[EUS-FNA: how to improve biopsy results? An evidence based review]. / EUS-geführte Feinnadelbiopsie (EUS-FNP): Wie gelingen gute Biopsien? Eine evidenzbasierte Analyse.

Endosonography with fine-needle aspiration biopsy (EUS-FNA) has become a widespreadly available clinical tool to diagnose numerous different lesions in humans. EUS-FNA is frequently used for tissue-based diagnoses such as lymphatic diseases (ranging from tuberculosis / sarcoidosis to malignant lymphoma) or solid tumors (such as pancreatic carcinoma, neuroendocrine tumors, sub-epithelial gastrointestinal tumors and others). Outcomes of EUS-FNA results, however, vary which is caused by several different factors ranging from experience of the endoscopist over technical factors such as use of stylet or suction for puncture through the skills of the cyto-pathologist who takes care of the specimen obtained by EUS-FNA. Though introduced since more than 20 years ago EUS-FNA has still not yet been perfectionized and several issues remain controversial among endoscopist. These issues include needle size and type (FNA versus TNB needles), use of a stylet and suction for FNA sampling, pure cytologic assessment versus cyto-histologic techniques, grading of the investigator´s and pathologist´s experience and improvement of EUS training for novices. In this report we briefly review the actual literature and summarize the available evidence on some controversely discussed issues. The results support the view that use of a stylet rarely aids to increase the amount of tissue obtained during EUS-FNA, whereas use of suction can be helpful in certain situations. Novel cutting needles may potentially improve number and size of core biopsies that can be rendered for special histologic tissue processing techniques. An in-room-cytopathologist not necessarily improves outcome of EUS-FNA results but may have a role during build-up of EUS units to become more successful. EUS-FNA education requires skilled endoscopists on both sides and can presumably be improved by objective testing of practical expertise by peer review and introducing objective sampling parameters. Novel techniques and equipment are about to evolve in the near future.

A randomised phase II trial of the Polo-like kinase inhibitor BI 2536 in chemo-naïve patients with unresectable exocrine adenocarcinoma of the pancreas - a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network.

BACKGROUND: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. METHODS: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ≥ 2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ≥ 12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). RESULTS: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). CONCLUSION: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population.

[COVID-19 and endoscopy services]. / COVID-19 und Endoskopieeinheiten: Erfahrungen und Empfehlungen nach 2 Jahren Pandemie.

In 2020, the coronavirus pandemic initially led to a significant decrease in elective endoscopic examinations in Germany. The main reasons for this were the hard lockdown and the lack of personal protective equipment (PPE) and testing procedures. Since then, international recommendations from professional societies on infection control in endoscopy have been published. The extent to which these have been implemented in Germany is unclear: during the 2nd and 3rd waves in 2020/2021, most endoscopy units remained open and the level of adherence to international protection guidelines was high. A uniform "standard procedure" has not yet been published. The exact role and effectiveness of testing procedures to protect patients and staff during endoscopy was unknown, and reliable figures on staff and patient infections acquired/transmitted in endoscopy units in Germany were lacking. Thus, the most important finding of this work is the determined rate of coronavirus disease 2019 (COVID-19) in endoscopy facilities. The data show that the infection rate among staff in German clinics and practices in early 2021 averaged up to 5%; most of these were acquired in the private setting. Clinics with gastroenterological endoscopy units had significantly higher infection rates (10%) than, for example, dental and otolaryngology practices. This result indicates the need for continued PPE efforts. The most important factors for infection safety are fully vaccinated (or recovered) staff and patients, a decreasing prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the use of PPE and-although controversial-the consistent use of screening tests.

KRAS mutation in metastatic pancreatic ductal adenocarcinoma: results of a multicenter phase II study evaluating efficacy of cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line therapy.

BACKGROUND: Genetic alterations within the epidermal growth factor receptor (EGFR) pathway, including KRAS mutations, have been demonstrated to be associated with response to EGFR inhibitors like cetuximab in colorectal cancers. Mutations in the KRAS gene have been found in 70-90% of pancreatic cancers. Unfortunately, the addition of cetuximab to chemotherapy did not increase response or survival in patients with advanced pancreatic cancer in phase II and phase III studies. The aim of this study was to evaluate the relationship between KRAS mutations and response or survival in patients with metastatic pancreatic cancer treated with cetuximab plus chemotherapy. METHODS: Within a multicenter phase II trial, 64 patients with metastatic pancreatic cancer were treated with cetuximab in combination with gemcitabine and oxaliplatin until disease progression. Analyses of the EGFR pathway, including KRAS mutations, could be performed in 25 patients. Analyses were carried out following microdissection of the tumor. RESULTS: Fourteen (56%) of the 25 patients examined harbored a point mutation in codon 12 of the KRAS gene. No differences between the groups were noted in median progression-free survival (104 days in KRAS wild-type patients vs. 118 days in patients with KRAS mutations). Overall survival was longer in wild-type patients compared to patients with KRAS mutations (263 vs. 162 days), but the difference did not reach statistical significance. A further analysis of our clinical phase II trial showed that the presence of a rash was significantly correlated with overall survival. CONCLUSIONS: KRAS mutation in codon 12 may be associated with reduced survival compared to KRAS wild type. The role of KRAS mutations for cetuximab therapy in pancreatic cancer warrants further investigation in larger trials to exclude an epiphenomenon. Furthermore, the development of a rash is indicative of clinical benefit.

Prospective comparison of endoscopic ultrasound-guided fine-needle aspiration and surgical histology in upper gastrointestinal submucosal tumors.

STUDY AIM: To assess the accuracy of ultrasound-guided fine-needle aspiration biopsy in the differential diagnosis of gastrointestinal stroma cell tumors (GIST) from other submucosal tumors, using both cytology and histology. PATIENTS AND METHODS: We conducted a prospective study from May 2005 to September 2008 in all patients presenting with upper gastrointestinal submucosal tumors. Only patients in whom surgical resection was carried out were included in the final analysis. In cases of mesenchymal tumor, immunocytochemistry was attempted for further differentiation between GIST and non-GIST. Surgical histopathology served as the gold standard. RESULTS: A total of 47 patients were analyzable, with a final histologic diagnosis of 35 mesenchymal tumors. Sufficient tissue for conventional cytologic diagnosis was obtained only in the 35 patients with mesenchymal tumors; in this subgroup, immunocytochemistry was possible in 46 %. If and only if enough material was available for immunocytochemistry, the sensitivity for (correct recognition of) GIST tumors was 93 %. In all 12 patients with nonmesenchymal tumors and lesions, cytology was nondiagnostic and the diagnosis had to be based on clinical suspicion and the appearance on endoscopy and endoscopic ultrasound (EUS). On an intention-to-diagnose basis, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) had a positive predictive value for mesenchymal tumors of 100 %, but no value for the diagnosis of other lesions; using immunocytochemistry, a GIST tumor was recognized among the mesenchymal tumors with a sensitivity of 58 % and a specificity of 8 %. CONCLUSIONS: EUS-FNA-based cytology is safe and has only limited value for the differential diagnosis of submucosal tumors, mainly because insufficient material is harvested. Better tissue acquisition techniques are necessary for better differential diagnosis.

Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study.

