Liver disease is increasingly common, estimated to affect over 25% of the world's population. Failure of the liver to maintain a normal metabolic milieu leads to impaired brain function (hepatic encephalopathy), and conditions that cause liver disease can themselves predispose to neurological disease. As neurologists' involvement with the acute take increases, it is important that we are familiar with the neurological complications of liver disease, their investigation and management, and to know which other neurological diseases occur in this patient population. In this article, we review the causes, presentation and treatment of hepatic encephalopathy, and discuss important differential diagnoses in patients with liver disease who present with neurological disturbance.

To determine short-term outcomes of patients with alcohol-associated cirrhosis (ALC) admitted to the intensive care unit (ICU) compared with other etiologies of liver disease. In addition, we investigate whether quick sequential organ failure assessment accurately predicts presence of sepsis and in-hospital mortality in critically ill patients with various etiologies of cirrhosis.

A retrospective cohort of 1174 consecutive patients with cirrhosis admitted to the ICU between January of 2006 and December of 2015 was analyzed. Outcomes of interest included survival rates within the ICU, post-ICU in-hospital, or at 30 days post-ICU discharge.

Five hundred seventy-eight patients were found to have ALC with 596 in the non-ALC group. There was no significant difference in ICU mortality rates in ALC versus non-ALC cohorts (10.2% vs 11.7%, P=.40). However, patients with ALC had significantly higher post-ICU in-hospital death (10.0% vs 6.5%, P=.04) as well as higher mortality at 30-day post-ICU discharge (18.7% vs 11.2%, P<.001). Sustained alcohol abstinence did not offer survival advantage over nonabstinence. The predictive power for quick sequential organ failure assessment for sepsis and in-hospital mortality for patients with cirrhosis was limited.

Critically ill patients with ALC have decreased survival after ICU discharge compared with patients with other etiologies of cirrhosis, independent of alcohol abstinence.

Patients with liver cirrhosis are susceptible to infections due to various mechanisms, including abnormalities of humoral and cell-mediated immunity and occurrence of bacterial translocation from the intestine. Bacterial infections are common and represent a reason for progression to liver failure and increased mortality. Fungal infections, mainly caused by Candida spp., are often associated to delayed diagnosis and high mortality rates. High level of suspicion along with prompt diagnosis and treatment of infections are warranted. Bacterial and fungal infections negatively affect the outcomes of liver transplant candidates and recipients, causing disease progression among patients on the waiting list and increasing mortality, especially in the early post-transplant period. Abdominal, biliary tract, and bloodstream infections caused by Gram-negative bacteria [e.g., Enterobacteriaceae and Pseudomonas aeruginosa (P. aeruginosa)] and Staphylococcus spp. are commonly encountered in liver transplant recipients. Due to frequent exposure to broad-spectrum antibiotics, invasive procedures, and prolonged hospitalizations, these patients are especially at risk of developing infections caused by multidrug resistant bacteria. The increase in antimicrobial resistance hampers the choice of an adequate empiric therapy and warrants the knowledge of the local microbial epidemiology and the implementation of infection control measures. The main characteristics and the management of bacterial and fungal infections in patients with liver cirrhosis and liver transplant recipients are presented.

Alcohol-related liver disease (ALD) remains the most important cause of death due to alcohol. Infections, particularly bacterial infections, are one of the most frequent and severe complications of advanced ALDs, such as alcoholic cirrhosis and severe alcoholic hepatitis (sAH). The specific mechanisms responsible for this altered host defence are yet to be deciphered. The aim of the present study is to review the current knowledge of infectious complications in ALD and its pathophysiological mechanisms, distinguishing the role of alcohol consumption and the contribution of different forms of ALD. To date, corticosteroids are the only treatment with proven efficacy in sAH, but their impact on the occurrence of infections remains controversial. The combination of an altered host defence and corticosteroid treatment in sAH has been suggested as a cause of opportunistic fungal and viral infections. A high level of suspicion with systematic screening and prompt, adequate treatment are warranted to improve outcomes in these patients. Prophylactic or preemptive strategies in this high-risk population might be a preferable option, because of the high short-term mortality rate despite adequate therapies. However, these strategies should be assessed in well-designed trials before clinical implementation.

Longitudinal, population-based data on the occurrence, localization, and severity of bacterial infections over time in patients with alcoholic compared with nonalcoholic cirrhosis are limited.

All patients with incident cirrhosis diagnosed in 2001-2010 (area of 600,000 inhabitants) were retrospectively identified. All bacterial infections resulting in or occurring during an inpatient hospital episode during this period were registered. The etiology of cirrhosis (alcoholic vs. nonalcoholic), infection localization, and outcome as well as bacterial resistance patterns were analyzed. Patients were followed until death, transplant, or the end of 2011.

