article: Portal-systemic encephalopathy (PSE) is classified as type B hepatic encephalopathy. Portal-systemic shunting rather than liver dysfunction is the main cause of PSE in chronic hepatic schistosomiasis japonicum (HSJ) patients. Owing to lack of detectable evidence of intrinsic liver disease, chronic HSJ patients with PSE are frequently clinically undetected or misdiagnosed, especially chronic HSJ patients with covert PSE (subclinical encephalopathy). In this study, we investigated whether magnetic resonance spectroscopy (MRS) could be a useful tool for diagnosing PSE in chronic HSJ patients. Magnetic resonance (MR) T1-weighted imaging, diffusion-weighted imaging, and MRS were performed in 41 chronic HSJ patients with suspected PSE and in 21 age-matched controls. The T1 signal intensity index (T1SI) and apparent diffusion coefficient (ADC) value were obtained in the Globus pallidus. Liver function was also investigated via serum ammonia and liver function tests. Higher T1SI and ADC values, increased lactate and glutamine levels, and decreased myo-inositol were found in the bilateral Globus pallidus in chronic HSJ patients with PSE. No significantly abnormal serum ammonia or liver function tests were observed in chronic HSJ patients with PSE. On the basis of these findings, we propose a diagnostic procedure for PSE in chronic HSJ patients. This study reveals that MRS can be useful for diagnosing PSE in chronic HSJ patients.
  Portal-systemic shunting is formed subsequent to portal hypertension, which is a common occurrence in patients with liver cirrhosis and can lead to neuropsychiatric abnormalities [1,2]. Portal-systemic encephalopathy (PSE) is classified as type B hepatic encephalopathy, which is an important complication of chronic liver cirrhosis and/or portal-systemic shunting [2,3]. Portal-systemic shunting is the main cause of PSE in hepatic schistosomiasis japonicum (HSJ) patients [4]. These patients were infected with Schistosoma japonicum many years previously, resulting in hepatopathy of varying severity at that time. Although the active HSJ was completely cured, one of the sequelae, i. e. , portal-systemic shunting persisted. These allegedly cured chronic HSJ patients lack biochemical evidence of intrinsic liver disease [5]; consequently, they do not receive suitable clinical management. Therefore, many patients develop PSE due to the portal-systemic shunting, which is frequently misdiagnosed as dementia, depression, or other psychiatric disorder [1]. Furthermore, chronic HSJ patients with covert PSE are usually clinically undetectable [1,6]. The pathophysiology of PSE is not completely understood. It appears to be similar to hepatic encephalopathy, in which elevated ammonia and brain edema are widely recognized as the significant changes [7]. Magnetic resonance spectroscopy (MRS) has been used to detect abnormal metabolism in the brain. Previous studies showed increased glutamine levels in patients with hepatic encephalopathy [6,8]. Recently, abnormal oxidation and carbohydrate fermentation were also found [9,10]. However, to the best of our knowledge, no studies have investigated changes in brain metabolism in PSE. In this study, we used MRS as a noninvasive tool to detect metabolic abnormalities in the brains of chronic HSJ patients with PSE. Further, the goals of this study were to propose an appropriate diagnostic procedure for PSE in chronic HSJ patients.
