other is metabolic alkalosis, which often emerges as the result of treatment. Hypoxia accompanying CO2 retention must be treated, because lack of oxygen is immediately dangerous both to the heart and brain. Traditional teaching has been that oxygen therapy for hypercapnic patients with an acute exacerbation of chronic obstructive pulmonary disease may be dangerous, as it may reduce respiratory drive and further worsen hypercapnia. Recent evidence suggests that most patients tolerate oxygen replacement well,258 and for those who are not comatose but require artificial ventilation, noninvasive ventilation with a face mask appears to suffice.259 Renal bicarbonate excretion is a relatively slow process. As a result, correction of CO2 narcosis by artificial respiration sometimes induces severe metabolic alkalosis if the carbon dioxide tension is returned quickly to normal in the face of a high serum bicarbonate level. Although metabolic alkalosis is usually asymptomatic, Rotheram and colleagues260 reported five patients with pulmonary emphysema treated vigorously by artificial ventilation in whom metabolic alkalosis was associated with serious neurologic symptoms. These patients, after initially recovering from CO2 narcosis, developed severe alkalosis with arterial blood pH values above 7.55 to 7.60 and again became obtunded. They developed multifocal myoclonus, had severe convulsions, and three died. Two patients regained consciousness after blood CO2 levels were raised again by deliberately reducing the level of

ventilation. We have observed a similar sequence of events in deeply comatose patients treated vigorously with artificial ventilation, but have found it difficult to conclude that alkalosis and not hypoxia, possibly from hypotension,261 was at fault. What seems likely is that too sudden hypocapnia induces cerebral vasoconstriction, which more than counterbalances the beneficial effects to the brain of raising the blood oxygen tension. Rotheram and his colleagues believe that the PCO2 should be lowered gradually during treatment of respiratory acidosis to allow renal compensation to take place and prevent severe metabolic alkalosis. This is a reasonable approach so long as hypoxemia is prevented.

Pancreatic Encephalopathy

Failure of either the exocrine or endocrine pancreas can cause stupor or coma. Failure of the endocrine pancreas (diabetes) is discussed in the next section. Failure of the exocrine pancreas causes pancreatic encephalopathy, a rare complication of acute or chronic pancreatitis. Chronic relapsing pancreatitis may cause episodic stupor or coma.262 Estrada and associates reported that six of 17 nonalcoholic patients with acute pancreatitis, whom they followed prospectively, developed encephalopathy.263 The pathogenesis of pancreatic encephalopathy is not known. Postmortem evidence of patchy demyelination of white matter in the brain has led to the suggestion that enzymes liberated from the damaged pancreas are responsible for the encephalopathy.263 Other hypotheses include coexistent viral pancreatitis and encephalitis, disseminated intravascular coagulation complicating pancreatitis, and fat embolism. In one patient with relapsing pancreatitis and episodic coma, there were marked increases in CSF, plasma citrulline, and arginine levels, and moderate increases of other amino acids.262 Acute pancreatitis raises dopamine levels in brains of rats.264 Pathologically, autopsies have revealed cerebral edema, patchy demyelination, occasional perivascular hemorrhages, and, at times, plugging of small vessels with fat or fibrin thrombi.265 Biochemical complications of acute pancreatitis also may cause encephalopathy. These include cerebral ischemia secondary to hypotension, hyperosmolality, hypocalcemia,266 and diabetic acidosis.

Pancreatic encephalopathy usually begins between the second and fifth day after the onset of pancreatitis. The clinical features include an acute agitated delirium with hallucinations, focal or generalized convulsions, and often signs of bilateral corticospinal tract dysfunction. The mental status may wax and wane, and patients often become stuporous or comatose. The CSF is usually normal or occasionally has a slightly

elevated protein concentration. The CSF lipase level is elevated.263 The EEG is always ab-

normal with diffuse or multifocal slow activity. The diagnosis usually suggests itself when, after several days of abdominal pain, the patient develops acute encephalopathy. The MRI may be normal267 or show diffuse white matter lesions.265 The differential diagnosis should include other factors complicating pancreatitis listed above, including, of course, mumps that can cause both pancreatitis and encephalopathy. CSF lipase is elevated in pancreatic encephalopathy.

Patient 5–15

A 72-year-old male with no significant past medical history presented to the hospital with abdominal pain and was diagnosed with acute pancreatitis. The next day the patient was noted to be confused with waxing and waning mental status changes, which became an acute agitated delirium on the fifth day requiring four-point restraints. EEG done at the time showed a diffuse theta rhythm. Initial CT and MRI studies were unrevealing and the patient remained mute in an awake state for several days, following which he recovered to a confused state with occasional lucid periods. Neurologic examination was notable for preserved arousal and confabulation, decreased spontaneous movements of the lower extremities, and increased muscle tone. Diffuse hyperreflexia and bilateral extensor plantar response were noted. Repeat MRI reveal diffuse white matter abnormalities consistent with demyelination.

