Pathophysiology of septic encephalopathy: A review The pathophysiology of septic encephalopathy is likely to be multifactorial.

Early reports suggested that septic encephalopathy may be caused by disseminated cerebral microabscesses (17, 18), but a more recent postmortem study (10) failed to nd microabscesses in the brains of four patients with septic encephalopathy. Similar proportions of septic patients with Gramnegative bacteremia, Grampositive bacteremia, fungemia, or with no identied causative organism develop septic encephalopathy (6). These ndings, together with the fact that encephalopathy occurs in noninfectious conditions such as pancreatitis (19), suggest that infecting organisms and/or their toxins do not directly cause encephalopathy. The systemic inammation resulting from infection or other causes, appears more likely to be the cause of septic encephalopathy (20). Inammatory mediators released by leukocytes in sepsis have profound effects on endothelial cells and astrocytes; damage to these cells results in impaired neuronal function. Therefore, this review concentrates on four cell types that play a crucial role in the pathogenesis of septic encephalopathy: leukocytes, cerebral microvessel endothelial cells, astrocytes, and neurons. Leukocytes. The sequence of events leading to systemic inammation has been reviewed elsewhere (20). Although inammation is initially a local process, in severe infections, massive tissue injury, and in the presence of large amounts of necrotic tissue, a systemic release of inammatory mediators occurs (systemic inammatory response syndrome) that has adverse effects on the liver, lung, kidney, and heart (2124). These organs suffer panendothelial injury that causes reduced patency of microvessels (25). The lungs, liver, and spleen are underperfused (24) and accumulate activated leukocytes (22) that release lysosomal enzymes and oxygen free radicals. In contrast to organs of the reticuloendothelial system, the brain is resistant to leukocyte accumulation (26). Intracerebral injection of platelet activating

factor, interleukin-8, interleukin-1, or tumor necrosis factor-a fails to cause leukocyte exudation into the brain parenchyma in mice (27). There are a number of reasons for this (28, 29). First, the central nervous system is devoid of a lymphatic system that sequestrates potential antigens. Second, the central nervous system is protected from inammatory cell inltration by the bloodbrain barrier. Although cerebrovascular endothelial cell pinocytosis increases in sepsis (3032), allowing immunologically relevant molecules to pass through, the intercellular tight junctions remain morphologically intact (30 33) and thus, probably constitute a barrier to inammatory cells. Third, cells of the central nervous system express very low levels of the major histocompatibility complex antigens, which play a fundamental role in the induction and regulation of immune responses. Finally, the cerebrovascular endothelium expresses very low levels of leukocyte adhesion molecules such as VCAM-1 and ICAM-1 compared with the peripheral vascular endothelium (28, 29). Although leukocyte accumulation does not occur in the brain during sepsis, inammatory mediators cross the bloodbrain barrier and have adverse effects on the brain. Tumor necrosis factor-a and interferon-g increase the permeability of cultured bovine (30) and human (31) cerebral endothelial cells by promoting pinocytosis without apparently affecting the intercellular tight junctions. Intracerebral injection of interleukin-1 or interleukin-2 into experimental animals has been reported to mimic the electroencephalographic changes and soporic effects of septic encephalopathy (3436) and to cause fever by their effect on the hypothalamus (37). Subarachnoid injection of tumor necrosis factor-a in rabbits reduces cerebral oxygen uptake and cerebral blood ow and increases intracranial pressure and cerebrospinal uid lactate (38). Tumor necrosis factor-a enhances the production of endothelin and inhibits the formation of nitric oxide by cultured cerebral endothelial and smooth muscle cells (39). Activated leukocytes in the circulation generate oxygen free radicals that react with

