LAUSR

Acute liver failure may make patients quickly drowsy and inattentive, and most of it has been attributed to the toxic effects of ammonia. Acute hepatic failure often results in rapid decline in consciousness and the need for early intubation for airway protection. Neurologic findings also change rapidly, and pupils may become fixed with extensor motor responses out of proportion to any degree of hepatic encephalopathy. Pathologists have long debated whether a structural injury exists. When patients with acutely worsening chronic liver failure came to autopsy, the identified changes included large Alzheimer type II astrocytes, neuronal loss in the cerebellar cortex and basal ganglia, and glycogen-staining inclusions in astrocytes [1]. Acceptance of cerebral edema as a major manifestation in fulminant hepatic failure and distinct from hepatic encephalopathy was not immediate. Edema is still not described in some leading neuropathology texts [2] as opposed to leading neurology texts such as Adams and Victor’s Principles of Neurology, Bradley and Daroff ’s Neurology in Practice, and Merritt’s Neurology, which do have detailed sections [3–5]. In Plum and Posner’s first text in 1966 [6], the autopsies were considered insufficiently detailed. Although they correctly noted that “none of the reports included descriptions of the brain by experienced neuropathologists,” they felt that the observation was possibly considered “a terminal complication,” a position they maintained until the fourth edition in 2017 [7]. Change came through astute clinical observation, which noted improved outcome with recognition and treatment of brain swelling. A Conceptional Change A key series from Boston City Hospital was the largest series, with 18 patients seen in a decade, representing less than 0.2% of all autopsies [8]. Most patients “became hypotensive and died in hepatic coma.... Terminally these patients developed generalized bleeding with hemorrhages into the skin, lungs, or gastrointestinal tract [8].” Causes were considered viral, and sometimes a hepatotoxin (e.g., halothane) and vasopressors were considered. None of these earlier autopsy studies examined brain tissue [9, 10]. Early reports of cerebral edema in acute liver failure emerged in the early 1970s, and a clinical understanding emerged of a better separation of fulminant hepatic failure (‘massive liver cell necrosis’) as a separate entity from acutely worsening chronic liver disease. The very first clinical article came in 1971 from the Liver-Gastrointestinal Unit at the University of Texas Southwestern Medical School in Dallas, which reviewed case material of 48 patients with massive hepatic necrosis from 1958 to 1970 (Fig. 1) [5]. Brain examination revealed cerebral edema in 16 of 32 patients. Macroscopically, there was flattening of the gyri, compression of the ventricles, and poor differentiation of white or gray matter. Herniation of cerebellar tonsils were seen in three patients and uncal herniation in two patients. Microscopically, gray matter edema in 14 patients featured large prominent swollen glial cells. As expected from an article without a neurologist as a coauthor, clinical neurologic examination and clinicopathologic correlation were incomplete. Twelve of 16 patients were in stage IV hepatic encephalopathy (coma) for more than 48 h. Three illustrative cases described patients developing “grand mal seizure” and deteriorating to deep coma with “decerebrate opisthotonic movements [5].” Lumbar puncture showed markedly increased opening pressure (> 300 mm H2O). Papilledema was noted in one patient, who developed light, fixed pupils followed by *Correspondence: [email protected] Division of Neurocritical Care and Hospital Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA