Plum and posner’s diagnosis of stupor and coma fourth Edition series editor sid Gilman, md, frcp
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be abnormally elevated to over 160 to 180 mm in some patients. EEG slowing correlates with increasing degrees of azotemia, but many pa- tients with slow records have little or no ac- companying mental changes. 246
The electro- physiologic changes are nonspecific and of no help in establishing the diagnosis. In differential diagnosis, uremia must be distinguished from other causes of acute met- abolic acidosis, from acute water intoxica- tion, and from hypertensive encephalopathy. Penicillin and its analogs can be a diagnos- tic problem when given to uremic patients, as these drugs can cause delirium, asterixis, myoclonus, convulsions, and nonconvulsive status epilepticus. 243 Laboratory studies dis- tinguish uremia from other causes of meta- bolic acidosis causing the triad of clouded consciousness, hyperpnea, and a low serum bicarbonate (uremia, diabetes, lactic acidosis, ingestion of exogenous poisons), but only ure- mia 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. Exces- sive water ingestion, inappropriate fluid ther- apy, and hemodialysis all potentially reduce the serum osmolarity in uremia and thereby risk inducing or accentuating delirium and con- vulsions. The presence of water intoxication is 228
Plum and Posner’s Diagnosis of Stupor and Coma confirmed by measuring a low serum osmolar- ity (less than 260 mOsm/L), but the disorder can be suspected when the serum sodium con- centration falls below 120 mEq/L (see page 253). Interestingly, rapid correction of hypo- natremia does not seem to be associated with pontine myelinolysis (see page 171) when it occurs in uremic patients. The osmotic pres- sure 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 osmo- lality, 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 neuro- logic manifestations that mimic uremia. 248 It may be difficult to separate the symptoms of uremia from those of hypertensive enceph- alopathy if both azotemia and advanced hy- pertension plague the same patient. Each con- dition can cause seizures, focal neurologic signs, increased ICP, and delirium or stupor. The MRI of typical posterior leukoencephalopa- thy (see page 215) establishes the diagnosis of hypertensive encephalopathy. The treatment of uremia by hemodialysis sometimes adds to the neurologic complex- ity of the syndrome. Neurologic recovery does not always immediately follow effective dialy- sis, and patients often continue temporarily in coma or stupor. One of our own patients re- mained comatose for 5 days after his blood nitrogen and electrolytes returned to normal. Such a delayed recovery did not imply per- manent brain damage, as this man, like others with similar but less protracted delays, enjoyed normal neurologic function on chronic hemo- dialysis. 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 se- rious symptoms caused by a sudden osmolar gradient shifting of water into the brain, in- cluding asterixis, myoclonus, delirium, convul- sions, 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 ac- companies uremia. Wernicke’s encephalopathy with its attendant confusional state (page 223) has developed in patients receiving chronic dialysis who were not being given vitamin sup- plements. 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, includ- ing electrolytes and idiogenic osmols 251
(mol- ecules, 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., H þ , Na þ , C1 À ) 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 hyperos- molar relative to blood and probably loses so- dium, 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 tis- sue acidosis because the increased PCO 2 in the blood rapidly diffuses into the brain, whereas the bicarbonate moves much more slowly because of the slow movement of bi- carbonate into the brain. Symptoms of water intoxication can be prevented by slower dial- ysis 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 mu- rine monoclonal antibody, muromonab-CD3, can be neurotoxic, causing aseptic meningitis with headache and blurred vision and some- times encephalopathy and seizures. 252,253 MRI
shows patchy enhancement in the corticomed- ullary junction, indicating blood-brain barrier Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma 229
dysfunction. The pathogenesis of the enceph- alopathy 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 tu- mors similar to other immune-suppressed pa- tients, such as those with HIV infection. These include lymphomas, which may occur primar- ily in the CNS, as the patient description in- dicates on page 362, and lead to stupor or coma. Opportunistic infections include fungi, such as Aspergillus, Cryptococcus, or Can- dida, 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 fail- ure 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 en- cephalopathy probably depends on a variable interaction of hypoxemia, hypercapnia, con- gestive heart failure, and other factors such as systemic infection and the fatigue of pro- longed, ineffective respiratory efforts. Airway obstruction due to obstructive sleep apnea may awaken patients at night, adding to their day- time lethargy. 256 However, unless some com- plication such as respiratory arrest occurs lead- ing to prolonged hypoxia, permanent changes in the brain are lacking and the encephalopa- thy is fully reversible. Serum acidosis per se is probably not an important factor, as alkali in- fusions unaccompanied by ventilatory therapy fail to improve the neurologic status of these patients. Also, although hypoxia may potenti- ate the illness, it is unlikely that it is the sole cause of the cerebral symptoms, as patients with congestive heart failure commonly toler- ate equal degrees of hypoxemia with no en- cephalopathy. Of all the variables, the degree of carbon dioxide retention correlates most closely with the neurologic symptoms. The development of cerebral symptoms also de- pends in part on the duration of the condition. For example, some subjects with chronic hy- percarbia have no cerebral symptoms despite PaCO
2 levels of 55 to 60 mm Hg, whereas pa- tients with previously compensated, but mar- ginal, pulmonary function suddenly become hypoxic and hypercapnic because of an infec- tion or excess sedation. Such patients may be erroneously suspected of having sedative poi- soning or other causes of coma, but as in the following example, blood gas measure- ments make the diagnosis. Patient 5–14 A 60-year-old woman with severe chronic pul- monary disease went to a physician complaining of nervousness and insomnia. An examination dis- closed 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 nox- ious stimuli. She was cyanotic, and her respira- tions 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 re- sponses. The arterial blood pH was 7.17, the PaCO 2
25 mEq/L, and the PaO 2 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 PaCO 2 at its normal level of 45 mm Hg. Comment: This is not an unusual history. It is possible that the increased nervousness and in- somnia 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 PaCO 2 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 CO 2
plaints of insidiously appearing headache, som- nolence, and confusion may occasionally attract 230 Plum and Posner’s Diagnosis of Stupor and Coma 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 in- creases respiration, lowering the PCO 2 and,
thus, the ICP. In its most severe form, pulmonary enceph- alopathy may cause increased ICP, papil- ledema,
257 and bilateral extensor plantar re- sponses, symptoms that may at first raise the question of a brain tumor or some other ex- panding mass. The important differential fea- tures are that in CO 2 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 re- lated to CO 2 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 CO 2 retention must be treated, because lack of oxygen is immediately dan- gerous both to the heart and brain. Traditional teaching has been that oxygen therapy for hy- percapnic patients with an acute exacerba- tion 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 venti- lation, noninvasive ventilation with a face mask appears to suffice. 259 Renal bicarbonate excre- tion is a relatively slow process. As a result, correction of CO 2 narcosis by artificial respi- ration sometimes induces severe metabolic al- kalosis 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 col- leagues
260 reported five patients with pulmo- nary emphysema treated vigorously by artifi- cial ventilation in whom metabolic alkalosis was associated with serious neurologic symptoms. These patients, after initially recovering from CO 2
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 con- sciousness after blood CO 2 levels were raised again by deliberately reducing the level of ventilation. We have observed a similar se- quence 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 vasocon- striction, which more than counterbalances the beneficial effects to the brain of raising the blood oxygen tension. Rotheram and his col- leagues believe that the PCO 2 should be low- ered 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 hyp- oxemia is prevented. Pancreatic Encephalopathy Failure of either the exocrine or endocrine pan- creas can cause stupor or coma. Failure of the endocrine pancreas (diabetes) is discussed in the next section. Failure of the exocrine pan- creas causes pancreatic encephalopathy, a rare complication of acute or chronic pancreatitis. Chronic relapsing pancreatitis may cause epi- sodic stupor or coma. 262 Estrada and associates reported that six of 17 nonalcoholic patients with acute pancreatitis, whom they followed pro- spectively, developed encephalopathy. 263
The pathogenesis of pancreatic encephalopathy is not known. Postmortem evidence of patchy de- myelination 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 compli- cating 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 mod- erate increases of other amino acids. 262 Acute
pancreatitis raises dopamine levels in brains of rats.
264 Pathologically, autopsies have revealed cerebral edema, patchy demyelination, occa- sional 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. Multifocal, Diffuse, and Metabolic Brain Diseases Causing Delirium, Stupor, or Coma 231
Pancreatic encephalopathy usually begins between the second and fifth day after the on- set 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, af- ter several days of abdominal pain, the patient develops acute encephalopathy. The MRI may be normal 267 or show diffuse white matter le- sions. 265
The differential diagnosis should in- clude other factors complicating pancreatitis listed above, including, of course, mumps that can cause both pancreatitis and encephalopa- thy. CSF lipase is elevated in pancreatic en- cephalopathy. Patient 5–15 A 72-year-old male with no significant past med- ical history presented to the hospital with abdom- inal pain and was diagnosed with acute pancrea- titis. The next day the patient was noted to be confused with waxing and waning mental status changes, which became an acute agitated delir- ium on the fifth day requiring four-point restraints. EEG done at the time showed a diffuse theta rhythm. Initial CT and MRI studies were unreveal- ing and the patient remained mute in an awake state for several days, following which he recov- ered 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 abnormali- ties consistent with demyelination. Diabetes Mellitus Diabetes is the most common endocrine dis- ease presenting as undiagnosed stupor or coma. Pituitary, adrenal, or thyroid failure may occa- sionally present similarly, and these disorders are the subject of this section. Hyper- and hy- poparathyroidism are discussed with abnormal- ities of electrolyte metabolism (page 256). Diabetes, an illness increasing alarmingly in incidence, 268 is an endocrine disease with pro- tean systemic manifestations. The clinical ef- fects of diabetes may appear in virtually any organ of the body, either alone or in combina- tion with other organs. The brain is both directly and indirectly affected by diabetes; delirium, stupor, and coma are common symptoms of cer- tain stages of the disease. 269–271
The potential causes of stupor or coma in patients with dia- betes 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 contrib- uting cause in patients with diabetic ketoaci- dosis or lactic acidosis. Diabetic ketoacidosis 269,272 causes impair- ment of consciousness in about 20% of af- fected patients and coma in about 10%. In general, patients with alteration of conscious- ness 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 232
Plum and Posner’s Diagnosis of Stupor and Coma |