Assessment of Cirrhotic Patients by the EncephalApp Fails to Predict Low-Grade Hepatic Encephalopathy.

INTRODUCTION: An early detection of low-grade hepatic encephalopathy (HE) is of high importance. The aim of the study was to compare a neuropsychological with a psychophysical test on the basis of the psychometric hepatic encephalopathy score (PHES) regarding effectiveness in diagnosing minimal HE (MHE). METHODS: In our prospective controlled observational study, we examined a total of 103 patients with liver cirrhosis for HE. The PHES, CFF, and EncephalApp were performed in all patients. Graduation was based on the result of the PHES. Patients without evidence for HE 1&2 according to the mental state (West-Haven criteria) with a PHES <-4 value points and no clinical symptoms were defined as having MHE. Patients were considered as HE0 when in the PHES none of the psychometric subtest results was abnormal or with a PHES ≥-4 value points. Patients with clinical symptoms were considered HE 1&2 patients. Different cut-off values were determined, and their specificity and sensitivity were calculated. RESULTS: Ninety-six of the involved patients had liver cirrhosis and 25 acted as a healthy control group. The ROC analysis for the classification resulted in an AUC of 0.806, with the highest Youden index for the cut-off time >224 s, for which the sensitivity was 82% and the specificity 75%. Cases of withdrawals were seen in 10.74% of all tested patients. CONCLUSION: The EncephalApp distinguishes well between HE0 and MHE but has its limitations in grading higher forms of HE. Diagnosis using only the EncephalApp is not sufficient.

Trichromatic critical flicker frequency as potential visual test in cataract and macula disease patients.

PURPOSE: To investigate the capacity of critical flicker frequency (CFF) in discriminating cataract eyes with or without macula disease using trichromatic flickers, and to develop a model to predict postoperative best corrected visual acuity (BCVA). METHODS: Patients were divided into two groups based on the presence or absence of macular disease. CFF threshold measurements of red (R-CFF), green (G-CFF), and yellow (Y-CFF) flickers were conducted both preoperatively and postoperatively. A generalized estimating equations model (GEE) was employed to examine the relationship between CFF threshold and 3-month postoperative BCVA. RESULTS: A total of 115 eyes were enrolled, with 59 eyes in the cataract alone group and 56 eyes in the cataract with macular disease group completing the follow-up. R-CFF was found to be consistent before and after cataract removal (P = 0.06), even in cases where OCT was not performed successfully (P > 0.05). Y-CFF showed the highest AUC (0.798) for differentiating ocular comorbidities. According to the GEE model, in patients with a CFF threshold below 26 Hz, the odds ratios for achieving a postoperative VA of 20/40 or better were 34.8% for R-CFF, 26.0% for G-CFF, and 24.5% for Y-CFF. CONCLUSION: CFF emerges as a promising tool for predicting postoperative BCVA, providing valuable supplementary insights when fundus examination is obstructed. R-CFF demonstrates the best resistance to cataracts, while Y-CFF exhibits the highest sensitivity both in identifying macular diseases and predicting postoperative BCVA of 20/40 or better.

Development and validation of the AMMON-OHE model to predict risk of overt hepatic encephalopathy occurrence in outpatients with cirrhosis.

BACKGROUND & AIMS: Neuropsychological and psychophysical tests are recommended to assess the risk of overt hepatic encephalopathy (OHE), but their accuracy is limited. Hyperammonaemia is central in the pathogenesis of OHE, but its predictive utility is unknown. In this study, we aimed to determine the role of neuropsychological or psychophysical tests and ammonia, and to develop a model (AMMON-OHE) to stratify the risk of subsequent OHE development in outpatients with cirrhosis. METHODS: This observational, prospective study included 426 outpatients without previous OHE from three liver units followed for a median of 2.5 years. Psychometric hepatic encephalopathy score (PHES) <-4 or critical flicker frequency (CFF) <39 was considered abnormal. Ammonia was normalized to upper limit of normal (AMM-ULN) at the respective reference laboratory. Multivariable frailty competing risk and random survival forest analyses were performed to predict future OHE and to develop the AMMON-OHE model. External validation was carried out using 267 and 381 patients from two independent units. RESULTS: Significant differences were found in time-to-OHE (log-rank p <0.001) according to PHES or CFF and ammonia, with the highest risk in patients with abnormal PHES plus high AMM-ULN (hazard ratio 4.4; 95% CI 2.4-8.1; p <0.001 compared with normal PHES and AMM-ULN). On multivariable analysis, AMM-ULN but not PHES or CFF was an independent predictor of the development of OHE (hazard ratio 1.4; 95% CI 1.1-1.9; p = 0.015). The AMMON-OHE model (sex, diabetes, albumin, creatinine and AMM-ULN) showed a C-index of 0.844 and 0.728 for the prediction of a first episode of OHE in two external validation cohorts. CONCLUSIONS: In this study, we developed and validated the AMMON-OHE model, comprising readily available clinical and biochemical variables that can be used to identify outpatients at the highest risk of developing a first episode of OHE. IMPACT AND IMPLICATIONS: In this study, we aimed to develop a model to predict which patients with cirrhosis are at risk of developing overt hepatic encephalopathy (OHE). Using data from three units and including 426 outpatients with cirrhosis, we developed the AMMON-OHE model - comprising sex, diabetes, albumin, creatinine and ammonia levels - which demonstrated good predictive ability. The AMMON-OHE model performs better than PHES and CFF to predict the first episode of OHE in outpatients with cirrhosis. This model was validated in 267 and 381 patients from two independent liver units. The AMMON-OHE model is available online for clinical use.

J-difference GABA-edited MRS reveals altered cerebello-thalamo-cortical metabolism in patients with hepatic encephalopathy.

Hepatic encephalopathy (HE) is a common neurological manifestation of liver cirrhosis and is characterized by an increase of ammonia in the brain accompanied by a disrupted neurotransmitter balance, including the GABAergic and glutamatergic systems. The aim of this study is to investigate metabolic abnormalities in the cerebello-thalamo-cortical system of HE patients using GABA-edited MRS and links between metabolite levels, disease severity, critical flicker frequency (CFF), motor performance scores, and blood ammonia levels. GABA-edited MRS was performed in 35 participants (16 controls, 19 HE patients) on a clinical 3 T MRI system. MRS voxels were placed in the right cerebellum, left thalamus, and left motor cortex. Levels of GABA+ and of other metabolites of interest (glutamine, glutamate, myo-inositol, glutathione, total choline, total NAA, and total creatine) were assessed. Group differences in metabolite levels and associations with clinical metrics were tested. GABA+ levels were significantly increased in the cerebellum of patients with HE. GABA+ levels in the motor cortex were significantly decreased in HE patients, and correlated with the CFF (r = 0.73; p < .05) and motor performance scores (r = -0.65; p < .05). Well-established HE-typical metabolite patterns (increased glutamine, decreased myo-inositol and total choline) were confirmed in all three regions and were closely linked to clinical metrics. In summary, our findings provide further evidence for alterations in the GABAergic system in the cerebellum and motor cortex in HE. These changes were accompanied by characteristic patterns of osmolytes and oxidative stress markers in the cerebello-thalamo-cortical system. These metabolic disturbances are a likely contributor to HE motor symptoms in HE. In patients with hepatic encephalopathy, GABA+ levels in the cerebello-thalamo-cortical loop are significantly increased in the cerebellum and significantly decreased in the motor cortex. GABA+ levels in the motor cortex strongly correlate with critical flicker frequency (CFF) and motor performance score (pegboard test tPEG), but not blood ammonia levels (NH3).

Performance of EncephalApp Stroop Test in Cirrhotic Patients for Evaluating Covert Hepatic Encephalopathy.

