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 uremic or hepatic encephalopathies. often life-threatening) systemic illness and dys- Although the hallmark of the toxic-metabolic function, underscoring the importance of accu- encephalopathies is disordered attention, seizures rate diagnosis and treatment no matter what the can occur in some syndromes as well, particu- underlying systemic process. larly when severe; these include disorders such as 286 S.L. Lewis hypoglycemia and hyperglycemia, some electro- of a diffuse cerebral process. The EEG fi nding of lyte disorders, acute hepatic failure, and various triphasic waves is rather specifi c, but not sensi- medication-related encephalopathies (see the tive, for a toxic-metabolic encephalopathic pro- section on “Encephalopathic Syndromes” below). cess, but is not specifi c as to the actual cause; however, like asterixis, in clinical practice this fi nding is often encountered with hepatic and Diagnosis of Toxic-Metabolic uremic encephalopathies. Encephalopathy Laboratory testing is the mainstay of investi- gation of the etiology of toxic-metabolic enceph- As when taking any neurologic history, the alopathy. Serum glucose testing (including rapid physician should delineate the clinical symptoms fi nger stick determination as well as laboratory and their time course (especially from witnesses analysis of a drawn blood sample) and pulse oxi- if the patient is unable to provide a history), metry should be immediately assessed in all carefully detailing the current systemic context, patients because of the potentially irreversible other medical comorbidities, and all current and nature of hypoglycemic and hypoxic encephalop- recent medications. Examination should focus athy unless rapidly diagnosed and treated. A com- not only on the generalized neurologic fi ndings plete metabolic profi le (including electrolytes expected in a diffuse encephalopathy, including and liver and kidney function tests) will quickly assessment for asterixis, but should also focus on assess for the most common metabolic and sys- assessing vital signs, signs of meningeal irrita- temic derangements, and a complete blood count tion, observation for aphasia (especially the fl u- will quickly exclude profound anemia, while also ent kind, as a mimic of a confusional state), looking for clues to an underlying infectious funduscopic examination for signs of increased process. intracranial pressure, and exclusion of obvious Lumbar puncture (LP) will show only nonspe- motor or other asymmetries for which an alterna- cifi c, if any, cerebrospinal fl uid abnormalities in a tive diagnosis may be more likely. patient with a toxic-metabolic encephalopathy; Despite the diffuse neurologic presentation of however, this should be performed when there is patients with a probable toxic-metabolic enceph- any clinical concern for meningoencephalitis alopathy, diagnostic evaluation often necessitates (including autoimmune encephalitis) or suba- brain imaging studies (CT or MRI) to rule out rachnoid hemorrhage. Lumbar puncture in the causative focal structural or ischemic lesions, encephalopathic patient typically should be per- especially if there is any uncertainty as to the formed only after screening neuroimaging has diagnosis. Although these imaging studies are excluded a focal cerebral mass lesion which typically performed specifi cally to exclude focal might contraindicate this procedure. structural or ischemic processes, and should therefore typically be unrevealing in the patient ultimately diagnosed with a diffuse encephalopa- Encephalopathic Syndromes thy, some toxic-metabolic processes are them- selves associated with abnormal imaging features Patients with diffuse toxic-metabolic encephal- that may be helpful in diagnosis [ 4 ] and are dis- opathies are medically, and secondarily neuro- cussed further in the section on “Encephalopathic logically, ill. Therefore, despite the ubiquity of Syndromes” below. these clinical syndromes in typical inpatient EEG can be helpful in the evaluation of the neurological consultative practice, evaluation of patient with encephalopathy, particularly when patients with diffuse encephalopathies represents subclinical status epilepticus is a diagnostic con- a unique and important opportunity for the neu- sideration. Diffuse slowing on the EEG is a non- rologist to positively impact the medical manage- specifi c, and a nearly ubiquitous fi nding in these ment, and both the neurological and medical patients, simply paralleling the clinical syndrome recovery, of these systemically ill patients. 15 Encephalopathy 287