Targeting the epidermal growth factor receptor pathway in pancreatic cancer seems to be an attractive therapeutic approach. This study assessed the efficacy of cetuximab plus the combination of gemcitabine/oxaliplatin in metastatic pancreatic cancer. Eligible subjects had histological or cytological diagnosis of metastatic pancreatic adenocarcinoma. The primary end point was response according to RECIST. Patients received cetuximab 400 mg m(-2) at first infusion followed by weekly 250 mg m(-2) combined with gemcitabine 1000 mg m(-2) as a 100 min infusion on day 1 and oxaliplatin 100 mg m(-2) as a 2-h infusion on day 2 every 2 weeks. Between January 2005 and August 2006, a total of 64 patients (22 women (34%), 42 men (66%); median age 64 years (range 31-78)) were enrolled at seven study centres. On October 2007, a total of 17 patients were alive. Sixty-two patients were evaluable for baseline and 61 for assessment of response to treatment in an intention-to-treat analysis. Six patients had an incomplete drug combination within the first cycle of the treatment plan (n=4 hypersensitivity reactions to the first cetuximab infusion, n=2 refused to continue therapy). Reported grade 3/4 toxicities (% of patients) were leukopaenia 15%, anaemia 8%, thrombocytopaenia 10%, diarrhoea 7%, nausea 18%, infection 18% and allergy 7%. Cetuximab-attributable skin reactions occurred as follows: grade 0: 20%, grade 1: 41%, grade 2: 30% and grade 3: 10%. The intention-to-treat analysis of 61 evaluable patients showed an overall response rate of 33%, including 1 (2%) complete and 19 (31%) partial remissions. There were 31% patients with stable and 36% with progressive disease or discontinuation of the therapy before re-staging. The presence of a grade 2 or higher skin rash was associated with a higher likelihood of achieving objective response. Median time to progression was 118 days, with a median overall survival of 213 days. A clinical benefit response was noted in 24 of the evaluable 61 patients (39%). The addition of cetuximab to the combination of gemcitabine and oxaliplatin is well tolerated but does not increase response or survival in patients with metastatic pancreatic cancer.

Systematic review: the safety and tolerability of pharmacological agents for treatment of irritable bowel syndrome--a European perspective.

AIM: To use an evidence-based approach to evaluate the safety and tolerability of the treatments available for irritable bowel syndrome (IBS), or in clinical development, in Europe. A separate review appraises the evidence for the efficacy of these therapies. METHODS: A literature search (for 1980 to 2005) was completed for all relevant clinical trial data and other articles which included safety information on the use of pharmacological IBS therapies. Clinical trials were scored according to the level of safety information, and adverse event incidence reported when possible. RESULTS: The tolerability of many of the agents used to treat IBS in Europe is poorly understood. However, serotonergic agents, such as tegaserod and alosetron, which are currently unavailable in Europe, have undergone rigorous assessment in IBS and their benefits have been established. Following initial marketing of alosetron for use in patients with IBS with diarrhoea, concerns about severe constipation and ischaemic colitis resulted in restriction of its use to women with severe IBS symptoms. This highlights the importance of post-marketing surveillance and post-marketing studies in refining the therapeutic indication of new IBS therapies, which will help to identify appropriate recipients for the drug and establish the impact of adverse reactions in clinical practice. CONCLUSIONS: There is a significant lack of data on the safety and tolerability of the therapies currently used routinely to treat IBS in Europe. The newer agents have undergone rigorous assessment, such that their benefits and risks in treating IBS are established. Defining their place among the spectrum of available therapies remains challenging when the benefits and risks of the older treatments are so poorly characterized.

Neurocardiac and cerebral responses evoked by esophageal vago-afferent stimulation in humans: effect of varying intensities.

OBJECTIVE: This study was designed to determine whether esophageal vago-afferent electrostimulation, over a wide range of stimulus intensities, can sustain a cardiac vago-efferent effect by way of central nervous system processing. METHODS: Studies were performed in ten healthy male subjects (23.9 +/- 6.3 years). Esophageal electrostimulation was carried out using a stimulating electrode placed in the distal esophagus. Stimulation of esophageal vago-afferent fibres was employed using electrical impulses (200 microseconds at 0.2 Hz x 128 s) varying from 2.7 to 20 mA. Respiratory frequencies, beat-to-beat heart rate autospectra and cerebral evoked potentials were recorded at baseline and at each stimulus intensity in random order. RESULTS: With esophageal electrical stimulation, we observed a small non-significant decrease in heart rate. There was a dramatic shift of the instantaneous heart rate power spectra towards enhanced cardiac vagal modulation with intensities as low as 5 mA. This effect was sustained throughout all intensities with no further change in either the low frequency or high frequency power. Conversely, there was a linear dose response relationship between cerebral evoked potential amplitude and stimulus intensity mainly occurring above perception threshold (10 mA). Esophageal stimulation had no significant effect on heart rate or respiratory frequency at any stimulus intensity. CONCLUSIONS: These results indicate that electrical stimulation of the distal esophagus across a wide range of current intensities elicits a reproducible shift in the heart rate power spectrum towards enhanced vagal modulation. The data suggest a closed loop afferent/efferent circuitry wherein tonic visceral afferent impulses appear to elicit a phasic or modulatory vago-efferent cardiac response in healthy subjects.