  This study was approved by the Institutional Review Board of Jinshan Hospital, and written informed consent was obtained in all cases prior to magnetic resonance imaging (MRI) and laboratory tests. From August 2014 to April 2016,151 consecutive chronic HSJ patients were recruited from the gastroenterology department of Jinshan Hospital. Chronic HSJ was diagnosed on the basis of a history of schistosomiasis and typical liver CT (linear hyper dense calcifications) or ultrasonic findings (linear strong echoes) [11]. The diagnosis of portal-systemic shunting was based on abdominal CT scanning for abnormal shunting vessels [12]. Thirteen shunting vessels were identified, namely, coronary, gastroepiploic, esophageal, para-esophageal, short gastric, peri splenic, splenorenal, gastrorenal, paraumbilical, abdominal wall vein, retroperitoneal-paravertebral, mesenteric, and omental vessels. Overt PSE was diagnosed on the basis of clinical symptoms and conventional neurological examinations. Covert PSE was diagnosed using the Digit Symbol Test (DST) and Number Connection Test A (NCT-A). Patients with test scores greater than two standard deviations were considered as covert PSE [13]. The exclusion criteria were as follows: liver cirrhotic patients (n = 73), history of alcoholism (n = 8), hepatocellular carcinoma (n = 11), patients using any drugs having liver (n = 2) or central nervous system toxicity (n = 3), and patients with total parenteral nutrition (n = 1). Patients unable to complete the MRI or MRS scanning (n = 5) and patients unable to complete the neuropsychological tests (n = 7) were also excluded. Finally, 41 patients were evaluated (25 males, 16 females; aged 49 to 87 years; mean, 67. 2 ± 9. 1 years) and divided into three groups according to the diagnostic criteria: non-PSE (n = 10), covert PSE (n = 12), and overt PSE (n = 19). Twenty-one age-matched healthy volunteers served as controls. These volunteers were recruited from the local population attending for routine physical examination (12 males, 9 females; aged 48 to 81 years; mean, 63. 1 ± 9. 9 years). After 6 to 8 hours of fasting, blood samples were collected on the same day prior to MRI scanning. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), direct bilirubin (DB), prothrombin time (PT), albumin, and plasma ammonia tests were performed in all patients to evaluate liver function. Whole blood manganese was also measured. All the liver function tests were also performed in the controls. MRI was performed on a 3. 0-Tesla scanner (Verio, Siemens, Erlangen, Germany). First, an axial spin-echo T1-weighted imaging (T1WI), a diffusion-weighted imaging (DWI) with a simultaneously generated apparent diffusion coefficient (ADC) map were performed. Then, a multi-voxel MRS was performed using a point-resolved spectroscopy (PRESS) sequence with TR of 2000 ms, TE of 30 ms, and FOV of 10 cm × 10 cm. After automatic shimming, the spectral acquisition was performed with 256 averages. All the data were processed on a workstation using the MR manufacturer’s software. A 0. 2 cm2-sized region of interest (ROI) was placed in the bilateral Globus pallidus on TIWI and ADC map. T1 signal intensity index (T1SI) and ADC value were measured three times and averaged. T1SI were calculated as follows: mean signal intensity divided by standard deviation (SD) of noise. Spectral reconstruction was performed and spectral quality was assessed by measuring the full-width half maximum. The signal-to-noise ratio was considered acceptable when the amplitude of metabolite peaks was three times greater than that of the background noise. The resonance peak integrals of lactate (Lac, 1. 33 ppm), N-acetyl aspartate (NAA, 2. 01 ppm), glutamine (Glx, 2. 15–2. 45ppm), creatine (Cr, 3. 02 ppm), choline (Cho, 3. 22 ppm), and myo-inositol (mI, 3. 55 ppm) were obtained. Cr peak was used as an internal reference, and the ratios of Lac/Cr, NAA/Cr, Glx/Cr, Cho/Cr, and mI/Cr were calculated. The sample size was estimated using a clinical research sample size calculator (CRESS V1. 3). Statistical analyses were performed using SPSS 16. 0 for Windows (SPSS Inc. , Chicago, IL, USA). A nonparametric Kruskal-Wallis H-test was used to evaluate the differences in the ADC value and TISI among groups. One way ANOVA with a Bonferroni correction was used for liver function tests and metabolite ratios among groups. All values are represented as the mean ± standard deviation. A p value less than 0. 05 was considered statistically significant.