Diabetes Mellitus

Diabetes is the most common endocrine disease presenting as undiagnosed stupor or coma.

Pituitary, adrenal, or thyroid failure may occasionally present similarly, and these disorders are the subject of this section. Hyperand hypoparathyroidism are discussed with abnormalities of electrolyte metabolism (page 256).

Diabetes, an illness increasing alarmingly in incidence,268 is an endocrine disease with protean systemic manifestations. The clinical effects of diabetes may appear in virtually any organ of the body, either alone or in combination with other organs. The brain is both directly and indirectly affected by diabetes; delirium, stupor, and coma are common symptoms of certain stages of the disease.269–271 The potential causes of stupor or coma in patients with diabetes are many; some are listed in Table 5–10. When a diabetic patient develops stupor or coma, more than one of the defects listed in Table 5–10 may be present, and all must be dealt with if one is to bring about an adequate recovery.

Hyperosmolality is the single most common cause of coma in the diabetic patient.270 This disorder, which is discussed in detail on page 255, can be an isolated cause of coma in a nonketotic hyperglycemic state or a contributing cause in patients with diabetic ketoaci-

dosis or lactic acidosis.

Diabetic ketoacidosis269,272 causes impairment of consciousness in about 20% of affected patients and coma in about 10%. In general, patients with alteration of consciousness generally have arterial pHs below 7.0,271 but neither the arterial nor the CSF pH (which

Table 5–10 Some Causes of Stupor or Coma in Diabetic Patients

Nonketotic hyperglycemic hyperosmolar coma Ketoacidosis

Lactic acidosis

Central nervous system acidosis complicating treatment

Cerebral edema complicating treatment Hyponatremia (inappropriate secretion of

antidiuretic hormone) Disseminated intravascular coagulation Hypophosphatemia

Hypoglycemia

Uremia-hypertensive encephalopathy Cerebral infarction

Hypotension Sepsis

is typically normal) correlates well with level of consciousness.273 There is poor correlation between the plasma glucose level and the severity of diabetic ketoacidosis, but patients who are comatose from severe diabetic ketoacidosis almost always have some degree of hyperosmolality as well. The hyperglycemia is caused both by glucose underuse (usually from insulin deficiency) and from overproduction of glucose, a result of glucagon stimulating hepatic glycogenolysis and gluconeogenesis. Spillage of glucose into the urine causes an osmotic diuresis and leads to dehydration, which in turn leads to hyperosmolarity (see page 255). Ketogenesis is caused by the breakdown of triglycerides and release of free fatty acids into the blood. In the absence of insulin, fatty acids are unable to enter the citric acid cycle, but instead enter the mitochondria, where they are oxidized to ketone bodies, mostly acetoacetate and beta-hydroxybutyrate. Although ketone bodies are weak acids, as they accumulate they overcome the body’s buffering capacity and produce acidosis.269

Diabetic ketoacidosis usually develops in the insulin-dependent (type 1) diabetic but also occurs, albeit at lesser incidence, in patients with non-insulin-dependent (type 2) diabetes. The most common precipitating factor is infection; other precipitating causes include failure to take hypoglycemic medications, alcohol abuse, pancreatitis, cerebral or cardiovascular events, and drugs.269 Corticosteroids may precipitate diabetic complications and represent a significant problem among neurooncology patients with diabetes who require steroids to reduce brain edema from tumors. The catabolic effect of corticosteroids provides increased amino acid precursors for gluconeogenesis.

Most affected patients are awake when they come to the hospital and have a history of thirst, polyuria, anorexia, and fatigue. They are obviously dehydrated, and deep regular (Kussmaul) respirations mark the hyperventilation, which partially compensates for the metabolic acidosis. The breath generally has the hallmark fruity smell of ketosis. There is often some degree of hypotension and tachycardia because the hyperglycemic-induced osmotic diuresis has reduced the blood volume. Such patients are rarely febrile, and if stuporous or comatose, are likely to be mildly hypothermic even when an acute infection has precipitated the

ketoacidosis. The lack of fever, coupled with the fact that ketoacidosis itself can produce a leukocytosis, makes the diagnosis of a concomitant infection difficult. Nausea, vomiting, and acute abdominal pain also may complicate the early course of patients with diabetic ketoacidosis; some patients develop hemorrhagic gastritis.

Although it may be difficult to identify the precipitating factors, the diagnosis of ketoacidosis is rarely difficult; the obvious hyperventilation in all but terminal patients should lead the physician to suspect metabolic acidosis and diabetic ketoacidosis as one of its common causes (see Table 5–4, page 189).

