Neuroradiology DOI 10.1007/s00234-014-1409-0
PAEDIATRIC NEURORADIOLOGY
Minimal hepatic encephalopathy in children with liver cirrhosis: diffusion-weighted MR imaging and proton MR spectroscopy of the brain Ahmed Abdel Khalek Abdel Razek & Ahmed Abdalla & Amany Ezzat & Ahmed Megahed & Tarek Barakat
Received: 11 April 2014 / Accepted: 16 July 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Introduction The aim of this work was to detect minimal hepatic encephalopathy (minHE) in children with diffusionweighted MR imaging (DWI) and proton magnetic resonance spectroscopy (1H-MRS) of the brain. Methods Prospective study conducted upon 30 consecutive children (age range 6–16 years, 21 boys and 9 girls) with liver cirrhosis and 15 age- and sex-matched healthy control children. Patients with minHE (n=17) and with no minHE (n=13) groups and control group underwent DWI, 1HMRS, and neuropsychological tests (NPTs). The glutamate or glutamine (Glx), myoinositol (mI), choline (Cho), and creatine (Cr) at the right ganglionic region were determined at 1H-MRS. The apparent diffusion coefficient (ADC) value and metabolic ratios of Glx/Cr, mI/Cr, and Cho/Cr were calculated. Results There was elevated ADC value and Glx/Cr and decreased mI/CI and Ch/Cr in patients with minHE compared to no minHE and control group. There was significant difference between minHE, no minHE, and control group in the ADC value (P=0.001 for all groups), GLx/Cr (P=0.001 for all groups), mI/Cr (P=0.004, 0.001, and 0.001, respectively), Ch/Cr (P=0.001 for all groups), and full-scale IQ of NPT (P =0.001, 0.001, and 0.143, respectively). The NPT of minHE had negative correlation with ADC value (r=−0.872, P=0.001) and GLx/Cr (r=−0.812, P=0.001) and positive correlation with mI/Cr (r=0.732, P=0.001).
A. A. K. A. Razek (*) : A. Ezzat Department of Diagnostic Radiology, Mansoura Faculty of Medicine, Mansoura University Hospital, Mansoura 13551, Egypt e-mail: [email protected] A. Abdalla : A. Megahed : T. Barakat Gastroenterology and Hepatology Unit, Mansoura Faculty of Medicine, Mansoura Children Hospital, Mansoura, Egypt
Conclusion DWI and 1H-MRS are imaging modalities that can detect minHE in children with liver cirrhosis and correlate well with parameters of NPT. Keywords Hepatic . Encephalopathy . Children . Diffusion . MR spectroscopy Abbreviations Cho Choline Cr Creatine DWI Diffusion-weighted MR imaging HE Hepatic encephalopathy mI Myoinositol minHE Minimal hepatic encephalopathy NAA N-acetylaspartate NPT Neuropsychological tests OHE Overt hepatic encephalopathy H-MRS Proton magnetic resonance spectroscopy Glx Glutamate or glutamine IQ Intelligence quotient
Introduction Minimal hepatic encephalopathy (minHE) is a subclinical complication of liver cirrhosis in which the patients have subtle cognitive and psychomotor disturbances that are not obvious at neurological examination and detected at neuropsychological test (NPT). The minHE found in up to 70 % of adult cirrhotic patients. The incidence of minHE in children with liver cirrhosis is still unknown [1–7]. Early diagnosis and treatment of minHE in children is important for the preservation of brain function in which brain experiencing maturation and cognitive development as well as about 50 % of cirrhotic children with minHE present with overt HE (OHE) after
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3 years as opposed to 8 % of the patients without minHE [2–4]. In addition, abnormal cognitive functions interfere significantly with the daily activities. Early detection of minHE may be helpful in mitigating the neurocognitive declines seen in children with liver disease by consideration of liver transplantation before obvious end-stage liver disease [8–11]. MinHE characterized by mild cognitive and psychomotor deficits that detected with NPT [6–10]. There is a consensus and standardization in using the NPT battery to assess the presence of minHE [2–5]. Abnormal NPT is sufficient to establish diagnosis of minHE. However, the tests are not specific and affected by patient age, anxiety, mood disorders, educational effects, and linguistic abilities [13–16]. Magnetic resonance (MR) imaging studies [17–22] including proton magnetic resonance spectroscopy spectroscopy (1H-MRS) [23–30], magnetization transfer ratios [31], voxel-based morphometry [32], and diffusion tensor imaging [33–37] have been used to understand cerebral alterations of hepatic encephalopathy (HE). There are few studies that discuss the role of MR imaging in children with minHE [8], HE with extrahepatic portal vein obstruction [9–11], and acute liver failure [38]. The aim of this work was to detect minHE in children with DWI and 1H-MRS and to correlate DWI and 1H-MRS findings with NPT results.
Material and methods Patient selection Prospective study conducted upon 40 consecutive children with liver cirrhosis. Ten patients were excluded from the study due to OHE (n=7) and recent gastrointestinal bleeding (n=3). The final included patients were 30 children with age range, 6–16 years; mean age was 12.5 years, 21 boys/9 girls. All patients had established liver cirrhosis that diagnosed at liver biopsy. The causes of cirrhosis were autoimmune hepatitis (n=22), viral hepatitis (n=3), alpha one antitrypsin deficiency (n = 3), and cryptogenic (n = 2). Fifteen age-, sex-, and education-matched healthy children (with age range, 7– 15 years; mean age was 11 years, 10 boys/5 girls) were included as controls. The mean number of education years of patients was 7.2 years and of controls was 6.9 years. All patients and controls underwent NPT, conventional MR, DWI, and 1H-MRS of the brain. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee. Approval of ethics committee was obtained and informed consent obtained from legal guardian of children and controls before they participated in the study.
Neuropsychological test The NPT was done using well-established Egyptian version of Wechsler intelligence tests. These tests were quoted from the original version of Wechsler Intelligence Scale for ChildrenIII (WISC-III) [39]. The test battery includes six verbal subtests (information, digit span, vocabulary, arithmetic, comprehension, and similarity) and six performance subtests (picture completion, picture arrangement, block design, object assembly, digit symbol, and symbol search). Individual subtests scaled scores; verbal IQ, performance IQ, and full-scale IQ were the parameters of interest. The time taken for completing the NP test battery ranged from 35 to 45 min. Test scores considered abnormal if patients’ values lay beyond mean±2 SD, from normal established in age-, gender-, and education-matched healthy controls. MinHE diagnosed if ≥2NPTs were abnormal. Based on NP test results, patients grouped into minHE and no minHE [33]. Conventional magnetic resonance imaging MR imaging performed using a 1.5-Tesla scanner equipped with echoplanar capabilities (Symphony, Siemens, Erlangen, Germany). The machine was equipped with a self-shielding gradient set (30 mT/m maximum gradient strength and 120 T/ m/s slew rate) and a commercially available circularly polarized head coil. MR imaging consisted of transverse T1- and T2-weighted imaging. The imaging parameters were TR/TE= 500/14 ms for T1-weighted images and 5,000/86 ms for T2weighted images, field of view (FOV)=240×240 mm, section thickness=5 mm, and intersection gap=0.5 mm. The brain MR imaging was reviewed to exclude other pathologic processes. Diffusion magnetic resonance imaging Diffusion-weighted MR imaging conducted by using singleshot spin-echo echoplanar imaging. The diffusion-weighting gradients were applied on each of the three physical axes x, y, and z with b factor values of 0, 500, and 1,000 mm2/s. The scanning parameters were TR/TE=4,000/100 ms, number of averages=1, FOV=240×240 mm, slice thickness=5 mm, interslice gap=0.5 mm, and matrix=96×128 pixels. After application of diffusion-weighted sequence, we obtained a set of images corresponding to each b value applied. The apparent diffusion coefficient (ADC) map automatically was calculated from the data set obtained at three b values by commercially available software (Leonardo, version 2.0; Siemens AG Medical systems, Forchheim, Germany). The data acquisition time for the diffusion-weighted MR images was 1 min. The mean ADC was determined in manually drawn regions of interest placed in the right basal ganglia.