In all, 633 cirrhotics (363 alcoholic, 270 nonalcoholic) experienced a total of 398 infections (2276 patient-years). Among patients diagnosed with cirrhosis each year from 2001 to 2010, increasing trends were noted in the occurrence of infection (from 13 to 27%, P<0.001) and infection-related in-hospital mortality (from 2 to 7%, P=0.05), the latter mainly in the alcoholic group. Although alcoholic etiology was related to the occurrence of more frequent infection (Kaplan-Meier, P<0.001), this relationship was not significant after adjustment for confounders in Cox regression analysis (P=0.056). Resistance to piperacilin-tazobactam and carbapenems was more common in infections occurring in alcoholic versus nonalcoholic cirrhosis (13 vs. 5%, P=0.057 and 12 vs. 2%, P=0.009). Alcoholic etiology predicted pneumonia and infections caused by Gram-positive bacteria in multivariate analysis (P<0.05 for both).

In a population-based cirrhotic cohort, bacterial infections increased over time, which, in the case of alcoholic cirrhosis, was associated with pneumonia and bacterial resistance to antibiotics. However, alcoholic etiology was not related indepedently to the occurrence of bacterial infections.

Cirrhotic patients are immunocompromised with a high risk of infection. Proinflammatory cytokines and hemodynamic circulation derangement further facilitate the development of serious consequences of infections. Other than spontaneous bacterial peritonitis, bacteremia and bacterial infections of other organ systems are frequently observed. Gram-negative enteric bacteria are the most common causative organism. Other bacterial infections, such as enterococci, Vibrio spp., Aeromonas spp., Clostridium spp., Listeria monocytogenes, Plesiomonas shigelloides and Mycobacterium tuberculosis are more prevalent and more virulent. Generally, intravenous third generation cephalosporins are recommended as empirical antibiotic therapy. Increased incidences of gram-positive and drug-resistant organisms have been reported, particularly in hospital-acquired infections and in patients receiving quinolones prophylaxis. This review focuses upon epidemiology, microbiology, clinical features and treatment of infections in cirrhosis other than spontaneous bacterial peritonitis, including pathogen-specific and liver disease-specific issues.

This study aimed to analyze the clinical features, causative pathogens and therapeutic outcomes of bacterial meningitis in patients with liver cirrhosis.

Adult cirrhotic patients with community-acquired bacterial meningitis were evaluated. Clinical data were collected over a 22-year period. For comparison, the clinical features and therapeutic outcomes between patients with and without liver cirrhosis were analyzed.

Liver cirrhosis accounted for 11% (25/217) of the predisposing factors. Significant statistical analysis between the 2 groups (patients with and without liver cirrhosis) included median Glasgow Coma Scale score at presentation, presence of seizure, bacteremia and septic shock. The mean duration between arrival at the emergency room and confirmed diagnosis of bacterial meningitis was 39 hours (range, 2-240 hours). Ten (10/25, 40%) were initially diagnosed with bacterial meningitis, and 6 (6/25, 24%) were initially suggested as having infection of unknown origin. In this study, Klebsiella pneumoniae was the most frequent causative pathogen in patients with liver cirrhosis. The overall case fatality rates for patients with and without liver cirrhosis were 38.5% (74/192) and 64% (16/25), respectively.

Patients with liver cirrhosis have a more fulminant course with a higher prevalence of disturbed consciousness, bacteremia, seizure and shock. Diagnosis and effective treatment ARE often delayed, resulting in high overall mortality. When patients with liver cirrhosis develop disturbed consciousness, seizures and septicemia, immediate neuroimaging and cerebrospinal fluid studies should be undertaken to determine bacterial meningitis. Early diagnosis and treatment are essential for survival.

Patients with cirrhosis of liver are at risk of developing serious bacterial infections due to altered immune defenses. Despite the widespread use of broad spectrum antibiotics, bacterial infection is responsible for up to a quarter of the deaths of patients with liver disease. Cirrhotic patients with gastrointestinal bleed have a considerably higher incidence of bacterial infections particularly spontaneous bacterial peritonitis. High index of suspicion is required to identify infections at an early stage in the absence of classical signs and symptoms. Energetic use of antibacterial treatment and supportive care has decreased the morbidity and mortality over the years; however, use of antibiotics has to be judicious, as their indiscriminate use can lead to antibiotic resistance with potentially disastrous consequences. Preventive strategies are still in evolution and involve use of antibiotic prophylaxis in patients with gastrointestinal bleeding and spontaneous bacterial infections and selective decontamination of the gut and oropharynx.

To analyze the mortality risk factors in cirrhotic patients with bacterial meningitis (BM).

Cirrhotic patients are susceptible to infections. Despite its high mortality rate, BM has not been extensively studied in this group of patients.

BM patients diagnosed with cirrhosis, between 1987 and 2008, were studied. BM was defined as the presence of signs or symptoms of meningitis and a cerebrospinal fluid (CSF) leukocyte count >100/mm3 or the presence of bacteria in CSF.