This section outlines four common and dis- important coenzyme in a number of intracellular tinct (but overlapping) presentations the physi- enzymatic activities, including energy production cian is likely to encounter in clinical practice: and various biosynthetic pathways. Defi ciency of encephalopathy from metabolic disorder or defi - thiamine causes Wernicke’s encephalopathy, ciency, encephalopathy due to a severe systemic characterized classically by the clinical triad of illness or organ failure, encephalopathy due to ophthalmoplegia, mental status changes, and medication-related toxicity, and encephalopa- ataxia. This is a very important cause of enceph- thies diagnosable primarily by fi ndings on brain alopathy due to the potential irreversibility of imaging. clinical fi ndings, and especially because of the development of an irreversible amnestic state, if thiamine defi ciency is not recognized and treated Encephalopathy from Basic Metabolic emergently [ 5, 6 ] . Although commonly thought Disorder or Defi ciency of as a disease of alcoholics, Wernicke’s enceph- alopathy can occur due to any process that leads Oxygen, Glucose, and Electrolytes to inadequate absorption of thiamine, including As stated above, hypoxemia and hypoglycemia hyperemesis states such as hyperemesis gravi- are critical to consider and quickly exclude in any darum, malnutrition from any cause, bariatric encephalopathic patient, as defi ciencies of these surgery, chronic diarrheal illnesses, and in the basic and critical neuronal energy substrates will course of many systemic illnesses [6, 7 ] . lead to irreversible neuronal death unless recog- Despite the commonly memorized clinical nized and reversed quickly; most other metabolic triad, the clinical symptoms and signs in patients disorders are less likely to directly lead (or lead with Wernicke’s encephalopathy vary, and the full quickly) to neuronal cell death and irreversible triad is often not present in an individual patient. injury. Likewise, profound hypotension or ane- The most common symptom is mental status mia can lead to loss of energy supply to neurons change, manifesting as agitation and confusion or and should be excluded quickly via immediate apathy, and can progress to coma. Eye fi ndings, if assessment of vital signs, oxygen saturation, and present, most commonly include nystagmus and hemoglobin concentration; careful therapeutic sometimes sixth nerve palsies; complete “oph- attention should be placed on these basic emer- thalmoplegia,” as listed in the classic triad, is gency resuscitation parameters in all encephalo- actually rare. Ataxia of gait is often present. Other pathic patients, as in any critically ill patient. signs and symptoms that may be seen in patients In addition to hypoxemia and hypoglycemia, with Wernicke’s encephalopathy include hypo- encephalopathy frequently occurs in the setting thermia, hypotension, and tachycardia [6 ] . of hyperglycemia and of certain electrolyte Brain regions commonly involved in abnormalities, especially hyponatremia, hyper- Wernicke’s encephalopathy include the mamil- natremia, and hypercalcemia. Though hyper- lary bodies, periaqueductal gray matter, and kalemia and hypokalemia are well-known causes medial thalami; changes in these regions may be of neuromuscular dysfunction (and of cardiac seen on diffusion-weighted and T2-weighted MRI dysfunction which can secondarily cause in some patients with Wernicke’s encephalopathy. hypoxic-ischemic encephalopathy), these com- These particularly vulnerable brain regions mon potassium abnormalities are not typically explain the characteristically severe, and poten- associated with encephalopathy. tially irreversible, amnestic state (Korsakoff’s syndrome) that occurs in patients with Wernicke’s Thiamine Defi ciency (Wernicke’s disease if prompt treatment is not initiated. Encephalopathy) Because of the treatable aspect of this condi- Thiamine, in the form of its active phosphory- tion, and its neurological irreversibility if lated derivatives (especially thiamine diphos- untreated in a timely fashion, neurologists need phate, also called thiamine pyrophosphate), is an to keep this diagnosis in mind in all patients 288 S.L. Lewis presenting with encephalopathy, whether or not barrier dysfunction, and other possible metabolic other features of the syndrome (e.g., nystagmus effects of the severe systemic dysfunction [11 ] . or gait ataxia) are present. The diagnosis is pri- Although sepsis or severe acute medical ill- marily and typically entirely clinical; thiamine nesses of any cause are common etiologies of levels are not useful in practice, especially due to encephalopathy, encephalopathies also occur due delay in obtaining these results. Although MRI to single-organ dysfunction or failure. In each of fi ndings can be seen in some patients with these clinical scenarios, the neurologist can play Wernicke’s encephalopathy, these fi ndings are an important role in helping to pinpoint the caus- insensitive for the diagnosis; importantly, one of ative medical illness, which may have a direct the priorities is to try to make the clinical diagno- impact on systemic treatment and the course of sis and begin treatment prior to the development neurologic improvement. The specifi c single- of