The true incidence of the neurological complications of medical illness is difficult to determine but a guide sense can be obtained from the study carried out by Isensee and colleagues who evaluated 100 consecutive medical intensive care unit (MICU) patients within 72 hours of admission to detect neurological problems (3). Their study excluded those with primarily cardiac problems. Eighteen patients were admitted for acute neurological disease and five others for encephalopathy caused by drug overdose. Of the remaining 67, fully one third had a serious neurological complication of a medical condition (11 metabolic encephalopathy, four hypoxic-ischemic encephalopathy, and seven other neurological problems). Furthermore, 59% of the patients with neurological complications died, in contrast to 20% of the non-neurological patients.

Bleck and associates have carried out a 2-year prospective study among MICU patients in order to describe the neurological complications encountered and identify their effects on mortality and length of stay (LOS) (4). As with the above-noted study, patients with a primarily neurological reason for admission to the MICU were excluded from analyses of mortality and LOS. More than half of this group had either a major ischemic stroke or intracranial hemorrhage. The others were classified as having a complication of a critical illness if they developed a neurological problem from a medical disorder or directly from its treatment. They collected the medical diagnoses into four categories for analysis: (a) sepsis, bacteremia with shock, the “sepsis syndrome,” and acute respiratory distress syndrome; (b) acute coronary artery disease, including myocardial infarction (MI); (c) other cardiac problems; and (d) all others (e.g., ventilatory
failure, gastrointestinal hemorrhage, hypotension without sepsis). Patients with neurological complications were further divided into those with metabolic encephalopathies, seizures, cerebrovascular disorders, hypoxic-ischemic encephalopathy, or other global brain disorders. These neurological categories were not mutually exclusive. Patients with clinically apparent peripheral nervous system disorders were classified in the “other” group.

During the study, 1,850 patients were admitted to the MICU; of these, 92 (4.9%) were admitted for a primary neurological reason. Among the remaining 1,758 patients of principal interest, 217 (12%) experienced neurological complications of their underlying medical disease (Table 11.1). Table 11.2 details the neurological complication rates by MICU admission category. The overall mortality rate for all MICU patients was 32%, compared to 55% for the 217 patients with neurological complications, compared to 29% for those without neurological complications. The neurological group also had significantly longer MICU and hospital stays.

Metabolic encephalopathy was the most frequent complication, occurring in 62 patients. Of these, the largest group was attributed to sepsis, without evidence for hepatic or renal dysfunction or hypoxemia. The frequencies of different metabolic encephalopathies are detailed in Table 11.3. Seizures occurred in 61 patients, most often with cerebrovascular lesions. Hypoxic-ischemic encephalopathy occurred in 51 patients, primarily because of a cardiac disorder in 27, and pulmonary disease in the remaining 24.

It is of interest (and perhaps not widely appreciated) that 48 patients had strokes while in the ICU. Thirty-two of these were infarcts, 14 were intracerebral hemorrhages, and two were subarachnoid hemorrhages. Thirteen stroke patients had an identified cause other than arteriosclerosis, including underlying connective tissue diseases and bacterial endocarditis. Stroke occurred in only 1% of patients with acute MI, a rate less than the usually cited range of 1.7% to 2.4% (5,6).

During the past 30 years, clinical analyses and investigations of cytokine mechanisms have contributed to our understanding of the causes and pathogenesis of sepsis (7), but the causes of the associated encephalopathy remain obscure. Although bacteremia was previously considered to be the sine qua non of systemic sepsis, occurring as a consequence of local infection, it is clear that many patients suffer the same vasomotor disturbances and organ dysfunctions without positive blood cultures. Bone has suggested that sepsis be defined as “clinical evidence of infection, tachypnea, tachycardia, and hyperthermia or hypothermia” (8). He further defined the sepsis syndrome as “sepsis with evidence of altered organ perfusion.” Subsequent investigators have refined these definitions and added more quantitative factors to help guide clinical studies (9). In this current view, the crucial systemic aspects of the sepsis syndrome are altered distribution of blood flow (microcirculatory abnormalities), endothelial damage, and parenchymal injury (10). The pathogenesis of these problems is the subject of intense study, but the most convincing hypotheses regarding the systemic manifestations involve the effects of tumor necrosis factor, several interleukins, platelet activating factor, and other mediators of inflammation (11).

The epidemiologic data cited herein as well as other studies too numerous to cite, indicate that septic encephalopathy is the most frequent neurological disorder encountered in medical intensive care; it is also one of the more poorly recognized and understood. Septic encephalopathy was described in 1827 (12), but has only recently become a subject of organized neurological interest. Young and coworkers (13) should be credited with providing a thorough prospective analysis of this disorder in a large university MICU and bringing the disorder to attention in the current era. They required fever and a positive blood culture for inclusion into their study, a very restrictive definition of sepsis that nonetheless provided a homogeneous group for analysis. Patients were excluded if they had preexisting brain disease; frequent sedative or opiate administration; pulmonary, hepatic, or renal failure; endocarditis; or long bone fractures that might have produced fat embolism.

These workers identified 69 septic patients over 31 months; by clinical examination, 20 of them were not encephalopathic, 17 were mildly encephalopathic, and 32 were severely encephalopathic. The patient’s age, blood pressure on entry into the study, and temperature did not vary significantly among the groups. The lowest systolic and diastolic blood pressures were statistically significantly lower (but probably not importantly so from a biological perspective) in the mildly and severely affected groups when compared with those without encephalopathy. Mortality was linked to the category of encephalopathy: None of the unaffected patients died, whereas 35% of the moderately and 53% of the severely affected patients died. It was of interest that a number of laboratory values showed a linear relationship with the severity of encephalopathy, including white blood cell count, PaO₂, blood urea nitrogen, creatinine, bilirubin, alkaline phosphatase, and potassium. The serum albumin concentration was inversely related to encephalopathy. The cerebrospinal fluid (CSF) protein content was mildly elevated (60 to 85 mg/dL).

Electroencephalography (EEG) has been found by several groups to be a more sensitive test for central nervous system (CNS) dysfunction than the clinical examination, and a correspondingly more powerful predictor of survival (Fig. 11.1) (14). Evoked potential studies in septic patients suggest that brain dysfunction is even more prevalent than detected by EEG, the evoked potentials being abnormal in 84% (15). Sprung and coworkers, reporting for the Veterans’ Administration Cooperative Sepsis study, also showed that “alterations in mental status are common in septic patients, and are associated with significantly higher mortality” (16).

Eidelman and colleagues (17) studied 50 patients with severe sepsis, and showed that encephalopathy was associated with bacteremia and hepatic dysfunction. The severity of encephalopathy, measured by as simple a tool as the Glasgow Coma Scale, correlated directly with mortality. Using encephalopathy as a marker, they found that 59% of encephalopathic patients were bacteremic, whereas only 13% of patients with normal mental status were bacteremic.