We identified 4955 infections among 7591 cirrhotic patients; 12 (0.2%) had BM. The mean age at diagnosis was 60±16 years. Abnormal mental status (83%), fever (67%), and neck stiffness (67%) were the most frequent clinical presentations. The sensitivity of CSF culture was 75% (Streptococcus pneumoniae, 2; Staphylococcus aureus, 2; Listeria monocytogenes, 1; Group B Streptococcus, 1; Streptococcus agalactiae, 1; Streptococcus bovis, 1; and Escherichia coli, 1), and its correlation with blood culture was 78%. Five patients died. On admission, the serum creatinine level was 1.63±0.93 mg/dL. A serum creatinine level ≥1.3 mg/dL was associated with increased mortality (P=0.028). The model for end-stage liver disease score, gastrointestinal bleeding, bilirubin level >3.5 mg/dL, hepatic encephalopathy, diabetes mellitus, and results of cytology and biochemistry tests of CSF were not associated with mortality.

BM in cirrhotic patients is associated with a high mortality rate. The clinical and microbiologic features of BM in cirrhotic patients differ from those in the general population. A serum creatinine level ≥1.3 mg/dL on admission is associated with a higher risk of mortality.

A staged prognostic model of cirrhosis based on varices, ascites, and bleeding has been proposed. We analyzed data on infections in patients with cirrhosis to determine whether it is also a prognostic factor.

Studies were identified by MEDLINE, EMBASE, COCHRANE, and ISI Web of Science searches (1978-2009); search terms included sepsis, infection, mortality, and cirrhosis. Studies (n = 178) reporting more than 10 patients and mortality data were evaluated (225 cohorts, 11,987 patients). Mortality after 1, 3, and 12 months was compared with severity, site, microbial cause of infection, etiology of cirrhosis, and publication year. Pooled odds ratio of death was compared for infected versus noninfected groups (18 cohorts, 2317 patients).

Overall median mortality of infected patients was 38%: 30.3% at 1 month and 63% at 12 months. Pooled odds ratio for death of infected versus noninfected patients was 3.75 (95% confidence interval, 2.12-4.23). In 101 studies that reported spontaneous bacterial peritonitis (7062 patients), the median mortality was 43.7%: 31.5% at 1 month and 66.2% at 12 months. In 30 studies that reported bacteremia (1437 patients), the median mortality rate was 42.2%. Mortality before 2000 was 47.7% and after 2000 was 32.3% (P = .023); mortality was reduced only at 30 days after spontaneous bacterial peritonitis (49% vs 31.5%; P = .005).

In patients with cirrhosis, infections increase mortality 4-fold; 30% of patients die within 1 month after infection and another 30% die by 1 year. Prospective studies with prolonged follow-up evaluation and to evaluate preventative strategies are needed.

To identify to what degree in-hospital delay of antibiotic therapy correlated to outcome in community acquired bacterial meningitis.

All cases of culture-positive cerebrospinal fluids in east Denmark from 2002 to 2004 were included. Medical records were collected retrospectively with 98.4% case completeness. Glasgow Outcome Scale was used. Multiple regression outcome analyses included the hypothesised factors: delay of therapy, age, bacterial aetiology, adjuvant steroid therapy, coma at admission and the presence of risk factors.

One hundred and eighty seven cases were included. Adult mortality was 33% and the proportion of unfavourable outcome in adults was 52%, which differed significantly from that of children (<18 years) with a mortality of 3% (OR=15.8, 95% confidence interval: 3.7-67.6) and an unfavourable outcome of 14% (OR=12.7, CI: 4.3-37.2). Delay of antibiotic therapy correlated independently to unfavourable outcome (OR=1.09/h, CI: 1.01-1.19) among the 125 adult cases. In the group of adults receiving adequate antibiotic therapy within 12h (n=109), the independent correlation between antibiotic delay and unfavourable outcome was even more prominent (OR=1.30/h, CI: 1.08-1.57). The median delay to the first dose of adequate antibiotics was 1h and 39min (1h and 14min in children vs. 2h in adults, p<0.01), and treatment delay exceeded 2h in 21-37% of the cases with clinically evident meningitis.

The delay in antibiotic therapy correlated independently to unfavourable outcome. The odds for unfavourable outcome may increase by up to 30% per hour of treatment delay.