any imaging fi ndings. organ causes of encephalopathy discussed below Treatment with parenteral thiamine should be include hepatic encephalopathy, uremic enceph- initiated emergently in any patient in whom the alopathy, pancreatic encephalopathy, and the fat diagnosis is a reasonable consideration, and must embolus syndrome. be given prior to any glucose administration due to the risk of glucose precipitating or worsening Hepatic Encephalopathy Wernicke’s encephalopathy. Although the opti- Hepatic encephalopathy can occur in patients mal evidence-based dose of thiamine is uncer- with either chronic liver disease (cirrhosis) or tain, recent expert recommendations suggest that acute liver failure [12 ] . Encephalopathy due to initial parenteral thiamine dosing should be chronic liver disease typically progresses slowly, >500 mg daily, given as a once- or twice-daily with the clinical features defi ned in stages, or regimen, for 3–5 days [6, 8 ] . grades; minimal hepatic encephalopathy is char- acterized by subtle fi ndings detectable mainly by formal neuropsychological testing: grade I is Encephalopathy Due to Severe characterized by psychomotor slowing and lack Systemic Illness or Organ Failure of attention; grade II is characterized by disorien- tation, lethargy, and unusual behavior; grade III Severe Systemic Illness and Septic is characterized by somnolence and stupor; and Encephalopathy patients in grade IV hepatic encephalopathy are As discussed in the preceding sections (and to a in coma. great extent inherent in the diagnosis of the clini- Asterixis is most commonly associated with cal syndrome of a toxic-metabolic encephalopa- grade II hepatic encephalopathy, but can also be thy) encephalopathies commonly occur in the seen in other stages. Some patients with chronic setting of a severe underlying systemic illness. liver disease present as a slowly progressive par- Encephalopathy is especially common in patients kinsonian syndrome (sometimes called acquired in the medical ICU [ 9, 10 ] , and in patients whose (non-Wilsonian) hepatolenticular (or hepatocer- illness may be severe enough to warrant transfer ebral) degeneration) consisting of bradykinesia, to a medical ICU setting. Any medical illness of rigidity, tremor, dysarthria, and ataxia [ 13 ] . suffi cient severity can lead to the clinical syn- Seizures are uncommon in patients with hepatic drome of a toxic-metabolic encephalopathy; in encephalopathy due to chronic liver disease. addition, the common fi nding of encephalopathy The diagnosis of hepatic encephalopathy due in the specifi c clinical setting of systemic sepsis, to cirrhosis is made by observing the characteris- with or without multiorgan failure, has led to the tic neurologic clinical features in the appropriate designation of a septic encephalopathy [ 11 ] . The clinical context. Ammonia levels remain helpful pathophysiology of septic encephalopathy is in the clinical diagnosis of hepatic encephalopa- unclear, although theoretical mechanisms include thy, although these levels do not correlate well the effects of infl ammatory mediators, blood–brain with the various stages of encephalopathy, and a 15 Encephalopathy 289 normal serum ammonia level does not exclude The clinical symptoms and signs, including the the diagnosis of hepatic encephalopathy. As men- EEG fi nding of triphasic waves in severe uremic tioned in the section on “Diagnosis” (above), tri- encephalopathy, mimic those of many other phasic waves may be seen on EEG in some metabolic encephalopathies; however, the tremu- patients with hepatic encephalopathy, but this lousness and twitching seen in many patients fi nding is neither sensitive nor specifi c for hepatic with uremic encephalopathy, although not very encephalopathy. specifi c, may be somewhat more suggestive of The MRI fi nding of high signal in the bilateral this cause of encephalopathy compared to other globus pallidus on noncontrast T1-weighted systemic processes. images has been attributed to manganese deposi- The diagnosis of uremic encephalopathy is tion in the brain due to reduced biliary manga- clinical, supported by appropriate laboratory nese excretion; this MRI fi nding, however, is studies showing severe kidney dysfunction, along common in patients with chronic liver disease, with the reasonable exclusion of other potentially whether or not a clinical encephalopathy is causative systemic, or other, processes. Other present [13 ] . systemic causes of encephalopathy that espe- Treatment of hepatic encephalopathy is aimed cially need to be considered in the uremic patient at reducing ammonia production through the use include drug toxicities (especially those that are of antibiotics such as rifaximin, and reducing renally metabolized or excreted), electrolyte dis- ammonia absorption through the use of nonab- turbances, and thiamine defi ciency [17 ] . sorbable disaccharides, such as lactulose. A recent Treatment of uremic