  All patients had a history of HSJ more than 30 years ago. No active HSJ was found in any of these patients, nor was any upper gastrointestinal bleeding found within three months in any patients. Deficits in attention (n = 9,21. 9%), disturbance of sleep (n = 7,17%), logopathy (n = 3,7. 3%), rigidity (n = 9,21. 9%), tremor (n = 6,14. 6%), and bradykinesia (n = 8,19. 5%) were observed in overt PSE. Liver function tests, magnetic resonance imaging, and spectroscopy findings in the different groups are listed in Table 1. No significant differences in any parameters were found between chronic HSJ patients without PSE and the controls. Increased DST (p < 0. 05) and decreased NTC-A (p < 0. 05) were observed in covert PSE group compared with the controls. No significant differences in ALT, AST, TB, DB, PT, and albumin or plasma ammonia levels were detected among the groups. Overt PSE and covert PSE patients showed higher blood manganese levels compared to non-PSE patients and controls (all p<0. 001). T1-hyperintensity in the bilateral Globus pallidus was observed in one patient without PSE (1/10,10%), five patients with covert PSE (5/12,41. 6%), and 17 patients with overt PSE (17/19,89. 4%). T1SI and ADC value in the Globus pallidus progressively increased with the severity of PSE, being significantly higher in covert PSE and overt PSE patients than in non-PSE patients and controls (p < 0. 05). Lac/Cr and Glx/Cr ratios progressively increased and mI/Cr ratio progressively decreased with the severity of PSE; a significant difference was observed in covert PSE (p < 0. 05) and overt PSE patients (p < 0. 001) as compared to controls (Fig 1). Furthermore, MRS findings (increased Lac, Glx, and decrease mI) was used as a gold standard. Using ROC analysis, a cut-off value of 54. 85 μg/L for blood manganese was yielded a sensitivity and specificity of 94. 7% and 88. 4%, respectively for identify HSJ patients with PSE (S1 Fig). Based on these findings, we have proposed a diagnostic procedure for PSE in chronic HSJ patients (Fig 2).
  This study has some limitations. First, glutamate and glutamine could not be distinguished on 3. 0T MRI. Thus, we used Glx to represent both glutamate and glutamine. According to previous studies, excessive brain glutamine was found in hepatic encephalopathy [6]. Second, we did not compare the differences in metabolites on MRS between chronic HSJ patients with PSE and patients with hepatic encephalopathy. Third, a larger sample size is needed to validate the cut-off values of metabolites between non-PSE and PSE and covert and overt PSE in chronic HSJ patients.
  The present study demonstrated elevated Lac and Glx and decreased mI in the bilateral Globus pallidus in chronic HSJ patients with PSE. Thus, MRS can be a useful noninvasive tool for the diagnosis of PSE in chronic HSJ patients. Chemical Abstracts Service (CAS) Number
summary: Portal-systemic encephalopathy (PSE) is classified as type B hepatic encephalopathy. Portal-systemic shunting rather than liver dysfunction is the main cause of PSE in chronic hepatic schistosomiasis japonicum (HSJ) patients. Chronic HSJ patients with PSE are frequently misdiagnosed as suffering from dementia, depression, and other psychiatric disorders. However, there are few studies of this type of encephalopathy. In this study, magnetic resonance spectroscopy (MRS) was used as a noninvasive tool to detect abnormalities in brain metabolism in chronic HSJ patient with PSE. The results demonstrate that MRS would be useful for the diagnosis of PSE in chronic HSJ patients. Based on the results, a diagnostic procedure for PSE has also been proposed.
keywords: medicine and health sciences
  diagnostic radiology
  chemical compounds
  manganese
  tropical diseases
  brain
  parasitic diseases
  magnetic resonance imaging
  globus pallidus
  gastroenterology and hepatology
  neglected tropical diseases
  liver function tests
  research and analysis methods
  imaging techniques
  chemistry
  helminth infections
  schistosomiasis
  magnetic resonance spectroscopy
  radiology and imaging
  ammonia
  diagnostic medicine
  anatomy
  biology and life sciences
  physical sciences
  chemical elements
title: Magnetic Resonance Spectroscopy for Evaluating Portal-Systemic Encephalopathy in Patients with Chronic Hepatic Schistosomiasis Japonicum