The Hospital Universitari de Bellvitge (Barcelona, Spain) records all cases of bacterial meningitis in a 120-variable database. The characteristics of bacterial meningitis in cirrhotic patients are not well-known, and all cases of community-acquired bacterial meningitis occurring in cirrhotic patients were therefore identified. During 1977-2002, there were 602 episodes of community-acquired bacterial meningitis in adults, of which 29 (4.8%) occurred in cirrhotic patients. Compared to non-cirrhotic patients, there were significant differences in: duration of disease for >4 days at the time of diagnosis; absence of nuchal rigidity; certain aetiologies, e.g., Escherichia coli and Listeria monocytogenes; renal and liver function impairment; relapse of fever; and incidence of relapse and mortality. Overall, bacterial meningitis in cirrhotic patients was associated with a high mortality rate and a large number of complications. A high index of suspicion is necessary because of the frequent absence of meningeal signs. In addition to the classic meningeal pathogens, other aetiologies, including E. coli and L. monocytogenes, should be considered when prescribing empirical therapy.

Bacterial infections are acknowledged causes of morbidity and mortality in cirrhotic patients; yet, apart from spontaneous bacterial peritonitis, other infection issues have been understudied. We evaluated the existing medical data on infectious risks and related preventive and treatment data for cirrhotic patients.

Medical literature search through MEDLINE, using a variety of keywords focused on: (a) immunodeficiency parameters of cirrhosis and attempts at therapeutic reversal, (b) relative incidence of various focal infections and implications for prevention, and (c) specific pathogens posing a risk in cirrhosis and availability of preventive strategies.

Immunodeficiency in cirrhosis is multifactorial and might not be reversed by isolated interventions. Epidemiologic data on the incidence of specific infections and risk factors are scarce, only Child-Pugh stage C being a common denominator. A variety of common, such as Staphylococcus aureus, Streptococcus pneumoniae, and Mycobacterium tuberculosis, as well as uncommon pathogens possess significant risks in cirrhosis. Certain aspects of these risks remain though unrecognized.

To better understand the overall burden of bacterial infections on cirrhotic patients' survival, more data on preventive efficacy of pneumococcal vaccination, on the overall burden of tuberculosis, and the relative incidence of specific infections as endocarditis are warranted.

Patients who have liver cirrhosis are at increased risk of bacterial infections, such as bacteremia, meningitis, pneumonia, urinary tract infections, and spontaneous bacterial peritonitis, due to immunodeficiency associated with the severity of the cirrhosis. Although bacterial infections are frequent in cirrhotic patients, only isolated cases of brain abscess have been reported. In these cirrhotic patients, the initial presentation of brain abscess may not be fever or leukocytosis, but focal neurologic deficits. In addition, for consideration of blood-brain barrier penetration, the anti-biotic choice postoperatively is also quite different from other infections outside the central nervous system. We will discuss two cases of brain abscess in cirrhotic patients with special emphasis on the clinical presentation, magnetic resonance spectroscopic findings, organism encountered, therapeutic strategy, and prognosis.

Alcohol abuse adversely affects essentially all the organs of the body, either directly or indirectly. Ethanol may contribute to brain damage via inflammation. Ethanol may also alter CNS immunocompetence and further the progression of certain CNS infections. Nuclear factor (NF)-kappa B helps regulate inflammatory gene expression in glia. It is possible that ethanol effects on CNS pathology are partly a consequence of ethanol modulation of NF-kappa B-associated pathways in glia. We have assessed the effects of 0.5-6 h ethanol exposure on cytokine (5 ng/ml interleukin-1 beta + 100 ng/ml interferon gamma + 30 ng/ml tumor necrosis factor-alpha)-induced NF-kappa B activation in human A172 astroglial cells. Immunoblot analysis indicated that NF-kappa B p65 nuclear translocation occurred within 0.5 h after cytokine stimulation. Stimulation in the presence of ethanol resulted in increased nuclear p65 levels at 3 h, with 200 mM causing a greater increase than 50 mM ethanol. Gel shift assay data suggested that cytokine-induced NF-kappa B binding activity was greatest in cells exposed to 50 mM ethanol, followed by 200 and 0 mM ethanol exposed cells, respectively. Thus, in cytokine-stimulated cells, 200 mM ethanol resulted in greater nuclear p65 levels, yet, 50 mM ethanol exposure resulted in more pronounced DNA binding by NF-kappa B. These findings demonstrate that acute ethanol enhances p65 activity in human astroglia and further support the hypothesis that ethanol-mediated brain pathology involves modulation of NF-kappa B pathways. A better understanding of the mechanistic events involved in ethanol-induced CNS pathology should provide for therapeutic strategies to combat detrimental effects of alcohol on the CNS.

Multiple Escherichia coli isolates from four adults with extraintestinal infections underwent molecular phylotyping and virulence profiling. A patient with secondary peritonitis had two low-virulence E. coli strains from phylogenetic groups A and D. In contrast, three patients with invasive extraurinary infections (septic arthritis/pyomyositis, nontraumatic meningitis/hematogenous osteomyelitis, and pneumonia) each had a single high-virulence phylogenetic group B2 strain resembling typical isolates causing urinary infection and/or sepsis, i.e., extraintestinal pathogenic E. coli.