erythrocyte cell membranes and reduce the deformability of normal human erythrocytes treated with endotoxin (40, 41), erythrocytes in septic patients (42), erythrocytes in dogs infused with Escherichia Coli (43), and erythrocytes in rats after cecal ligation and puncture (44 46). Erythrocytes in cerebral microvessels appear enlarged and rounded in pigs with fecal peritonitis (33). These abnormally-shaped erythrocytes may be unable to squeeze through microvessels, thus exacerbating the cerebral hypoperfusion that occurs in sepsis (47, 48). Inotropes improve cardiac output that may be suppressed in the later stages of sepsis. b2 adrenergic agents are also antiinammatory (4952), but a1 adrenergic agents are proinammatory (53, 54). In pigs with faecal peritonitis, dopexamine (a b2 adrenoceptor, vascular DA1 receptor, and prejunctional DA2 receptor agonist) protects against cerebral edema (55) and attenuates the leukostasis that occurs in the liver (56). Further studies are required to assess whether inotropes with a1 activity aggravate septic encephalopathy in humans, whereas inotropes with b2 activity offer protection against septic encephalopathy in humans. Cerebral Endothelial Cells. Blood is separated from the brain parenchyma by the blood-brain barrier, which depends on the integrity of cerebral microvessel endothelial cells. Normal cerebral microvessel endothelium, in contrast to that of most other tissues, has no fenestrations, possesses intercellular tight junctions, and contains few pinocytotic vesicles (57, 58). Septic encephalopathy appears to be associated with breakdown of the blood-brain barrier because patients with septic encephalopathy have high protein levels in the cerebrospinal uid (14) and colloidal iron oxide (32), 14 C-amino acids (59), and 125 Ialbumin (24) pass from the circulation into the brain parenchyma in septic rodents. Normally, low doses of circulating catecholamines have no effect on cerebral blood vessels because they are excluded from the central nervous system by the blood-brain barrier (60, 61). Higher concentrations of circulating catecholamines may result in dilation of cerebral blood vessels

resulting from an increase in arterial blood pressure and thus, distension of the vascular walls. Disruption of the blood-brain barrier allows the high levels of endogenous catecholamines that occur in sepsis (61) and the various vasopressors administered in intensive care units to directly inuence cerebral vascular resistance (62). Agents with a1 -adrenoceptor activity, such as norepinephrine, have been reported to cross the blood-brain barrier and cause cerebral vasoconstriction in sepsis (63). In contrast, during hemorrhagic shock, where blood-brain barrier permeability is unaffected, norepinephrine has no effect on the cerebral vasculature (64). Impaired blood-brain barrier function may also explain why cerebral oxygen consumption is 33% of normal in septic patients and remains constant when the cerebral blood ow is increased (47, 48). The cerebral perimicrovessel edema, seen in pigs after fecal peritonitis (33) and in rabbits with endotoxemia (32), is likely to limit the diffusion and hence utilization of oxygen, nutrients, and cellular waste across the microvessel wall. In dogs (65), pigs (63), and humans (47, 48), endotoxic shock has been shown to cause a reduction in cerebral blood ow that cannot be increased by improving the mean arterial pressure with vasopressors, suggesting that cerebral edema may increase intracranial pressure in sepsis, thus opposing the increase in cerebral blood ow after elevation of mean arterial pressure. This hypothesis is also supported by the fact that endotoxemia in pigs causes intracranial hypertension despite arterial hypotension (66). Systemic administration of E. Coli endotoxin to healthy volunteers did not affect cerebral blood ow or the rate of cerebral oxygen metabolism, despite replicating many of the systemic and hemodynamic features of sepsis (67). Although this model of sepsis (67) avoids many of the confounding variables present in critically ill patients, the lack of effect of E. Coli endotoxin on the cerebral circulation probably reects the low dose of endotoxin used. Another cause of impaired cerebral oxygen utilization during sepsis may be the inhibition of mitochondrial function. There is