encephalopathy is based on double-blind, placebo-controlled trial of rifaximin improvement of the uremic state and appropriate in hepatic encephalopathy showed that rifaximin- adjustment, if possible, of renally metabolized/ treated patients had an approximately 50% reduc- excreted medications. tion in episodes of hepatic encephalopathy and hepatic encephalopathy-related hospitalizations; Pancreatic Encephalopathy many of the patients in this study received con- The term “pancreatic encephalopathy” was comitant lactulose therapy, attesting to the com- coined in 1941 to describe the known association mon clinical requirement for both modes of between acute pancreatitis and a severe diffuse therapy [14 ] . Rifaximin was approved by the US encephalopathy [18 ] . Since then a number of Food and Drug Administration for the treatment reports have further elucidated this syndrome of hepatic encephalopathy in March 2010. [ 19– 21] which we have recently reviewed [ 1 ] . In contrast to patients with chronic cirrhosis Pancreatic encephalopathy typically has been and portosystemic shunting, acute liver failure reported to occur within 2 weeks of pancreatitis commonly presents as rapidly progressive neuro- onset, especially between the second and fi fth logic deterioration leading to life-threatening days, with varying incidences (up to as high as cerebral edema, with coma and seizures [15 ] . The 35%) reported [1 ] . neurologic assessment and treatment of patients The diagnosis of pancreatic encephalopathy with acute hepatic encephalopathy consist of ICP should be considered in any patient with a diffuse monitoring with aggressive reduction of increased encephalopathy occurring in the setting of acute ICP and management of any associated seizures. pancreatitis. Other than the laboratory fi ndings diagnostic of pancreatitis, no specifi c laboratory Uremic Encephalopathy or imaging feature is diagnostic of pancreatic Encephalopathy can occur due to either acute or encephalopathy; however, one report described chronic renal failure, and typically develops more severe diffuse white matter abnormalities on MRI rapidly in patients with acute kidney dysfunction in a patient with this syndrome [22 ] . [ 16] . Symptoms of uremic encephalopathy Treatment consists solely of management of include asterixis, myoclonus (uremic twitching), the pancreatitis; there is no specifi c neurologic and coarse tremor; seizures may also be seen. treatment beyond supportive care and avoidance 290 S.L. Lewis of benzodiazepines, which may worsen the Two major mechanisms have been proposed encephalopathy. Neurologic improvement typi- to explain fat embolism syndrome. The mechani- cally parallels the patient’s systemic recovery. cal theory proposes that bone marrow contents Unfortunately, the mortality rate for patients with enter the lungs via the venous system, where they pancreatic encephalopathy is high [1 ] . may also gain access to the systemic circulation The pathogenesis of pancreatic encephalopa- and enter the brain via pulmonary arteriovenous thy has been proposed to relate to blood–brain shunts or patent foramen ovale. The biochemical barrier breakdown as a consequence of activation theory proposes that pulmonary abnormalities of phospholipase A and conversion of lecithin result from a toxic effect on lung cells by circu- into its hemolytic form [19 ] , although fat embo- lating free fatty acids. These theories are not lism (see below) is another putative mechanism. mutually exclusive and both mechanisms may be Patients with pancreatitis are also at risk for the responsible for various aspects of the clinical development of Wernicke’s encephalopathy, syndrome [25 ] . which should strongly be considered in the dif- The possibility of fat embolism should be con- ferential diagnosis, or as an additional comorbid sidered in any patient with encephalopathy occur- process, in these patients [23 ] . ring in the appropriate clinical context, especially if other causes have been excluded. Treatment is Fat Embolism currently supportive and revolves mainly around Fat embolism should be considered among the appropriate pulmonary management [24 ] . potential emergent diagnoses of any patient pre- senting with a diffuse encephalopathy in character- istic clinical settings, such as after recent orthopedic Medication-Related Encephalopathy procedures or trauma. The fat embolism syndrome is characterized by the classic clinical triad of Encephalopathy due to medications with central encephalopathy, pulmonary dysfunction, and a nervous system effects, including sedatives, petechial rash [ 24 ] . Although most commonly analgesics, anticholinergics, anticonvulsants, associated with long-bone trauma, fat embolism anxiolytics, and any of the wide variety of CNS- also occurs in a variety of other scenarios, includ- active drugs, is well recognized. However, sev- ing acute pancreatitis, diabetes mellitus, burns, eral medications in current