Diabetic lactic acidosis usually occurs in patients receiving oral hypoglycemic agents, particularly metformin,274 but has also been reported in patients not being treated for diabetes. The mechanism of excess lactate production is unknown. Clinical signs and symptoms are the same as those of diabetic ketoacidosis or any other severe metabolic acidosis, with the exception that patients with lactic acidosis are more likely to be hypotensive or in shock. Lactic acidosis in diabetics is distinguished from diabetic ketoacidosis by the absence of high levels of ketone bodies in the serum.271

The treatment of diabetic ketoacidosis or lactic acidosis, although usually lifesaving, can itself sometimes have serious or even fatal consequences. The CSF, which is usually normal in the untreated patient with diabetic acidosis, may become transiently acidotic if the serum acidosis is treated by intravenous bicarbonate infusion, and this may be associated with some

short-lived worsening of the patient’s state of consciousness.273,275 Potentially more danger-

ous is the sudden lowering of serum osmolality that occurs as insulin lowers the serum glucose and intravenous fluids correct the dehydrated state. This lowering of serum osmolality causes

a shift of water into the brain, leading to cerebral edema, which is sometimes fatal.269,276

The condition should be suspected clinically when patients recovering from diabetic ketoacidosis or lactic acidosis complain of headache and become lethargic and difficult to arouse. Assuming that no evidence of meningitis is present, patients affected with cerebral edema may then develop hyperpyrexia, hypotension, tachycardia, and signs of transtentorial herniation, which, if not promptly and effectively treated with hyperosmolar agents, can

culminate in death. At autopsy, the brain shows edema with transtentorial herniation. In a study of eight children and adolescents after treatment for a diabetic ketoacidosis who were scanned for headache and confusion, hyperintensity was found in the medial frontal cortex on FLAIR and diffusion-weighted images, suggesting edema. However, apparent diffusion coefficient values were normal, indicating vasogenic edema rather than cytotoxic edema from infarction. Spectroscopy demonstrated increased levels of myo-inositol and glucose with decreased levels of taurine. The abnormalities were more marked in the frontal than in the occipital region. Changes gradually resolved over time.277 Cerebral edema in adults is much rarer.

Also complicating the treatment of diabetic ketoacidosis and lactic acidosis is the fact that some patients who suffer from the syndrome of inappropriate release of antidiuretic hormone may become more easily hypo-osmolar during rehydration. Other factors that may complicate the course of diabetic ketoacidosis and add to stupor or coma include disseminated intravascular coagulation (see page 217), hypokalemia, and hypophosphatemia. Profound hypophosphatemia can cause generalized convulsions, stupor, and coma.278 Fluid overload, acute respiratory distress syndrome, thromboembolism including cerebral infarction, and acute gastric dilation269 can also cause problems.

Increasing evidence suggests that hypergly-

cemia may worsen symptoms in patients with brain injury from either head trauma279,280

or acute stroke281 (see page 203)72 or even acutely ill patients in intensive care units.73 Hyperglycemia is an independent risk factor for stroke, both in people with and without diabetes.282 The cause of worsening brain injury from hyperglycemia is not clear. Some evidence suggests that preischemic hyperglycemia enhances the accumulation of extracellular glutamate, perhaps causing excitotoxic nerve damage.283 Other evidence suggests that hyperglycemia affects protein kinase and protein phosphorylation in the brain.284 Furthermore, hyperglycemia in and of itself appears to deleteriously affect cognition. In adult diabetics, when the blood glucose is greater than 15 mmol/L (270 mg/dL), cognition was deleteriously affected.71 Chronic diabetes may lead to permanent changes in cognition (diabetic

encephalopathy)216 that are not believed to be solely related to vascular changes. Diabetes both facilitates long-term depression and inhibits long-term potentiation in the hippocampus.285 This effect on synaptic plasticity could impair memory. In animals, hyperglycemia during brain ischemia causes cytochrome C release, activates caspase 3, and exacerbates DNA fragmentation induced by ischemia, mechanisms by which hyperglycemia may cause neuronal apoptosis.286

Hypoglycemia (see page 203) is a common

and serious cause of stupor or coma in diabetic patients269,287,288 and usually occurs in those

taking hypoglycemic agents or during the correction of severe diabetic ketoacidosis. However, spontaneous hypoglycemia, particularly reactive hypoglycemia,289 can be an early man-

ifestation of diabetes in patients not known to be diabetic,290,291 presumably a result of in-

sulin dysregulation, or in those known to be diabetic and suffering from renal insufficiency. We have also seen hypoglycemia as a cause of sudden loss of consciousness in rare patients with insulin-secreting tumors of the pancreas.

Diabetes can lead to severe renal insufficiency, producing uremic coma or hypertensive encephalopathy. Severe cerebral arteriosclerosis associated with diabetes is a cause of cerebral infarction that can produce coma if in the posterior fossa distribution.