Pseudo-affective visceromotor responses and HPA axis activation following colorectal distension in rats with increased cholinergic sensitivity.

We analysed visceromotor (VMR) and corticosterone responses to colorectal stimuli under control conditions and following acoustic stress in rats selectively bred for increased sensitivity to cholinergic agonists, the Flinders Sensitive Line (FSL) rats, compared with Flinders Resistant Line (FRL) rats. FSL rats demonstrated a significant VMR response at the smallest distension pressure, whereas no response was evident in FRL controls. FSL rats also demonstrated enhanced VMR responses at both larger distension levels compared with FRL rats. Colorectal distension (CRD) produced significant increases in serum corticosterone levels, which were comparable in FRL and FSL. Noise stress induced divergent corticosterone responses in FRL and FSL, but did not affect VMR to CRD in either group. These data suggest that FSL rats show altered VMR responses to CRD and disturbed hypothalamic-pituitary-adrenal axis responses to acute stress.

The cerebral response to electrical stimuli in the oesophagus is altered by increasing stimulus frequencies.

Recording of cerebral evoked responses (EP) allows the assessment of visceral afferent pathways and gut-brain communication, but the optimal stimulation parameters remain to be established. The present study determined the optimal stimulation frequency of electrical stimulation of the oesophagus to elicit EP responses. In 13 healthy male volunteers (24.1 +/- 5.9 years), a 5 mm stainless-steel electrode was placed in the distal oesophagus for electrical stimulation (ES). EP were recorded from 21 scalp electrodes placed according to the 10/20 International system. ES (15 mA, 200 microseconds) were delivered in repeated series of 24 stimuli. Stimulus frequency was randomly altered in different series using a pseudologarithmic range (0.1, 0.2, 0.3, 0.5, and 1 Hz). Two series of stimuli were applied using each stimulation frequency. Two-dimensional topographic brain maps were created using interpolation techniques at each stimulation frequency. With increasing stimulus frequency, a significant and progressive decrease of EP amplitudes was observed between frequencies of 0.1 Hz and 1.0 Hz (P1/N2: 7.6 +/- 1.2 vs 1.4 +/- 0.3* microV, N2/P2: 17.2 +/- 1.7 vs 4.6 +/- 0.4* microV, P2/N3: 6.9 +/- 0.7 vs 4.2 +/- 0.5* microV; * = P < 0.05). In addition, there was a significant shortening of the mean peak latency of the intercalated P2 peak (P < 0.0005), with a similar trend for the P3 peak (P < 0.06), with increasing stimulus frequency from 0.1-1.0 Hz. Topographic brain maps localized the maximal early peaks (N1,P1.N2) in the paracentral cortical region (C3, Cz, C4), whereas the later peaks (P2 to P3) were symmetrically spread over the centroparietal and temporal regions (Cz, Pz, T5, T4). There was no difference in the cortical location of maximal EP amplitudes with increasing stimulus frequency. In conclusion, there is a clear relationship between stimulus frequency and amplitude of EP, suggesting rapid attenuation of the cerebral autonomic neural responses with increased electrical stimulation frequency. The effect of increased frequency on peak latencies suggests an alteration of stimulus processing in the thalamocortical region due to an altered perception of stimuli. Early EP peaks originate from basal structures of primarily the dominant hemisphere, while later peaks are localized in centroparietal cortical regions.

Cognitive evoked potentials to anticipated oesophageal stimulus in humans: quantitative assessment of the cognitive aspects of visceral perception.

Evoked potential studies provide an objective measure of the neural pathways involved with perception. The effects of cognitive factors, such as anticipation or awareness, on evoked potentials are not known. The aim was to compare the evoked potential response to oesophageal stimulation with the cortical activity associated with anticipation of the same stimulus. In 12 healthy men (23.5 +/- 4 years), oesophageal electrical stimulation (15 mA, 0.2 Hz, 0.2 msec) was applied, and the evoked potentials recorded using scalp electrodes. A computerized model of randomly skipped stimuli (4:1 ratio) was used to separately record the evoked potentials associated with stimulation and those associated with an anticipated stimulus. The electrical stimulus represented the nontarget stimulus and the skipped impulse the target (anticipatory) stimulus. This anticipatory evoked potential was also compared to auditory P300 evoked potentials. Reproducible evoked potentials and auditory P300 responses were elicited in all subjects. Anticipatory evoked potentials (peak latency 282.1 +/- 7.9 msec, amplitude 8.2 +/- 0.7 microV, P < 0.05 vs auditory P300 evoked potential) were obtained with the skipped stimulus. This anticipatory evoked potential was located frontocentrally, while the auditory P300 potential was located in the centro-parietal cortex. The anticipatory evoked potential associated with expectation of an oesophageal stimulus, although of similar latency to that of the auditory P300 evoked response, originates from a different cortical location. The recording of cognitive evoked potentials to an expected oesophageal stimulus depends on attention to, and awareness of, the actual stimulus. Anticipatory evoked potentials to GI stimuli may provide an objective electrophysiological tool for the assessment of the cognitive factors associated with visceral perception.

Abnormal cerebral processing of oesophageal stimuli in patients with noncardiac chest pain (NCCP).

In noncardiac chest pain (NCCP), altered visceral perception may result from abnormal cerebral processing of sensory input rather than abnormalities of afferent pathways. However, the interactions between symptoms, autonomic function and oesophageal stimuli are poorly studied. Oesophageal stimulation elicits reproducible cortical evoked potentials [CEP] and modulates heart rate variability via vagal pathways, as visible on power spectrum analysis of heart rate variability [PS-HRV]. These methods are increasingly used to study the function of visceral afferent neural pathways in human. The aim of this study was to compare EP and PS-HRV during oesophageal stimuli in NCCP and controls. Twelve healthy volunteers (one female, 11 male; aged 24-51 years; mean 32 +/- 8 years), and eight NCCP patients (three female, five male; age range 26-58, mean 40.5 +/- 10 years) were studied. Electrical oesophageal stimulation (EOS; 200 microseconds, 0.2 Hz, 25 stimuli) was applied to the oesophageal wall 5 cm above the lower oesophageal sphincter (LOS), and perception thresholds (measured in mA) determined. EP responses were recorded using 22 standard electroencephalogram scalp electrodes. Autonomic activity was assessed using PS-HRV, before, during, and after oesophageal stimulation. Measured PS-HRV indices included high frequency (HF; 0. 15-0.5 Hz) and low frequency (LF; 0.06-0.15 Hz) power, respectively, assessing vagal and sympathetic activity, and the LF/HF ratio. EOS perception occurred at lower thresholds in NCCP than in controls (3. 6 +/- 1 vs. 7.8 +/- 2 mA, P < 0.05). EP amplitude was greater (13 +/- 2 vs. 6 +/- 1 microV, P < 0.0001), and latency longer in controls vs. NCCP (191 +/- 7 ms vs. 219 +/- 6 ms, P < 0.001). In NCCP, EOS decreased sympathetic outflow (low frequency peak on PS-HRV) and increased cardiovagal activity (high frequency peak, P < 0.02) to a significantly higher degree in comparison with controls. During EOS, heart rate decreased in NCCP from 68 vs. 62 beats min-1 (P < 0.003) but not in controls. In NCCP patients, EOS was perceived at lower intensities and was associated with a greater cardiovagal reflex response. EP responses associated with EOS were smaller in NCCP than in controls, suggesting that an increased perception of oesophageal stimuli results from an enhanced cerebral processing of visceral sensory input in NCCP, rather than from hyperalgesic responses in visceral afferent pathways.