BACKGROUND: Covert hepatic encephalopathy (HE) is the mildest HE spectrum that is difficult to detect, but associated with significant decrease in quality of life. Currently, there is no gold standard to detect covert HE. EncephalApp Stroop Test as a newer diagnostic tool is easier, faster and its ease of availability in various health institutions is expected to be applied in Indonesia for covert HE detection. This study aimed to validate and test the reliability and diagnostic ability of EncephalApp Stroop Test to diagnose covert HE, compared to the Psychometric Hepatic Encephalopathy Score (PHES) and critical flicker frequency (CFF). METHODS: This study is a cross-sectional test, conducted from August to September 2018, targeted at patient with cirrhosis in Jakarta, to obtain Area Under The Curve (AUC), sensitivity, specificity, cut-off point, predictive value, likelihood ratio, and post-test probability of the EncephalApp Stroop Test, compared to PHES and CFF. The Validity and reliability tests were done before diagnostic study. Translation of the EncephalApp Stroop Test were first carried out using WHO protocol. All patients first underwent a Mini Mental State Examination and Ishihara Test to rule out color blindness. RESULTS: Thirty subjects participated in validity and reliability tests, and eighty in diagnostic tests. The translated application showed excellent internal consistency (Chronbach's Alpha of 0.942) and correlation coefficient of 0.82. The diagnostic study showed OnTime + OffTime as the best parameter (AUC: 0.897 (95% CI: 82.9% - 96.5%); sensitivity: 88.6%; specificity: 80%; positive predictive value (PPV): 0.77; negative predictive value (NPV): 0.9; positive likelihood ratio (LK+): 4.4; negative likelihood ratio (LK-): 1.4; positive post-test probability: 0,775; negative post-test probability: 0,1; and cut-off point ≥ 188.8 seconds. CONCLUSION: The EncephalApp Stroop Test is valid and reliable, with good AUC value, sensitivity, specificity, PPV, NPV and likelihood ratio in diagnosing covert hepatic encephalopathy in patients with cirrhosis in Indonesia.

Temporal vision: measures, mechanisms and meaning.

Time is largely a hidden variable in vision. It is the condition for seeing interesting things such as spatial forms and patterns, colours and movements in the external world, and yet is not meant to be noticed in itself. Temporal aspects of visual processing have received comparatively little attention in research. Temporal properties have been made explicit mainly in measurements of resolution and integration in simple tasks such as detection of spatially homogeneous flicker or light pulses of varying duration. Only through a mechanistic understanding of their basis in retinal photoreceptors and circuits can such measures guide modelling of natural vision in different species and illuminate functional and evolutionary trade-offs. Temporal vision research would benefit from bridging traditions that speak different languages. Towards that goal, I here review studies from the fields of human psychophysics, retinal physiology and neuroethology, with a focus on fundamental constraints set by early vision.

Evaluation of cerebral dysfunction in patients with chronic kidney disease using neuropsychometric and neurophysiological tests.

BACKGROUND: Uremic encephalopathy is defined as cerebral dysfunction due to toxin accumulation in patients with chronic kidney disease (CKD). This condition is characterized by subtle to florid symptoms, and its clinical course is always progressive when untreated but partially reversible with renal replacement therapy. While no test exists to measure subclinical uremic encephalopathy, two tests have been validated to measure minimal hepatic encephalopathy: the critical flicker frequency (CFF) test and the psychometric hepatic encephalopathy score (PHES). OBJECTIVE: To use CFF and PHES to measure the prevalence of cerebral dysfunction in individuals with CKD. METHODS: This cross-sectional study included a total of 69 patients with stage-5 CKD. Cutoff points for minimal encephalopathy were established using existing clinical guidelines: ≤39 Hz for CFF and < -4 for PHES. All participants were also screened for cognitive function and depression. RESULTS: Eighteen cases (26.1%) of cerebral dysfunction linked to uremic encephalopathy were detected with CFF, while twelve (17.4%) were detected by PHES; only six cases (8.7%) were diagnosed by both methods. Half of the cases (50%) had diabetes, and 61% were on hemodialysis. Cognitive function scores did not differ significantly between those receiving dialysis, hemodialysis, or no renal replacement therapy. CONCLUSIONS: It is essential to identify cerebral dysfunction when uremic encephalopathy is in early subclinical stages to reduce preventable events as traffic and work accidents.

