Encephalopathy 1 5 Steven L. Lewis Abstract The term encephalopathy describes a general alteration in brain function manifesting as an attentional disorder anywhere within the continuum between a hyperalert agitated state and coma, and typically refers to the commonly encountered clinical scenario of diffuse brain dysfunction felt to be due to a systemic, metabolic, or toxic derangement. This chapter discusses an approach to the emergency evaluation and management of patients with encephalopathy, with an emphasis on those causes of toxic- metabolic encephalopathy that will lead to irreversible neurological dys- function if not recognized and treated urgently, as well as those encephalopathies whose recognition might lead to more prompt diagnosis and treatment of the causative medical illness. The encephalopathies discussed in this chapter are divided into four common, though overlapping, scenarios the neurologist is likely to encoun- ter in clinical practice: encephalopathy from metabolic disorder or defi - ciency, encephalopathy due to a severe systemic illness or organ failure, encephalopathy due to medication-related toxicity, and encephalopathies diagnosable primarily by fi ndings on brain imaging. In many cases a spe- cifi c etiological diagnosis can be made—via history, examination, labora- tory studies, and in some cases, imaging—which may lead to specifi c medical intervention and more rapid clinical resolution, and may help pre- vent irreversible neurologic dysfunction. Since patients with diffuse, toxic-metabolic encephalopathies are med- ically—and secondarily neurologically—ill, the evaluation and manage- ment of patients with diffuse encephalopathies represents a unique and important opportunity for the neurologist to positively impact the medical management, and both the neurological and medical recovery, of these systemically ill patients. S. L. Lewis , MD (*) Department of Neurological Sciences , Rush University Medical Center , Chicago , IL , USA e-mail: [email protected] K.L. Roos (ed.), Emergency Neurology, DOI 10.1007/978-0-387-88585-8_15, 283 © Springer Science+Business Media, LLC 2012 284 S.L. Lewis Keywords Toxic-metabolic encephalopathy • Delirium • Wernicke’s encephalopathy • Hepatic encephalopathy • Uremic encephalopathy • Pancreatic encephalo- pathy • Fat embolism • Ifosfamide encephalopathy • Cefepime encephalo- pathy • Posterior reversible encephalopathy syndrome • Metronidazole encephalopathy context, usually with exclusion of other processes Introduction through imaging and other studies. The diagnosis of toxic-metabolic encephalopathy may lead to Encephalopathy is the term used to describe a the generic recommendation to correct any meta- general alteration in brain function, manifesting bolic abnormalities, treat any underlying acute as an attentional disorder anywhere within the systemic illness, and discontinue or limit the use continuum between a hyperalert agitated state of sedatives or other medications with central and coma. In clinical practice, the diagnosis of nervous system side effects. In many cases, encephalopathy is usually reserved for the diffuse though, a more specifi c diagnosis can be made, brain dysfunction felt to be due to a systemic, and prompt recognition of the causative systemic metabolic, or toxic derangement, rather than, for process or medication can lead to a more rapid example, a multifocal structural process; there- neurologic recovery, or in some cases, prevention fore the adjectives “metabolic” or “toxic- of irreversible neurologic injury [ 1 ] . metabolic” are usually implied when the diagnosis The purpose of this chapter is to discuss an of encephalopathy is made. The syndrome of approach to the emergency evaluation of patients toxic-metabolic encephalopathy is essentially with encephalopathy, with an emphasis on those synonymous with delirium , the term favored by causes of toxic-metabolic encephalopathy that most nonneurologists. Lately, autoimmune will lead to irreversible neurological dysfunction encephalopathies have been increasingly recog- if not recognized and treated urgently, as well as nized as another important mechanism of diffuse the encephalopathies whose recognition (by clin- brain dysfunction; these syndromes—technically ical or neuroimaging fi ndings) might lead to more more consistent with “encephalitides” than prompt diagnosis and treatment of the causative “encephalopathies”—are characterized by sug- medical illness. gestive clinical and laboratory features and response to immune-based therapies (and often removal of an underlying neoplasm), distinguish- Epidemiology of Toxic-Metabolic ing them from the toxic-metabolic encephalopa- Encephalopathy thies discussed in this chapter. Neurologists are frequently asked to evaluate The evaluation of encephalopathy is a common patients with alteration in consciousness from a aspect of day-to-day neurologic practice, and toxic-metabolic encephalopathy. The consulting encephalopathy can occur in any patient at any physician likely requests the neurologic consulta- age with a severe systemic illness or with expo- tion because of concern for a structural, ischemic, sure to a metabolic or toxic derangement causing epileptic, or other focal cause of the patient’s cerebral dysfunction. The epidemiology of toxic- encephalopathic symptoms. The neurologic diag- metabolic encephalopathy, however, is best char- nosis of a diffuse, toxic-metabolic encephalopa- acterized for those patients over age 65, where thy is typically made by fi nding characteristic the incidence of delirium occurring during hospi- diffuse clinical symptoms and (mostly) nonlocal- talization in this age group has been reported to izing fi ndings within the appropriate clinical be as high as 56% (up to 87% in the ICU setting) 15 Encephalopathy 285 with high in-hospital mortality (varying between Although the basic underlying cellular studies), and with a 1-year mortality rate of up to pathophysiology of metabolic encephalopathies 40% [ 2 ] . These statistics underscore both the may differ, they share a common mechanism of ubiquity of this clinical syndrome and the fact generalized, rather than focal, alteration in corti- that encephalopathies are usually refl ective of cal and brainstem function, leading clinically to a severe underlying acute systemic disease or diffuse alteration in attention and arousal. Some dysfunction. encephalopathic syndromes, however, preferen- tially affect certain vulnerable brain regions spe- cifi c to the cause of the encephalopathy, such as Pathophysiology of Toxic-Metabolic the medial thalami and periaqueductal gray mat- Encephalopathy ter in thiamine defi ciency. A detailed discussion of the underlying pathophysiology of each of the many causes of Clinical Features of Toxic-Metabolic toxic-metabolic encephalopathy is outside the Encephalopathy scope of this chapter. However, among the many mechanisms of global neuronal and astrocytic Patients with toxic-metabolic encephalopathy typi- dysfunction that can occur due to metabolic or cally present with a global alteration in level of toxic derangements, general pathophysiologic alertness, varying between and within patients, mechanisms that underlie many of these clinical from obtundation and coma to an agitated delirium. syndromes include creation of an energy defi cit The time course of development of the encephal- through a decrease in the level of basic metabolic opathy can vary from rapid (e.g., from acute hypo- substrates necessary for neuronal survival, oxida- glycemia, hypoxia, or drug overdose), to the more tive stress, and functional alterations of neu- common subacute presentation from insidiously rotransmitter systems, including alterations in developing systemic metabolic processes. neurotransmitter synthesis and release [3 ] . On clinical examination, patients with enceph- From an emergency management perspective, alopathy are often lethargic, confused, or agi- with brain survival as the primary goal, those tated, typically without obvious focal localizing pathophysiologic causes of metabolic encephal- neurologic features. Many patients with toxic- opathy that may directly result in cell death due metabolic encephalopathies exhibit asterixis , to loss of neuronal energy substrates (e.g., glu- elicited by asking the patient to hold his or her cose, oxygen, and thiamine) are particularly arms outstretched. Asterixis is manifested by a critical to recognize and immediately treat in very brief loss of postural tone of the outstretched order to prevent irreversible neuronal death, and arms. It is not necessary for the wrists to be dor- to increase the likelihood of clinical neurologic sifl exed to evaluate for asterixis; however, if the recovery. Also critical to immediately recognize patient is able to perform this, the classic “fl ap” are those systemic processes that can secondarily of brief downward wrist fl exion may be observed. cause irreversible neuronal injury, for example, The fi nding of bilateral asterixis is rather specifi c by causing increased intracranial pressure (ICP) (but not sensitive) for the presence of a toxic- and potential cerebral herniation (e.g., acute metabolic encephalopathy from a number of hepatic encephalopathy from fulminant hepatic potential processes, but is not suggestive of any dysfunction). On the other hand, all causes of particular cause of the encephalopathy. In clinical toxic-metabolic encephalopathy share the under- practice, though, asterixis is commonly associ- lying pathophysiology of (usually severe and ated with