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The ADC value was calculated according to the following formula: ADC_−(lnSb2−lnSb1)/(b2−b1), where ln is the natural log, and Sb1 and Sb2 are the signal intensities in the ROI placed on sections corresponding to the two different b values (b1 and b2) [40, 41]. The ADC value automatically calculated in 10–3 mm2/s.
of the possibility of retrospective voxel shifting. The integrals of Glx, mI, Cho, and Cr were calculated. The ratios of integrals of various metabolites calculated with respect to Cr included Glx/Cr, mI/Cr, Cho/Cr, and NAA/Cr.
Proton magnetic resonance spectroscopy
The statistical analysis of data was done by using Statistical Package for Social Science version 16.0 (SPSS Inc., Chicago, IL, USA). The Kolmogorov-Smirnov (K-S) test was done for diagnosis normality of data distribution. All data were parametric with normal distribution. The mean and standard deviation (SD) of the ADC; Glx/Cr, mI/Cr, and Cho/Cr of MRS; and verbal IQ, performance IQ, and full-scale IQ of NPTs were calculated. The analysis of data was done to test statistical significant difference. Independent sample (student t test) and one-way ANOVA were done to study the difference of the ADC values, metabolites ratios, verbal IQ, performance IQ, and full-scale IQ of NPTs between patient groups (minHE, no minHE) and control group. Pearson correlation test was used to correlate the ADC value and metabolic ratios of minHE with full-scale IQ. The correlation coefficients r and P value were calculated. The P value was considered significant if ≤0.05 at confidence interval of 95 %.
The homogeneity of the magnetic field over the volume of interest was optimized by shimming. Suppression of the water signal was performed by using three preceding Gaussian pulses (60-Hz bandwidth). Single voxel point-resolved spectroscopy pulse sequence (PRESS) technique (Fig. 1) was applied using the following parameters: TR/ TE =1,500/ 35 ms, voxel size=8 cm3, and number of averages=128. Voxel of 2×2×2 cm3was located in the right basal ganglia according to previous study [9]. A standard software package (Syngo; Siemens) was used for postprocessing MR spectroscopic data. The peaks fitted included 3.75 ppm for glutamate or glutamine (Glx), 3.5 ppm for myoinositol (mI), 3.22 ppm for choline (Cho), 3.03 ppm for creatine (Cr), and 2.00 ppm for N-acetylaspartate (NAA). By using standardized postprocessing protocols, the raw data processed automatically, allowing for operator-independent quantifications. To minimize the amount of arbitrary operator input, no use was made
Statistical analysis
Results Among the 30 patients with liver cirrhosis included in this study, minHE was detected in 17 patients (56.7 %) and was absent in 13 (43.3 %; no minHE group) based on NPT results. Table 1 shows the ADC value, MRS metabolite ratios, and NPT in minHE, no minHE, and control groups. Neuropsychological test At NPT, both verbal IQ and performance IQ were significantly different in minHE group compared with healthy controls (P= 0.001, respectively), with consecutive affection of the fullscale IQ (P=0.001) while the no CHE group was insignificantly affected regarding verbal IQ, performance IQ, and fullscale IQ (P=0.988, P=0.070, and P=0.143, respectively) compared with healthy controls. The full-scale IQ had negative correlation with ADC value (r=−0.872, P=0.001) and GLx/Cr (r=−0.812, P=0.001) and positive correlation with mI/Cr (r=0.732, P=0.001). Conventional and diffusion magnetic resonance imaging
Fig. 1 Localization for 1H-MRS. Axial T2-weighted image shows that the voxel of interest is located in the right basal ganglion region
There are no areas of abnormal signal intensity that could be detected at T1- and T2-weighted images. The mean ADC value of the right basal ganglion in cirrhotic patients with minHE was 87.58±2.3×10−3 mm2/s, in patients with no
Neuroradiology Table 1 The mean and standard deviation of ADC value, MRS metabolites, and NPT in minHE, no minHE, and control groups minHE group (n=17) ADC (10−3 mm2/s) MRS Glx/Cr mI/Cr Cho/Cr NAA/Cr NPT Verbal IQ Performance IQ Full-scale IQ