Minimal Hepatic Encephalopathy in Patients with Alcohol Related and Non-alcoholic Steatohepatitis Related Cirrhosis by Psychometric Hepatic Cephalopathy Score and Critical Flicker Frequency.

BACKGROUND: alcohol may have additional neurotoxic ill-effects in patients with alcohol related cirrhosis apart from hepatic encephalopathy. We aimed to evaluate minimal hepatic encephalopathy (MHE) with Psychometric Hepatic Encephalopathy (PHES) score and Critical Flicker Frequency (CFF) in alcohol (ALD) and non-alcoholic steatohepatitis related (NASH) related cirrhosis. METHODS: 398 patients were screened between March 2016 and December 2018; of which 71 patients were included in ALD group and 69 in NASH group. All included patients underwent psychometric tests which included number connection test A and B (NCT-A and NCT-B), serial dot test (SDT), digit symbol test (DST), line tracing test (LTT) and CFF. MHE was diagnosed when their PHES was <-4. RESULTS: the prevalence of MHE was significantly higher in ALD group compared to NASH (69.01% vs 40.58%; P=0.007). The performance of individual psychometric tests was significantly poorer in ALD (P<0.05). Overall sensitivity and specificity of CFF was 76.62% (95%CI 65.59 - 85.52) and 46.03% (95%CI 33.39 - 59.06) respectively. Mean CFF was significantly lower in ALD than NASH (37.07 (SD 2.37) vs 39.05 (SD 2.40), P=0.001); also in presence of MHE (36.95 (SD 2.04) vs 37.96 (SD 1.87), P=0.033) and absence of MHE (37.34 (SD 3.01) vs 39.79 (SD 2.46), P=0.001). CONCLUSION: MHE is significantly more common in patients with ALD cirrhosis than NASH counterparts. Overall CFF values are less in alcohol related cirrhosis than NASH related cirrhosis, even in presence or absence of MHE. We recommend additional caution in managing MHE in ALD cirrhosis.

Impact of sustained viral response in the evolution of minimal hepatic encephalopathy: A prospective pilot study.

INTRODUCTION AND AIMS: To determine the prevalence of minimal hepatic encephalopathy(MHE) in patients with liver cirrhosis (LC) due to hepatitis C virus (HCV) infection and to evaluate the impact of sustained viral response (SVR) on MHE. MATERIALS AND METHODS: We performed a prospective study using MHE screening and follow-up on patients with HCV and LC. The patients were evaluated at the beginning of treatment and 24 weeks after treatment. RESULTS: 64 patients were included. 51.6% were male, the median age was 62 years, Child-Pugh classification A/B/C 93.8%/4.7%/1.6% and median MELD was 8.3. Prior hydropic decompensation was present in 11 patients. Median values of liver stiffness, as measured by transient elastography (TE) were 22.8kPa. Indirect signs of portal hypertension (PH) were present in 53.1% of patients, with a mean of 11.9mmHg among the ones with a measurement of the hepatic venous pressure gradient. The prevalence of MHE before treatment was 26.6%. After treatment, 98.4% of patients achieved SVR. The presence of MHE at 24 weeks post-treatment had an statistically significant association with the presence of pre-treatment MHE (80% vs. 21.6%; p<0.01), higher MELD scores at 24-weeks post-treatment (9.8 vs. 8; p=0.02), higher Child-Pugh scores at 24-weeks post-treatment (p=0.04), higher baseline INR levels (1.4 vs. 1.1; p<0.001) and with the presence of indirect signs of PH (100% vs. 47.1%; p=0.02). During follow-up, those patients without MHE at 24 weeks post-treatment had a higher probability of experiencing an improvement in post-treatment TE (80.9% vs. 40%, p=0.04). CONCLUSION: We found that SVR may lead to MHE resolution in a considerable proportion of patients, which has potential implications for disease prognosis.

Impact of Sustained Viral Response in the Evolution of Minimal Hepatic Encephalopathy: a Prospective Pilot Study.

INTRODUCTION AND AIMS: To determine the prevalence of minimal hepatic encephalopathy (MHE) in patients with liver cirrhosis (LC) due to hepatitis C virus (HCV) infection and to evaluate the impact of sustained viral response (SVR) on MHE. MATERIAL AND METHODS: We performed a prospective study using MHE screening and follow-up on patients with HCV and LC. The patients were evaluated at the beginning of treatment and 24 weeks after treatment. RESULTS: 64 patients were included. 51.6% were male, the median age was 62years, Child-Pugh classification A/B/C 93.8%/4.7%/1.6% and median MELD was 8.3. Prior hydropic decompensation was present in 11 patients. Median values of liver stiffness, as measured by transient elastography (TE) were 22.8 KPa. Indirect signs of portal hypertension (PH) were present in 53.1% of patients, with a mean of 11.9 mmHg among the ones with a measurement of the hepatic venous pressure gradient. The prevalence of MHE before treatment was 26.6%. After treatment, 98.4% of patients achieved SVR. The presence of MHE at 24weeks post-treatment had an statistically significant association with the presence of pre-treatment MHE (80% vs. 21.6%; p < 0.01), higher MELD scores at 24-weeks post-treatment (9.8 vs. 8; p = 0.02), higher Child-Pugh scores at 24-weeks post-treatment (p = 0.04), higher baseline INR levels (1.4 vs. 1.1; p < 0.001) and with the presence of indirect signs of PH (100% vs. 47.1%; p = 0.02). During follow-up, those patients without MHE at 24weeks post-treatment had a higher probability of experiencing an improvement in post-treatment TE (80.9% vs. 40%, p = 0.04). CONCLUSION: We found that SVR may lead to MHE resolution in a considerable proportion of patients, which has potential implications for disease prognosis.

Different responses of spontaneous and stimulus-related alpha activity to ambient luminance changes.

Alpha oscillations are particularly important in determining our percepts and have been implicated in fundamental brain functions. Oscillatory activity can be spontaneous or stimulus-related. Furthermore, stimulus-related responses can be phase- or non-phase-locked to the stimulus. Non-phase-locked (induced) activity can be identified as the average amplitude changes in response to a stimulation, while phase-locked activity can be measured via reverse-correlation techniques (echo function). However, the mechanisms and the functional roles of these oscillations are far from clear. Here, we investigated the effect of ambient luminance changes, known to dramatically modulate neural oscillations, on spontaneous and stimulus-related alpha. We investigated the effect of ambient luminance on EEG alpha during spontaneous human brain activity at rest (experiment 1) and during visual stimulation (experiment 2). Results show that spontaneous alpha amplitude increased by decreasing ambient luminance, while alpha frequency remained unaffected. In the second experiment, we found that under low-luminance viewing, the stimulus-related alpha amplitude was lower, and its frequency was slightly faster. These effects were evident in the phase-locked part of the alpha response (echo function), but weaker or absent in the induced (non-phase-locked) alpha responses. Finally, we explored the possible behavioural correlates of these modulations in a monocular critical flicker frequency task (experiment 3), finding that dark adaptation in the left eye decreased the temporal threshold of the right eye. Overall, we found that ambient luminance changes impact differently on spontaneous and stimulus-related alpha expression. We suggest that stimulus-related alpha activity is crucial in determining human temporal segmentation abilities.

Olfactory Function is Affected in Patients with Cirrhosis Depending on the Severity of Hepatic Encephalopathy.

INTRODUCTION AND AIM: Olfactory functions are altered to a variable degree by chronic liver disease. Few studies including only small populations of patients emphasized the possibility of hepatic encephalopathy (HE) influencing olfactory nervous tasks. So far, no study has explicitly focused on olfactory function depending on the severity of HE as assessed by objective diagnostic procedures. Thus we performed a study using the "Sniffin' Sticks" test system, critical flicker-fusion frequency (CFF) and clinical West Haven criteria. MATERIAL AND METHODS: 54 cirrhotic patients with liver cirrhosis were included. Furthermore, 43 adult volunteers participating as a non-cirrhotic control group. Olfactory testing was performed using the "Sniffin' Stick" test battery (Burghart Medizintechnik, Wedel, Germany) which renders a widely-used tool both in clinical and research settings for the assessment of olfactory threshold, odor identification and discrimination. Several complications of cirrhosis were diagnosed by reference methods. Statistical analysis of cirrhosis-associated complications and their relation to olfactory function was performed. Assessment of HE and classification of different stages were performed according to clinical criteria (West- Haven criteria) and according to CFF, which was determined using a portable analyzer. RESULTS: Olfactory function was significantly reduced in cirrhotic patients (in 61.1%) compared to controls (p < 0.001). Among cirrhotics patients, the prevalence of olfactory deficits (hyposmia, anosmia) increased with the severity of HE as assessed by CFF and clinical criteria (p = 0.008 and p = 0.097, respectively). No correlation was observed between olfactory deficits and severity of liver disease as assessed by Child-Pugh-Score, etiology of cirrhosis and complications of cirrhosis such as ascites and portal venous hypertension. CONCLUSIONS: Olfactory testing serves as a screening tool for HE and may facilitate grading of HE-severity.

Optimizing ERG Measures of Scotopic and Photopic Critical Flicker Frequency.

A visual response to flickering light requires complex retinal computation, and thus ERG measures are an excellent test of retinal circuit fidelity. Critical flicker frequency (CFF) is the frequency at which the retinal response is no longer modulated. Traditionally, CFF is obtained with a series of steady flicker stimuli with increasing frequencies. However, this method is slow and susceptible to experimental drift and/or adaptational effects. The current study compares the steady flicker method to CFF measurements obtained using a frequency sweep protocol. We introduce a light source programmed to produce a linear sweep of frequencies in a single trial. Using the traditional steady flicker method and a criterion response of 3 µV, we obtained a scotopic CFF of 18.4 ± 0.66 Hz and a photopic CFF of 44.4 ± 1.67 Hz. Our sweep flicker method, used on the same animals, produces a waveform best analyzed by Fourier transform; wherein a 6.18 log µV2 threshold was found to yield CFF values equal to those of the steady flicker method. Thus, the two flicker ERG techniques give comparable results, under both dark- and light-adapted conditions, and the flicker sweep method is faster to administer and analyze and may be less susceptible to blinking, breathing, and eye movement artifacts.

The performance of critical flicker frequency on determining of neurocognitive function loss in severe obstructive sleep apnea syndrome.

This study aimed to compare the critical flicker frequency (CFF) and the mail-in cognitive function screening instrument (MCFSI) tests' effectiveness in diagnosing neurocognitive function losses in patients having severe obstructive sleep apnea syndrome (OSAS). A total of 85 subjects (47 patients with a diagnosis of severe OSAS and 38 healthy controls) were included into the study. MCFSI scores greater than or equal to five and CFF scores less than 39 Hz were considered abnormal. Demographic and polysomnographic parameters of patients with OSAS were studied, and correlations between the MCFSI, CFF scores and Epworth Sleepiness Scale (ESS) scores were analysed. The mean age of the patients was 49.6 ± 12.0 years. In the OSAS group, the CFF score was found to be low when compared with the control group, while the MCFSI score was found to be high. Pathological CFF scores (<39) were found in 13 patients (27.7%) in the OSAS group, while pathological MCFSI scores (≥5) were found in 19 patients (40.4%). CFF scores were found to be low in only 26% of the patients with OSAS who were found to have high MCFSI scores. MCFSI scores were high in only 38% of the patients with OSAS who were found to have low CFF scores. There was a significant correlation between ESS and CFF scores. In conclusion, the usefulness of the CFF test in determining cognitive function loss in patients with OSAS needs to be demonstrated via studies which utilize a larger sample size.

A genetic variant in the promoter of phosphate-activated glutaminase is associated with hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy (HE) is a serious complication of liver cirrhosis. Recently, a microsatellite in the promoter region of the phosphate-activated glutaminase (GLS ) gene was associated with the risk of HE. The aim of the present study was to investigate, using the critical flicker frequency (CFF) test, whether the described GLS variant increases the risk of developing HE in patients with cirrhosis. METHODS: We recruited 158 patients (66% men; mean age 59 years, range 23-86) with liver cirrhosis. Mean model for end-stage liver disease score was 13.8 (range 5-35); 48% of patients presented with Child-Pugh score B or C. The presence and severity of HE were determined by the CFF test, with frequencies ≤39 Hz denoting cases. GLS variants were genotyped by sequencing the microsatellite in the promoter region and were classified as short, long or short-long forms (depending on the length of the macrosatellite alleles). RESULTS: In total, 53% of patients had abnormal CFF results (i.e. ≤39 Hz; range for entire cohort 26-57). The GLS microsatellite distribution amongst patients was short form (20%), long form (32%) and short-long form (48%) and was consistent with Hardy-Weinberg equilibrium. CFF values differed significantly between groups (P = 0.043). Carriers of the GLS long microsatellite had a significantly higher risk of HE according to multivariate analyses (odds ratio 3.23, 95% confidence interval 1.46-7.13, P = 0.004). CONCLUSION: CFF results were significantly lower amongst carriers of the GLS long microsatellite. Our findings support the role of the GLS long microsatellite in the development of HE; this could be important for identifying susceptible patients and for the prevention of this condition.

Patients with manifest hepatic encephalopathy can reveal impaired thermal perception.

OBJECTIVES: Previous evoked potential studies indicated central impairments of somatosensory function in patients suffering from hepatic encephalopathy (HE). The aim of this study was to quantify the somatosensory perception in patients with minimal and overt HE. MATERIALS AND METHODS: Forty-two patients with liver cirrhosis and HE up to grade 2 and 12 age-matched healthy controls underwent a comprehensive graduation of HE including the West Haven criteria, the critical flicker frequency (CFF), and neuropsychometric testing. Quantitative sensory testing, standardized by the German Research Network on Neuropathic Pain, was performed on both hands. RESULTS: Pain and mechanical detection thresholds were unchanged in HE. Tests of thermal processing revealed that patients with HE of grade 2 perceive cold at lower temperatures (cold detection threshold) and need a higher temperature difference to distinguish between warm and cold (thermal sensory limen). These impairments correlated with the CFF. A correction for attention deficits by performing partial correlations using neuropsychometric test results canceled these correlations. CONCLUSIONS: The present findings demonstrate an impairment of temperature perception in HE. The extent of this impairment correlates with HE severity as quantified by the CFF. The attenuation of the correlations after correction for attention deficits suggests a strong role of attention deficits for the impaired thermal perception. Thus, it provides initial evidence for a central impairment of thermal processing in HE due to alterations in high-level processes rather than due to peripheral neuropathic processes, which are a frequent complication in patients with liver cirrhosis.

Low visual cortex GABA levels in hepatic encephalopathy: links to blood ammonia, critical flicker frequency, and brain osmolytes.

The pathogenesis of hepatic encephalopathy (HE) is not fully understood yet. Hyperammonemia due to liver failure and subsequent disturbance of cerebral osmolytic balance is thought to play a pivotal role in the emergence of HE. The aim of this in-vivo MR spectroscopy study was to investigate the levels of γ-aminobutyric acid (GABA) and its correlations with clinical symptoms of HE, blood ammonia, critical flicker frequency, and osmolytic levels. Thirty patients with minimal HE or HE1 and 16 age-matched healthy controls underwent graduation of HE according to the West-Haven criteria and including the critical flicker frequency (CFF), neuropsychometric testing and blood testing. Edited proton magnetic resonance spectroscopy ((1)H MRS) was used to non-invasively measure the concentrations of GABA, glutamate (Glu), glutamine (Gln), and myo-inositol (mI) - all normalized to creatine (Cr) - in visual and sensorimotor cortex. GABA/Cr in the visual area was significantly decreased in mHE and HE1 patients and correlated both to the CFF (r = 0.401, P = 0.013) and blood ammonia levels (r = -0.434, P = 0.006). Visual GABA/Cr was also strongly linked to mI/Cr (r = 0.720, P < 0.001) and Gln/Cr (r = -0.699, P < 0.001). No group differences or correlations were found for GABA/Cr in the sensorimotor area. Hepatic encephalopathy is associated with a regional specific decrease of GABA levels in the visual cortex, while no changes were revealed for the sensorimotor cortex. Correlations of visual GABA/Cr with CFF, blood ammonia, and osmolytic regulators mI and Gln indicate that decreased visual GABA levels might contribute to HE symptoms, most likely as a consequence of hyperammonemia.

Orbital Decompression for Compressive Optic Neuropathy in Patients with a Metastatic Orbital Tumor from Breast Carcinoma.

We report two patients who underwent orbital decompression for compressive optic neuropathy due to a metastatic orbital tumor from breast cancer. One patient was a 47-year-old woman with right compressive optic neuropathy. Balanced orbital decompression was performed 11 days after her first visit. At postoperative week 1, her right visual acuity and critical flicker frequency value had improved from 0.1 and 20 Hz to 1.0 and 35 Hz, respectively, and good vision was maintained at 6 months postoperatively. The other patient was a 61-year-old woman with right compressive optic neuropathy. Medial orbital wall decompression was performed 5 days after her first visit. Her right visual acuity and critical flicker frequency values improved until 38 days after the surgery, from 0.5 and 19 Hz to 1.2 and 31 Hz, respectively, with stable good vision for the following 6 months.

An Arduino-Powered Device for the Study of White Perception beyond the Visual Chromatic Critical Flicker Fusion Frequency.

Arduino microcontrollers are used for a wide range of technological and biomedical applications, such as image classification, computer vision, brain-computer interaction and vision experiments. Here, we present a new cost-effective mini-device based on RGB LED flicker stimulation for the assessment of the chromatic temporal resolution of the visual function based on the concept of critical flicker fusion frequency (CFF). The assembly of the device and its testing in thirty young subjects demonstrate the steady white visual perception of a trichromatic flicker stimulus (mixture of red, green and blue stimuli) beyond the CFF. Macular function as measured by photo-stress recovery time (PRT) was found to be independent of the CFF measurements for red, green and blue lights. However, a statistical correlation was found between the contrast modulation for CFF for red and green stimuli and PRT. Finally, wavefront measurements demonstrate that high-order aberrations improve the temporal resolution of the visual function.

The slowed brain: cortical oscillatory activity in hepatic encephalopathy.

Oscillatory activity of the human brain has received growing interest as a key mechanism of large-scale integration across different brain regions. Besides a crucial role of oscillatory activity in the emergence of other neurological and psychiatric diseases, recent evidence indicates a key role in the pathophysiology of hepatic encephalopathy (HE). This review summarizes the current knowledge on pathological alterations of oscillatory brain activity in association with liver dysfunction and HE in the context of spontaneous brain activity, motor symptoms, sensory processing, and attention. The existing literature demonstrates a prominent slowing of the frequency of oscillatory activity as shown for spontaneous brain activity at rest, with respect to deficits of motor behavior and motor symptoms, and in the context of visual attention processes. The observed slowing extends across different subsystems of the brain and has been confirmed across different frequency bands, providing evidence for ubiquitous changes of oscillatory activity in HE. For example, the frequency of cortico-muscular coherence in HE patients appears at the frequency of the mini-asterixis (⩽12Hz), while cirrhotics without overt signs of HE show coherence similar to healthy subjects, i.e. at 13-30Hz. Interestingly, the so-called critical flicker frequency (CFF) as a measure of the processing of an oscillating visual stimulus has emerged as a useful tool to quantify HE disease severity, correlating with behavioral and neurophysiological alterations. Moreover, the CFF reliably distinguishes patients with manifest HE from cirrhotics without any signs of HE and healthy controls using a cut-off frequency of 39Hz. In conclusion, oscillatory activity is globally slowed in HE in close association with HE symptoms and disease severity. Although the underlying causal mechanisms are not yet understood, these results indicate that pathological changes of oscillatory activity play an important role in the pathophysiology of HE.