evidence from rat liver, smooth muscle, and pulmonary epithelium that endotoxemia and proinammatory cytokines cause mitochondrial dysfunction, probably by nitric oxide-mediated mechanisms (68). Alternatively, the reduced brain oxygen extraction in sepsis may be caused by, rather than be the cause of, the reduced brain activity in sepsis. In pigs with fecal peritonitis (33) and rabbits with endotoxemia (32), the interendothelial cell tight junctions appear to remain morphologically intact, although the permeability of the blood-brain barrier was increased. Therefore, the functional status of the tight junctions is unclear and requires investigation. Because the molecular structure of tight junctions has recently been elucidated (69), it would be interesting to use immunohistochemistry to investigate whether the glue-like tight junction protein occluding and its intracellular anchor ZO-1 are functionally disrupted in sepsis. Astrocytes. The perivascular endfeet of cortical astrocytes are disrupted in pigs with fecal peritonitis (33) and in rabbits injected with endotoxin (32). Astrocytes are important supportive and homeostatic cells in the central nervous system (70) and their injury may exacerbate neuronal damage by several mechanisms. First, in regions of high neuronal activity, there is a potassium ux from neurons to the extracellular space. The potassium is taken up by astrocytes and transferred to endothelial cells. It is then secreted into the vascular lumen to dilate local blood vessels (70, 71). Astrocyte damage may thus impair the regulation of local blood ow. Second, astrocytes transport energy substrates from microvessels to neurons in proportion to the level of synaptic activity (72). Injury to astrocyte endfeet may impair this coupling process and therefore reduce synaptic activity. Third, astrocytes are important in inducing blood-brain barrier properties in the cerebral endothelium (73) and their damage may exacerbate the increased bloodbrain barrier permeability in sepsis. Astrocytes possess receptors for in- ammatory mediators (74). In human astrocyte cultures, recombinant human g-interferon and interleukin-1b

induce the formation of reactive oxygen intermediates (75) that are toxic (76). Free radical scavengers inhibit the electrophysiological changes seen after addition of various interferons to hippocampal slices (77). The results of experiments using rodent cell cultures suggest that astrocytes inuence the vulnerability of neurons to hypoxic (78), excitotoxic (79), and free radical-mediated (80) injuries. Therefore, the role of astrocytes in modulating neuronal damage in sepsis merits further study. Neurons. Septic encephalopathy is associated with disturbances of the reticular activating system that controls consciousness and attention. Cecal ligation and puncture in rats has been shown to increase glucose utilization by the raphe nuclei (81) and to increase the turnover of serotonin throughout the brain (82). In the same animal model of sepsis, glucose utilization by the locus ceruleus (81) and the norepinephrine content of the whole brain were found to be reduced (83). Enhanced serotoninergic and reduced noradrenergic neurotransmission have also been reported in hepatic (84) and uremic (85) encephalopathy and may, therefore, be universal features of the encephalopathies (86, 87). However, it is unclear whether these changes in neurotransmission are causes of encephalopathy or epiphenomena. Altered levels of tyrosine, tryptophan, and phenylalanine might explain the changes in neurotransmission found in sepsis, although the data should be interpreted with caution because such alterations may be secondary to the liver and renal failure that occurs in sepsis. The plasma and brain concentrations of these aromatic amino acids are increased in septic patients (88, 89) and in rats after cecal ligation and puncture (59), because they are released into the circulation from muscle breakdown (90, 91). In humans, the severity of septic encephalopathy can be predicted from the plasma concentrations of these amino acids (89, 92), suggesting that they contribute to its pathophysiology. Increased brain levels of the serotonin precursor tryptophan may be responsible for the potentiation of the reticular activating system serotonergic pathways.