clinical use have been joint reconstruction, liposuction, cardiopulmonary relatively recently associated with specifi c and bypass, decompression sickness, and parenteral distinctive toxic encephalopathic syndromes and lipid infusion [25 ] . Clinical symptoms of fat embo- will be discussed here. These medications, ifosf- lism typically, though not invariably, occur 24–48 h amide and cefepime, are not uncommonly used after the inciting event [24 ] . and neurologists in clinical practice are likely to The primary neurologic manifestation of fat be asked to consult emergently on patients with embolism is a diffuse encephalopathy, though focal encephalopathy due to one of these agents. neurologic signs and seizures can occur. In some Recognition of these unusual encephalopathic patients, the neurologic manifestations may be the syndromes is important in the management of sole clinical feature; however, pulmonary symp- these patients to avoid unnecessary interventions toms are typically present and these symptoms may (other than discontinuation or reduction of the range from mild dyspnea to tachypnea to respira- offending agent) and possibly (in the case of tory failure [26 ] . The fi nding of petechiae on the ifosfamide encephalopathy) for consideration of skin completes the clinical triad, but this is seen in specifi c antidotal therapy. Metronidazole, a com- only about half of patients with the syndrome. MRI monly used antibiotic which is also associated in some patients has shown multifocal punctate with an encephalopathic syndrome, is discussed DWI-positive white matter lesions consistent with in the next section on encephalopathies associ- multifocal embolic lesions [ 27, 28 ] . ated with distinctive imaging fi ndings. 15 Encephalopathy 291

Ifosfamide Management involves discontinuation of Ifosfamide, a chemotherapeutic agent used in the cefepime, which leads to gradual resolution of the treatment of a variety of solid tumors, has been encephalopathy. In patients with nonconvulsive associated in some patients with the development status epilepticus due to cefepime (or other cepha- of a severe encephalopathy [ 29 ] . Ifosfamide losporin) neurotoxicity, several reports have encephalopathy typically develops 24–48 h after described short-term use of anticonvulsants in infusion, but may occur later. Encephalopathic addition to discontinuation of the cephalosporin symptoms due to ifosfamide may range from [40, 41] , although it is unclear as to whether mild to severe and progress to coma and death. In improvement was aided by the anticonvulsant. addition, a distinctive catatonic-like, severely abulic state with mutism can be seen in patients with ifosfamide encephalopathy [30 ] . Encephalopathies Diagnosed Primarily Due to theoretical considerations regarding by Brain Imaging Findings the presumptive mechanism of ifosfamide encephalopathy, methylene blue, an electron Findings on neuroimaging play an integral role in acceptor, has emerged as antidotal intravenous the timely recognition of several specifi c enceph- treatment of severe cases of this syndrome [ 31, alopathic conditions, including the posterior 32] . Although not based on controlled trials, reversible encephalopathy syndrome and metron- treatment with methylene blue has been gener- idazole encephalopathy; in addition, the fi nding ally thought to hasten what may otherwise be a of a splenial lesion on MRI, although nonspecifi c, prolonged recovery with occasional persistent has been recently associated with various causes neurologic sequelae [ 33 ] . Mild cases, however, of encephalopathy. The imaging fi ndings and typically resolve within days after stopping the clinical syndromes discussed in this section are agent and do not require specifi c antidotal treat- in contrast with some of the encephalopathic syn- ment. Thiamine treatment has also been anecdot- dromes discussed earlier, where the imaging fi nd- ally advocated for management of this syndrome ings are not specifi c or sensitive for the clinical [34 ] . A recent uncontrolled retrospective analy- presence of an encephalopathy (e.g., T1 high sig- sis, however, suggested no clear benefi t for rou- nal in the basal ganglia in patients with chronic tine prophylaxis of ifosfamide encephalopathy hepatic disease with or without encephalopathy) with methylene blue or thiamine [35 ] . or they represent late fi ndings that play little if any role in clinical diagnosis and emergent Cefepime empiric therapy (e.g., the MRI fi ndings in Cefepime is a fourth-generation cephalosporin Wernicke’s encephalopathy). commonly used to treat a variety of severe bacte- rial infections. This agent has been associated Posterior Reversible Encephalopathy with an encephalopathy (more common than that Syndrome associated with third-generation cephalosporins, This is an increasingly recognized clinical syn- such as ceftriaxone and ceftazidime), manifested drome, although controversially named since