No minHE group (n=13)
Control group (n=15)
P value a
b
c
87.58±2.30
73.66±2.02
69.65±2.28
0.001
0.001
0.001
2.85±0.40 0.30±0.08 0.62±0.05 2.54±0.43
2.14±0.44 0.48±0.12 0.71±0.04 2.62±0.32
1.69±0.37 0.60±0.24 0.85±0.02 2.75±0.15
0.001 0.004 0.001 0.886
0.001 0.001 0.001 0.535
0.001 0.001 0.001 0.659
94.24±8.4 78.06±10.8 85.47±9.5
108.69±6.05 88.76±12.09 98.62±6.09
108.73±5.56 95.40±2.67 102.60±3.73
0.001 0.004 0.001
0.001 0.001 0.001
0.988 0.070 0.143
a minHE versus no minHE, b minHE versus control, c no minHE versus control
minHE was 73.66±2.020×10−3 mm2/s, and in the control group was 69.65±2.28×10−3 mm2/s. The ADC values were significantly higher in minHE group compared to no minHE (P=0.001) and control groups (P=0.001). Proton magnetic resonance spectroscopy At 1H-MRS, the Glx/Cr was higher in patients with minHE and no minHE than control group. On the other hand, the mI/ Cr and Cho/Cr were lower in patients with minHE and no minHE than control group (Fig. 2). There was no significant difference in NAA/Cr between patients with minHE and no minHE. There was significant different between minHE versus no minHE, minHE versus control, and no minHE versus control in Glx/Cr (P=0.001, 0.001, and 0.001, respectively) and significant decrease in mI/Cr (P=0.001, 0.004, and 0.001, respectively) and Cho/Cr (P=0.001, 0.001, and 0.001, respectively) (Table 1).
Discussion The pathophysiology of HE remains incompletely defined. At least three elements are reported to contribute to the pathophysiology of HE: (1) neurotransmission abnormality, (2) neuroinflammation (microglia activation), and (3) astrocytic injury. Neurotransmission abnormalities are caused by an imbalance between the inhibitory and excitatory neurotransmission systems toward an increase of the inhibitory system with an increase in intra-astrocytic glutamine due to the high ammonia levels. Neuroinflammation in HE is characterized by microglial activation with local brain production and release of proinflammatory cytokines including TNF-α and interleukins IL-1b and IL-6. The most recent theory of how
astrocytic swelling occurs includes “Trojan horse” hypothesis of glutamine being carried into mitochondria causing oxidative stress and microglial activation, which also contributes to oxidative stress [20, 24, 42, 43]. In the present study, there is significantly higher ADC in patients with minHE compared to patients with no minHE and control groups, which is associated with poor NPT score due to extracellular accumulation of water in chronic liver failure. Plausible explanation is extracellular migration of macromolecules induced by increase astrocytic glutamate or increase blood-brain barrier permeability. In addition, hyperammonemia may increase blood-brain barrier permeability that leads to capillary water influx to the brain [20–24]. Several studies reported that ADC/mean diffusivity is reliable tool for quantification of low-grade edema in patients with minHE, as mean diffusivity increases in patients with minHE compared with controls. In addition, the mean diffusivity correlates with grades of HE, NPT scores, and 1H-MRS biomarkers in patients with chronic liver failure [33–37]. One study reported that cerebral edema is more extensive, involving the cortical and deep gray matter as well as deep white matter, in minHE than in no minHE in adults [33]. Other study added that regional difference of ADC/diffusivity in patients with minHE and proposed that higher diffusivity of frontal and parietal white matter can predict further bouts of OHE [34]. These implications applied to chronic liver failure patients and not to acute or OHE patients due to time-dependent compensatory mechanism. The significance of ADC and diffusivity being high or low varies according to the clinical stage and acuity of the disease. High ADC in chronic liver failure patient may be a sign of worsening disease, while a rapid decrease in ADC in acute liver failure patients due to acute cellular injury is a poor harbinger [18–20, 24].