Intracarotid infusion of tryptophan has been shown to induce drowsiness and sleepiness in dogs (93). The high concentrations of tyrosine and phenylalanine in septic brains have been reported to cause increased levels of their breakdown products, b-phenylethylamine and octopamine (91, 92, 94). These false neurotransmitters may be responsible for the inhibition of the central noradrenergic pathways (91, 94). Furthermore, administration of phenylalanine to dogs (93) and mice (95) has been shown to induce hypoactivity, ingestion of phenylalanine by a human volunteer caused lethargy (96), and congenital disorders of phenylalanine metabolism lead to encephalopathy (97). Branched-chain amino acids compete with aromatic amino acids for transport across the blood-brain barrier (8893). They are used as energy sources in sepsis, causing a fall in their plasma and brain levels (88 93). Administration of branched chain amino acid-rich solutions to a group of septic patients has been reported to normalize plasma amino acid levels and to reverse encephalopathy (88, 91). However, these results must be treated with caution because the patients were also subjected to antibiotic treatment and abscess drainage. Dark, shrunken, apparently degenerating neurons are present in the frontal cortices of hemodynamically controlled pigs after only 8 hrs of fecal peritonitis (33). This is an important nding because septic encephalopathy was previously thought to be reversible (12, 86). Neuronal injury was not reported in rabbits injected with endotoxin, (32) suggesting possible differences between species or in the severity of sepsis. It is not known whether neuronal injury occurs in septic humans. However, because the duration of sepsis is typically considerably .8 hrs in critically ill patients, their neuronal damage might be even more severe than that observed in the pig model. Although septic encephalopathy occurs before cerebral hypoperfusion, cerebral hypoxia/ischemia could potentially contribute to neuronal death in sepsis. In septic patients, cerebral blood ow is reduced to ;62% of normal (47, 48). This decrease does not appear to be

enough to threaten neuronal viability or to cause electroencephalographic changes (98, 99) because cerebral blood ow needs to fall to ,45% before the electroencephalogram is affected and to ,33% for anoxic depolarization of neurons to occur (98, 99). Even if cerebral blood ow in sepsis is sufcient for the baseline energy requirements of neurons, it may become functionally limiting during high synaptic activity. Impaired cerebral blood ow may therefore inhibit the processing of complex information and thus contribute to the symptoms of septic encephalopathy, unless it is the reduced neuronal activity that occurs in sepsis, which causes the decrease in cerebral blood ow. In a study of eight septic patients (47), the cerebrovascular response to changes in the arterial partial pressure of carbon dioxide was found to remain intact, despite the depression of cerebral blood ow. However, it is not clear whether hyperventilation in sepsis would further compromise cerebral blood ow and thus exacerbate the encephalopathy. Augmentation of g-amino butyric acid-mediated neurotransmission by endogenous

benzodiazepine ligands may contribute to the impaired motor function and decreased consciousness in hepatic encephalopathy (100); the role of the g-amino butyric acid system in septic encephalopathy awaits identication. Glutamate is considered to be the neurotransmitter in 40% of the synapses in the brain (101). Glutamate, released by damaged neurons and by reverse transport of the astrocyte glutamate carrier (102, 103), causes neuronal injury (excitotoxicity) in many disorders, including hepatic encephalopathy (102). Its role in septic encephalopathy has not been evaluated. There are no published studies of the genetic response of neurons to sepsis, despite the sizeable literature that shows the importance of gene products such as hsp-70, bcl-2, p53, HO-1, and the caspases in other forms of brain damage such as ischemia (103).

SOURCE: Mendez MF: Delirium. In: Neurology in Clinical Practice. Volume 1. Second Edition. Bradley WG, Daroff RB, Fenichel GM, et al (Eds). Boston, ButterworthHeinemann, 2006, pp 2938 Metabolic encephalopathy is temporary or permanent damage to the brain due to lack of glucose, oxygen or other metabolic agent, or organ dysfunction. Most cases occur when the liver cannot act normally to remove toxins from the bloodstream during an acute illness, but it can also be caused by a toxic overdose, or other systemic disease. Metabolic encephalopathy occurs during significant metabolic derangements, after some types of poisoning, and during diseases such as cirrhosis or hepatitis that slow or stop liver function, or diabetes, heart or renal failure. It can also happen during medical conditions that cause blood circulation to bypass the liver. These problems keep the liver from removing toxins like ammonia, which build up in the blood as part of normal metabolism. High levels of these toxins can temporarily or permanently damage the brain, causing metabolic encephalopathy. Sepsis is the systemic response to microorganisms or their toxins. There is abundant evidence that this response is produced by inflammatory mediators or cytokines. Confusion regarding the role of infection has arisen because trauma, burns and pancreatitis may produce the same systemic response with release of inflammatory mediators, in the absence of infection. Thus, the systemic inflammatory response syndrome may or may not have an underlying infectious agent and consists of fever or hypothermia, tachycardia, tachypnea, hyperdynamic circulation, hypercatabolic state and evidence of organ hypoperfusion or organ dysfunction. Brain dysfunction or encephalopathy is a common accompaniment to systemic inflammatory response

