Sepsis is a disease process that unleashes a variety of host reactions to the infectious process including a systemic inflammatory response (SIR) characterized by the balance between proinflammatory and anti-inflammatory responses to the pathogen. The SIR is initiated by the release of bacterial lipopolysaccharides (LPS) and other microbial substances into the circulatory and lymphatic organs and triggers a systemic response which unchecked can progress to multiple organ failure with profound pulmonary, cardiovascular, renal, and GI sequelae with a mortality of up to 30%. Survivors of sepsis can have pervasive dyspnea, fatigue, depression, and alterations in Central nervous system (CNS) function ranging from inattention, concentration difficulties, memory loss, to global cognitive impairment. Septic encephalopathy (SE) refers to the cerebral dysfunction that results from sepsis and septic shock. Although the brain is sequestered from the rest of the body and the SIR by the blood brain barrier (BBB), the sequelae of SE have the potential to disturb CNS homeostatic mechanisms that control the host responses at various behavioral, neuroendocrine, and autonomic levels and adversely influence the course of sepsis and shock, and in turn the adaptive responses leading to perpetuation of the immune-inflammatory response and even homodynamic failure.
SE has been reported to occur in 8–70% of septic patients and is the most common form of encephalopathy among patients in intensive care units (ICUs). The reported variation in incidence probably reflects differing definitions of sepsis and encephalopathy. SE has been shown to be an independent predictor of death and is associated with a high mortality of 16–63%. No large-scale multicenter cohort studies have investigated the clinical signs and laboratory tests of so-called sepsis-associated delirium to allow an accurate estimate of its prevalence.
Immunocompromised states increase risk of infection and sepsis; structural brain abnormalities increase susceptibility to encephalopathy.
- The etiopathogenesis is clearly multifactorial with disturbances in the BBB and CNS microenvironment responsible for development of early or acute SE, and secondary sequelae of sepsis as dominant factors in late or chronic SE often in association with enhanced neurotoxicity of medications and nutritional deficiency.
- Early or acute SE: The BBB regulates brain capillary flow and maintains the internal microenvironment. Early in acute SE, breakdown of the BBB leads to disturbances of ionic homeostasis with entry of toxic metabolites and inflammatory cells that can lead to neuronal damage. Proinflammatory molecules such as tumor necrosis factor (TNF): α, interferon-γ, and products of complement activation are increased in the systemic circulation, along with heightened expression of intercellular adhesion molecule on microvessels in sepsis, and this could contribute to SE by increasing permeability of the BBB leading to edema, disruption of astrocyte endfeet, leukocyte recruitment with their entry into the brain leading to neuronal dysfunction and ultimately cell death. An excess of circulating nitric oxide (NO) in SE alters autoregulated cerebral blood flow (CBF) and disturbs the coupling between metabolism and CBF. NO reacts with superoxide molecules that produce the highly reactive nitrogen intermediate peroxynitrite that is toxic to neurons leading to neuronal energy failure. The rapid release of brain glutamate from astrocytes and neurons produces secondary NMDA receptor mediated excitotoxic death as well as induction of elevated levels of calcium, which promote further cellular injury. While the effects of local alteration in neurotransmitter systems remain unclear, those of the sympathetic nervous system have a role in the modulation of the SIR to sepsis, by β-adrenergic receptor activation by release of epinephrine which reduces the TNF-α release response to LPS, and enhances release of IL-10, reducing anti-inflammatory effects.
- Late or chronic SE: With sustained sepsis and evolving septic shock, the secondary sequelae of metabolic disarray, homodynamic and respiratory embarrassment, and multiple organ failure become dominant manifestations of late SE. Hepatic encephalopathy (HE) may be due to acute liver failure (type A), portal-systemic shunting in the absence of intrinsic hepatic disease (type B), and with cirrhosis and portal hypertension or portosystemic shunting (type C). There are four clinical stages with increasingly severe encephalopathy and neurological deficits ranging from lethargy, disorientation, amnesia, and confusion (stage 1), to somnolence (stage 2), stupor (stage 3), and coma (stage 4) with nystagmus, focal or generalized weakness, hyperreflexia, Babinski signs, and clonus. Correction of HE depends upon the inciting cause including treatment of dehydration, GI bleeding, limiting dietary protein, transjugular intrahepatic portosystemic shunt catheter placement, and measures to inhibit the absorption or production of ammonia.