Finally, autonomic neuropathy caused by diabetes can be a cause of syncope or coma, resulting from cardiac arrhythmia, orthostatic hypotension, cardiac arrest, or painless myocardial infarction. Hypoglycemic unawareness292 is the failure of the patient to recognize the prodromal symptoms of hypoglycemia, often leading to stupor or coma without warning. This is particularly common in patients who take a combination of hypoglycemic drugs as well as beta blockers, which eliminate most of the warning signs of hypoglycemia (sweating, tachycardia) that are due to catecholamine release. However, hypoglycemic unawareness may also be a result of autonomic neuropathy293 or impaired epinephrine secretion of unknown cause.292

Adrenal Disorders

Both hyperand hypoadrenal corticosteroid states are occasional causes of altered consciousness,294 but the exact mechanisms re-

sponsible for those alterations are not fully understood. Adrenal corticosteroids have profound effects on the brain, influencing genes that control enzymes and receptors for biogenic amines and neuropeptides, growth factors, and cell adhesion factors.294

ADDISON’S DISEASE295,296

The pathogenesis of the encephalopathy of adrenal cortical failure in Addison’s disease probably involves several factors in addition to the removal of the effect of cortisol on brain tissue. The untreated disease also produces hypoglycemia as well as hyponatremia and hyperkalemia due to hypoaldosteronism. Hypotension is the rule and, if severe, this alone can cause cerebral symptoms from orthostatic hypotension. Symptoms do not entirely clear until both mineralocorticosteroids and glucocorticosteroids are replaced. Some untreated and undertreated patients with Addison’s disease are mildly delirious. In a series of 86 patients with adrenal insufficiency associated with the antiphospholipid syndrome, altered mental status was present in only 16 (19%). The major symptoms were abdominal pain (55%), hypotension (54%), and nausea or vomiting (31%). Weakness, fatigue, malaise, or asthenia was present in 31%.297 Stupor and coma usually appear, if at all, only during addisonian crises. Changes in consciousness, respiration, pupils, and ocular movements are not different from those of several other types of metabolic coma. The presence of certain motor signs, however, may be helpful in suggesting the diagnosis. Patients in addisonian crises have flaccid weakness and either hypoactive or absent deep tendon reflexes, probably resulting from hyperkalemia; a few suffer from generalized convulsions, which have been attributed to hyponatremia and water intoxication. Papilledema is occasionally present and presumably results from brain swelling caused by fluid shifts perhaps exacerbated by increased capillary permeability, which is normally limited by corticosteroids. The EEG is diffusely slow and not different from the pattern in other causes of metabolic encephalopathy.298

The neurologic signs of addisonian coma are only rarely sufficiently distinctive to be diagnostic, although the combination of metabolic coma, absence of deep tendon reflexes, and papilledema may suggest adrenal insufficiency.

A pigmented skin and hypotension are helpful supplementary signs and, when combined with a low serum sodium and a high serum potassium level, strongly suggest the diagnosis. The definitive diagnosis of adrenal insufficiency is made by the direct measurement of low blood or urine cortisol levels.

Surgical procedures and other acute illnesses put severe stress on the adrenal glands. A patient whose adrenal function has been marginal prior to an acute illness or surgical procedure may suddenly develop adrenal failure with its attendant delirium. The symptoms may be attributed inappropriately to the acute illness or to a ‘‘postoperative delirium’’ (see page 283) unless adrenal function studies are carried out. Some patients without known pre-existing adrenal insufficiency develop acute adrenal failure following surgical procedures, particularly cardiac surgery. Acute pituitary failure, as in pituitary apoplexy, may also cause an addisonian state.

The main error in differential diagnosis of Addison’s disease is with regard to the hyponatremia, hyperkalemia, or hypoglycemia as the primary cause of the metabolic coma, rather than recognizing the combination as caused by underlying adrenal insufficiency. This error can be avoided only by considering Addison’s disease as a potential cause of metabolic coma and by heeding the other general physical signs and laboratory values. Hypotension and hyperkalemia, for example, rarely combine together in other diseases causing hyponatremia or hypoglycemia. Patients with Addison’s disease are exceedingly sensitive to sedative drugs, including barbiturates and narcotics; ingestion of standard doses of these drugs may produce coma.

CUSHING’S SYNDROME

Cushing’s syndrome,299 whether naturally occurring or iatrogenic in origin, causes increased levels of blood corticosteroids, which frequently leads to an encephalopathy characterized primarily by behavioral changes (either elation or depression) and only rarely by stupor or coma. The changes in behavior associated with glucocorticoid excess are almost always a direct result of that agent on the brain. In a pilot study assessing the psychologic effects of high-dose steroids, we gave 100 mg of dexamethasone daily for 3 days to 10 patients suffering from epidural spinal cord compression