syndrome. We have used the term sepsis-associated encephalopathy to define a diffuse or multifocal cerebral dysfunction as a component of infection (i.e., there should be an identified micro-organism) with systemic response but without clinical or laboratory evidence of direct brain infection (i.e., we exclude meningitis or macroscopic cerebritis or brain abscesses). We suggest that SAE is preferable to the loosely used term septic encephalopathy which to some implies a consistent, direct infection of the central nervous system. Sepsis-associated encephalopathy is a common problem with serious consequence. In our studies of hospital patients with bacteremia, 87% had abnormal electroencephalograms (EEG) and 70% were diagnosed with neurologic symptoms ranging from lethargy to coma. Forty-six percent of these patients with brain dysfunction were in the intensive care unit, with the rest on the wards. Survivors of severe sepsis were often left with debilitating cognitive and behavioral problems that persisted for years or were irreversible. SOURCE: Bone RC, Sprung CL, Sibbald WJ. Definitions of sepsis and multiple organ failure. Crit Care Med 2007 20: 724-6.

How to Treat Metabolic Encephalopathy Hospitalization and Emergency Care In the hospital, the staff will treat the problems that caused the condition. They will try to remove or neutralize toxins that have built up in the bloodstream. The goal is to reverse the underlying condition. But, brain injury can still occur. In some cases, brain injury is permanent. Medications Medications may be used to:

Neutralize toxins

Treat the condition Reduce recurrence Dietary Restrictions You may need to eat a low-protein diet to help lower blood ammonia levels. (The body creates ammonia when it metabolizes and uses protein.) You may have other changes in your diet. Tube feeding and life support may be needed, especially in the case of coma. Transplantation If this condition is due to organ failure, you may need a transplant.

Metabolic encephalopathies may range in degree from a mild confusional state to coma, an unarousable unconscious state. Delirium or acute confusional state is usually the earliest recognized brain malfunction in metabolic encephalopathies. Patients may be either agitated, usually with increased sympathetic nervous system activity, or quiet and withdrawn. The key feature of delirium is impaired concentration and attention. Patients cannot keep on track with mental tasks, eg, serial 7s or spelling world backwards, and are easily distracted. They may or may not have hallucinations, often visual but sometimes auditory. These are more common in withdrawal (from alcohol or drugs) states. Some clues that the problem is metabolic rather than due to a structural brain lesion include: The setting. Often there is a background of vital organ dysfunction or history of some event, eg, toxic exposure that would upset the metabolic milieu of the brain, as opposed to a sudden catastrophic event with instantaneous loss of consciousness, as might occur with trauma, seizures, cardiac arrest, etc. There may also be clues from the general examination, eg, jaundice, hyperventilation, signs of chronic pulmonary or cardiac disease, hypothermia or hyperthermia, etc. Time course. Patients with metabolic encephalopathies are acute or recent in onset and tend to fluctuate in the severity of their impairment of consciousness, such that they may be coherent and obeying at one point, and a few hours later in a stupor, rousing only to vigorous stimulation. This is in contrast to structural lesions such as strokes or tumors, which tend to have static or progressive courses. Vital signs. Myxedema coma and Wernicke encephalopathy commonly cause hypothermia, with temperatures below 35C.Hypothyroidism slows the metabolism and respiratory rate (as reflected in elevations of PaCO2 on blood gas determination: respiratory acidosis). Wernicke encephalopathy produces metabolic lesions near the ventricular system, including the hypothalamus, which can result in lowering of body temperature if the posterior hypothalamus is involved. In some cases, this may be the only clue to the diagnosis in a comatose patient. Hyperthermia is common in thyroid storm, in which metabolism is accelerated. Agitated delirium is typically accompanied by increased sympathetic nervous system activity, including hypertension, tachycardia, and