Cerebral evoked responses to gastrointestinal stimulation in humans.

Recent advances have permitted recording of evoked potentials (EPs) in response to electrical and mechanical stimulation of the gastrointestinal (GI) organs via methods used primarily in clinical neurophysiology. Current research involving stimulation of the esophagus, rectum, and colon, and recording the corresponding responses on the scalp, is being practiced in only a few laboratories. This review examines the engineering aspects of recording EPs, such as characteristics of the stimuli, placement of stimulus electrodes in the GI tract, and enhancement of evoked potential signals. We also discuss the physiological concepts involved in the generation of EPs, and how these compare with somatosensory evoked responses. Current experimental techniques employed by various investigators and results reported from their laboratories are compared. We believe that cerebral EPs to GI stimulation could be useful in studying a number of pathophysiological conditions such as gastroesophageal reflux disease, diffuse esophageal spasm, chronic inflammatory bowel disorders, chronic abdominal pain, and irritable bowel syndrome, among others. We hope that the present review will generate interest in the use of EPs arising out of GI stimulation, aiding in understanding their physiological implications in healthy subjects and in GI disorders.

Effects of esophageal stimulation in healthy subjects.

We studied the effects of esophageal electrical stimulation on heart rate variability power spectra (PS/HRV) and cortical evoked potentials (EPs) in healthy subjects. The intensity of stimulation was varied from 2.7 to 20 mA. We found that the amplitude of the cortical evoked potentials (amplitude of the N2/P2 peak) increased from 5.1 +/- 0.7 microV at 5 mA to 16.3 +/- 1.1 microV at 20 mA. The PS/HRV showed an increase in the vagal modulation of the sinus node. When the stimulation frequency was varied from 0.1 to 1 Hz at a constant intensity of 15 mA, the amplitude of cortical EPs (N2/P2 peak) decreased with increase in the frequency of stimulation (p < 0.05). The LF:HF ratio decreased significantly for all frequencies of stimulation (p < 0.005). An experimental paradigm to evoke the cognitive component in the cortical EPs yielded a peak around 354 ms following the stimulus.

Effects of esophageal stimulation in patients with functional disorders of the gastrointestinal tract.

We studied the effects of esophageal electrical stimulation on cortical-evoked potentials (EPs) and power spectrum of heart rate variability (PS/HRV) in patients with diabetes and non-cardiac chest pain (NCCP). We also recorded cognitive-evoked potentials (P300 EPs) in response to an odd-ball stimulation in patients with NCCP. Diabetic patients did not yield reproducible cortical EPs. Their power spectra of heart rate variability (PS/HRV) showed an increased vagal modulation during stimulation. In patients with NCCP the P300 EPs were of greater amplitude (17 +/- 3 microV vs. 12 +/- 1 microV in controls, p < 0.04), while peak latencies were slightly elongated in patients (382 +/- 22 ms vs. 354 +/- 12 ms in controls). The PS/HRV in these patients also showed an increased vagal modulation of the sinus node activity. Our results suggest the following: (1) in patients with diabetes, afferent pathways and processing of sensory signals are likely to be impaired; (2) an increased perception of esophageal stimulation reflects an exaggerated brainstem response and altered cortical processing of visceral sensation in patients with NCCP.

Brain electrical activity mapping of EEG for the diagnosis of (sub)clinical hepatic encephalopathy in chronic liver disease.