- Uremic encephalopathy occurs with renal failure and varies in severity and speed of progression, with apathy, fatigue, irritability, and impaired concentration at onset, and marked confusion, disorientation, delusion, hallucinations, stupor and eventual coma, often in association with asterixis, focal or generalized twitching, hypertonicity, weakness, hyperreflexia, Babinski signs, clonus, and rarely meningeal signs, focal and generalized seizures.
- Pancreatic encephalopathy is associated with acute pancreatitis and elevation of the amylase level; there is no clear relationship between the latter and degree of encephalopathy. Clinical clues include severe upper abdominal pain, accompanied by nausea, vomiting, and fever. The impact of pancreatic encephalopathy has in large part been ascribed to activation of phospholipase A by trypsin and bile acid, which in turn converts lecithin and cephalin into their hemolytic forms, the latter of which can penetrate the BBB with CNS demyelination, hemorrhage, encephalomalacia, mitochondrial injury, impaired acetylcholine release, and edema due to heightened cytokine activation and increased vascular permeability. Unlike the insidious nature of hepatic and renal failure, electrolyte disturbances evolve in a rapid manner indicative of the severity of hypo- or hypernatremia, calcemia, magnesemia, and phosphatemia, all with varying degrees of encephalopathy and associated focal and generalized neurological deficits. Correction leads to prompt clinical improvement.
- Postmortem studies: 17 patients with fatal SE had postmortem studies revealing sterile microabscesses with active inflammation with associated central pontine myelinolysis, cerebral infarction, and varying fibrinoid necrosis of neighboring microvessels in 8 patients. Other postmortem findings have demonstrated proliferation of astrocytes and microglia.
- Drugs can result in varying encephalopathy, including benzodiazepines, narcotics, anticholinergics, cefepime, directly or secondarily due to enhanced neurotoxicity associated with increased permeability across a damaged BBB or reduced clearance in association with multiple organ insufficiency or failure.
- Malnutrition: Wernicke's encephalopathy is due to thiamine deficiency, which untreated, leads to profound encephalopathy and ultimately death. Anorexia followed by nausea, vomiting, ocular symptoms of diplopia, photophobia, and nystagmus, followed by cognitive impairment, sixth nerve palsy and complete ophthalmoplegia, memory loss, confabulation, and ataxia occur in the majority of severely affected patients, and predict the neuropathological sequelae of symmetrical shrinkage and discoloration of the mammillary bodies, periaqueductal gray, medial thalamus, superior and inferior colliculi and floor of the third ventricle, with symmetrical microscopic changes in other areas of the brainstem, fornix, and cerebellum. Although chronic alcoholism is the likeliest cause of thiamine deficiency in 90% of affected patients, protracted illnesses associated with vomiting, diarrhea, acute pancreatitis, and inflammatory bowel disease and malnutrition are important proximate causes. Replacement of thiamine is curative. Pellagra due to niacin deficiency presents with the triad of dermatitis, diarrhea, and dementia present altogether in a quarter of affected patients, which can progress to acute psychosis, delusions, hallucinations, encephalopathy, cogwheel rigidity, release phenomena of grasping, and suck reflexes. Although deficiency of niacin is the likeliest cause, several drugs can interfere with the metabolism/bioavailability of niacin, including isoniazid, azathioprine, 6-mercaptopurine, 5-fluorouracil, puromycin, chloramphenicol, and pyrazinamide; and patients with cancer, tuberculosis, and other systemic infections may have increased requirements for niacin leading to insidious deficiency, which when replaced or supplemented, can forestall later neurological sequelae.