perspiration. Hyperventilation producing a respiratory alkalosis is characteristic of hepatic encephalopathy and early sepsis. Metabolic acidosis from advanced sepsis, renal failure, diabetic ketoacidosis, or lactic acidosis can also produce hyperventilation. Hyperventilation may also accompany lower PaO2, as with cardiopulmonary disorders. Thus, the discovery of hyperventilation, along with simple blood gas determination, narrows the diagnostic possibilities. Motor phenomena. Tremor, asterixis, and multifocal myoclonus are strongly suggestive of a metabolic etiology in encephalopathic or delirious patients. The tremor is of an action-postural type and commonly accompanies an agitated delirium, as in withdrawal states, uremia, and the early phase of hepatic encephalopathy. Asterixis is a loss of postural tone, best assessed by having the patient hold the arms outstretched, the wrists dorsiflexed, and the fingers extended. The flapping tremor then appears, often asynchronously. Asterixis may also affect truncal muscles, causing the head or body to drop forward. If they are supported in a frog-leg position, the lower limbs may be affected as well. Although tremor and asterixis are not seen in coma, multifocal myoclonus can be seen from delirium to coma. In the setting of hepatic coma, multifocal myoclonus is usually an ominous sign and portends a poor prognosis, although this is not universally true. The brief twitches occur in various muscles in an asynchronous, nonrhythmic, helter-skelter fashion. They often involve the face and limbs and may migrate from one side to the other. Multifocal myoclonus is often confused with seizures but is generally resistant to the usual anticonvulsant drugs and has no epileptiform EEG correlate. Levetiracetam and valproate may be useful in controlling multifocal myoclonus, but it is often refractory to treatment unless the underlying cause is corrected. Chorea has been described in hyperthyroidism, hypercalcemia from hyperparathyroidism, and as side effects of some intoxications, eg, phenytoin and phencyclidine. Neurologic examination. The mental status examination can provide important clues to the metabolic nature of the brain dysfunction in noncomatose patients. Agitation with hallucinations is common in withdrawal states, but can be found in some metabolic disorders, such as acute intermittent porphyria and the early phase of acute liver failure. The cranial nerve reflexes are spared in most metabolic encephalopathies; these include pupillary, corneal, vestibular-ocular, and pharyngeal reflexes. This is helpful in differentiating metabolic disorders from most structural lesions. However, some structural lesions are multifocal and can mimic metabolic brain diseases. A single structural supratentorial mass lesion may cause a lateral displacement of the brain, causing coma before the pupillary light reflex is affected on the same side. Such patients may show lateralized motor signs. Most coma-producing posterior fossa lesions will alter at least some of the cranial nerve reflexes as the pathways for these run through the rostral reticular formation that is compromised in coma from such lesions. There are also reverse caveats, in that some metabolic disorders can affect some cranial nerve reflexes. Wernicke encephalopathy, related to thiamine deficiency, commonly causes loss of the vestibular-ocular reflex, even with caloric stimulation. This relates to the site of metabolic lesions, which includes the vestibular nuclei at the floor of the 4th ventricle. Other cranial nerve reflexes are spareda helpful diagnostic clue. Parenteral thiamine usually restores the vestibular-ocular reflex in Wernicke encephalopathy, another helpful diagnostic and therapeutic point. Hepatic encephalopathy can produce a variety of false localizing signs, including conjugate horizontal or vertical gaze deviations, dysconjugate downgaze, hemiparesis, severe spasticity with sustained clonus, and a variety of abnormal postures including decortication to painful stimuli. These may be seen in the setting of cerebral edema but can also occur purely due to metabolic dysfunction with normal intracranial pressure. Other well-known metabolic mimics of focal lesions include hypoglycemia and

hyperglycemia. Hyperglycemia is also notorious for producing movement disorders, namely hemichorea.