We studied the role of brain electrical activity mapping (BEAM) in the assessment of neuropsychiatric disturbances in 48 cirrhotic patients without clinical evidence of hepatic encephalopathy (no HE, n = 19), with subclinical HE (grade 0, denoting pathological psychometric tests, n = 13) and mild-to-moderate HE (grade I, n = 6; grade II, n = 10). Results were compared with 23 healthy controls. BEAM variables quantified were: (i) the peak frequency (PF); (ii) the amplitude of PF; and (iii) the topographic localization of the maximum peak amplitude digitized for quantification by using a coordinate system. Mean amplitudes and their topographic localization in the following frequency-bands were analysed: delta (1.0-3.5 Hz), theta (4.0-7.5 Hz), alpha 1 (8.0-9.5 Hz), alpha 2 (10.0-11.5 Hz), beta 1 (12.0-15.5 Hz), beta 2 (16.0-19.5 Hz), and beta 3 (20.0-23.5 Hz). The PF was significantly slower in all HE patients than in healthy controls (8.5 +/- 2.0 Hz v. 10.1 +/- 1.0 Hz, P< 0.001). Even in no HE, the PF was significantly slower than in controls (8.6 +/- 1.5 Hz v. 10.1 +/- 1.0 Hz, P< 0.01). No relevant topographic differences of PF were observed. The mean amplitudes of the following bands differed significantly between controls and patients: theta (increased in HE, P< 0.05), alpha 2 (decreased in HE, P< 0.05), and beta 2 and beta 3 (increased in HE, (P < 0.05). In HE patients, the topographic localization of all beta bands showed a significant shift from parieto-occipital areas to central areas of the cortex. We conclude that BEAM is a sensitive tool for detecting neuropsychiatric disturbances in cirrhotics with no HE and with subclinical HE. The combination of PF in the theta band, increased mean amplitude in the beta 2 band, and the localization of the latter band in the frontocentral area of the cortex is an objective and sensitive tool for identifying neuropsychiatric disturbances in 85% of cirrhotic patients with no HE. Further studies are required to determine the clinical implications of these abnormal findings in the absence of overt clinical symptoms.

Auditory event-related cerebral potentials (P300) in hepatic encephalopathy--topographic distribution and correlation with clinical and psychometric assessment.

BACKGROUND/AIMS: Early cognitive disturbances in patients with cirrhosis (Ci) are difficult to assess. Therefore, we evaluated the role of topographic auditory evoked cerebral potentials (P300-EP). METHODOLOGY: Prospective longitudinal study. SETTING: Tertiary clinical care institution. PARTICIPANTS: 45 patients with cirrhosis were compared to 22 healthy subjects. MAIN OUTCOME MEASURES: Hepatic Encephalopathy (HE) was assessed using the clinical grading, standardized psychometric tests, and auditory evoked P300-EP by multichannel EEG recordings. RESULTS: In the patients, the mean P300 peak latency was significantly increased (386.7 +/- 26.7 versus 318.6 +/- 22.2 ms in controls, p < 0.00001). Even in patients with cirrhosis but no HE (n = 18) the P300 peak latency was abnormally prolonged (> 384 ms) in 8 cases (44%). In addition, P180 peak latency was significantly longer in patients with liver cirrhosis as compared to controls (p = 0.021). The maximal P300 amplitude was significantly lowered in patients with liver cirrhosis in the frontocentral and central cortical regions (FZ: p < 0.008; Cz: p < 0.04). Liver function and etiology of liver disease were not related to the increased peak latencies of the P300 and P180 peaks. CONCLUSIONS: P300-EP is a sensitive measure to detect functional cognitive impairment in cirrhotic patients with subclinical HE and clinically apparent HE. Typical changes include latency prolongation and decreased central peak amplitude. Some 40% of patients with no clinical evidence of HE and normal psychometric tests show abnormal results during P300 testing, which is likely to reflect early impairment of cognitive function. Auditory evoked P300 potentials are more sensitive than psychometric testing alone.