it by progressive confusion and agitation which can does not always involve posterior brain regions progress to coma [ 36, 37 ] . Although cefepime and is not always completely reversible. The pos- encephalopathy was initially reported in patients terior reversible encephalopathy syndrome with renal failure (causing reduced clearance of typically presents clinically with encephalopathy, the drug), cefepime encephalopathy also occurs visual disturbances (due to cortical visual in patients with normal renal function [ 38, 39 ] . In dysfunction), and seizures, usually in association some patients with cefepime encephalopathy, with elevated systemic blood pressure. The clas- EEG has shown nonconvulsive status epilepticus sic imaging fi nding is hyperintensity on T2- and [39– 41 ] . FLAIR-weighted MRI consistent with vasogenic 292 S.L. Lewis edema, typically predominantly involving the have nonspecifi c encephalopathic symptoms posterior occipital white matter; however, more including drowsiness, confusion, and agitation. diffuse involvement (including the brainstem and Splenial high-signal lesions typically resolve on anterior hemispheres) can also be seen [ 42 ] . The follow-up imaging in parallel with the patient’s predisposing conditions for the development of clinical resolution. Although nonspecifi c, this this syndrome are vast, although common under- MRI fi nding can nonetheless be a useful fi nding lying systemic factors include eclampsia, hyper- supportive of a probable reversible metabolic (or tension with acute kidney disease, and exposure viral) encephalopathic syndrome, and despite its to various chemotherapeutic and immunosup- usual DWI positivity, should not be confused pressive medications. The cause of the posterior with a cerebrovascular ischemic process affect- reversible encephalopathy syndrome is unclear, ing the corpus callosum. but may involve capillary leak due to endothelial dysfunction. Treatment includes blood pressure control, withdrawal of the potentially offending Treatment agent, and seizure management. It is assumed that prompt recognition and management of this Treatment of the various encephalopathic syn- syndrome should decrease the likelihood of per- dromes has been discussed within the individual manent sequelae of this usually reversible condi- sections above. A general approach to manage- tion [43 ] . ment of the encephalopathic patient is, however, reviewed here. Metronidazole Encephalopathy As discussed at the outset of this chapter, ini- Metronidazole is a commonly prescribed antibiotic tial evaluation and treatment of the encephalo- which is associated with an uncommon, but char- pathic patient should focus on keeping a strong acteristic, toxic encephalopathy manifested primar- clinical suspicion for those causes of encephal- ily by confusion, dysarthria, and ataxia. MRI opathy that will lead to irreversible neurologic fi ndings typical of metronidazole encephalopathy dysfunction if not recognized and reversed imme- include T2 and FLAIR high-signal lesions involv- diately. Therefore, the immediate approach to ing the dentate nuclei [ 44 ] ; additional involvement treatment of any encephalopathic patient is of the corpus callosum and deep hemispheric white directed at correction of any circulatory defi - matter, and hypertrophy of the inferior olives have ciency and replacement of any potentially defi - also been described [45, 46 ] . The clinical and cient metabolic substrate (e.g., oxygen, thiamine, radiographic fi ndings of metronidazole-induced or glucose). This should be followed by correc- encephalopathy are usually reversible with discon- tion of any other potentially causative metabolic tinuation of the antibiotic, although severe persis- abnormality, treatment of any underlying caus- tent sequelae can occur [47 ] . ative acute systemic illness or complication of organ failure, and attempt at discontinuation or Splenial High-Signal Lesion removal of any likely offending medication or For about the last 10 years, the MRI fi nding of an toxin. ovoid or round lesion within the splenium of the Since toxic-metabolic encephalopathies are corpus callosum (high signal on FLAIR/T2 and due, by defi nition, to an underlying systemic pro- often also on DWI) has been described as a non- cess or medication (even if still unknown in the specifi c fi nding associated with a variety of individual patient), management should focus on encephalopathic syndromes, including those due diagnosis and treatment of systemic dysfunction to various metabolic disorders, viral infections and removal of potential offending agents while (termed “encephalitis/encephalopathy”), and the attempting to minimize any CNS-active or sedat- use of, or withdrawal from, antiepileptic agents ing medications which might complicate or [48, 49 ] . Patients with this imaging fi nding may worsen the encephalopathy. 15 Encephalopathy 293

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