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Fig. 2 1H-MRS of the brain in children with minHE (a), no minHE (b), and control (c). Child with minHE (a) shows higher Glx/Cr and lower Cho/Cr and mI/Cr compared to no minHE (b) and control child (c)
1
H-MRS used for assessment of diffuse metabolic disease of the brain [44]. 1H-MRS studies provided evidence for the presence of an osmoregulatory mechanism in patients with cirrhosis with HE and chronic hyperammonemia in the form of depletion of the mI peak and elevation of the Glx peak in children [8–11] and adults [10–13]. A characteristic triad of increased glutamine with decreased mI and Cho seen on brain 1 H-MRS considered the hallmark of hepatic dysfunction. These metabolite abnormalities are reversible after liver transplantation [23–30]. In this study, there was statistically significant increase in Glx/Cr ratio and reduction in mI/Cr and Cho/Cr ratios and insignificant difference in NAA/Cr ratio in patients with minHE group compared to patients with no minHE and control groups. The increase in Glx/Cr reflects increased glutamine concentration in the brain, a finding that attributed to increased detoxification of ammonia by astrocytes into glutamine via the amidation of glutamate [23–26]. In addition, in patients with cirrhosis with or without HE, a low level of mI has been reported because there is an increase in intracellular osmolality secondary to accumulation of glutamine that compensated by a decrease in intra-cellular mI [25–27]. Lastly, the Cho reduction in patients with liver cirrhosis is likely to reflect alterations in phospholipid metabolism and membrane fluidity because glycerophosphorylcholine is itself a cerebral osmolyte [26–30]. However, a normal Cho/Cr ratio was reported in children with extrahepatic portal venous obstruction and cirrhosis with or without HE [9]. The NPTs are of value for evaluating and quantifying cognitive impairment in patients with minHE. These tools allow better evaluation of the origin of cognitive complaints and help in estimating the risk of accidents [3–6]. These tests are a valid test for diagnosis of minHE, as they directly measure cognitive functions that are directly relevant to activities of daily living. However, these tests are associated with subjectivity of the individuals involved in their assessment
[13–15]. The NPTs tend to significantly correlated with functional status [14–16]. In this study, the NPT well correlated with ADC value and metabolic change, denoting that cerebral brain edema and altered metabolic changes were responsible for abnormalities in NPTs in these patients. There are few limitations of this work. First, we applied diffusion-weighted MR imaging. Further studies with application of diffusion tensor MR imaging and new post processing methods such as non-Gaussian (diffusion kurtosis) modeling or K-means clustering algorithms will improve the results with global assessment of diffusivity of the brain [45, 46]. Second, we applied single voxel study of basal ganglion at short TE (35 ms) for better assessment of some metabolites such as glutamate or glutamine (Glx) and mI. However, further studies done at 3-Tesla scanner using multivoxel chemical shift imaging at high (270 ms) and intermediate (135 ms) with application of advanced postprocessing and quantitative assessment of metabolites will improve the results and allow detection of subtypes of glutamate. Third, there is no follow-up of these patients after therapy or prognosis for longitudinal studies.
Conclusion We concluded that DWI and 1H-MRS are imaging modalities that can detect minHE of the children with cirrhosis and correlate well with parameters of NPT.
Ethical standards and patient consent We declare that all human studies have been approved by the local ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. We declare that all patients gave informed consent prior to inclusion in this study. Conflict of interest We declare that we have no conflict of interest.
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PAEDIATRIC NEURORADIOLOGY
Minimal hepatic encephalopathy in children with liver cirrhosis: diffusion-weighted MR imaging and proton MR spectroscopy of the brain Ahmed Abdel Khalek Abdel Razek & Ahmed Abdalla & Amany Ezzat & Ahmed Megahed & Tarek Barakat
Received: 11 April 2014 / Accepted: 16 July 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Introduction The aim of this work was to detect minimal hepatic encephalopathy (minHE) in children with diffusionweighted MR imaging (DWI) and proton magnetic resonance spectroscopy (1H-MRS) of the brain. Methods Prospective study conducted upon 30 consecutive children (age range 6–16 years, 21 boys and 9 girls) with liver cirrhosis and 15 age- and sex-matched healthy control children. Patients with minHE (n=17) and with no minHE (n=13) groups and control group underwent DWI, 1HMRS, and neuropsychological tests (NPTs). The glutamate or glutamine (Glx), myoinositol (mI), choline (Cho), and creatine (Cr) at the right ganglionic region were determined at 1H-MRS. The apparent diffusion coefficient (ADC) value and metabolic ratios of Glx/Cr, mI/Cr, and Cho/Cr were calculated. Results There was elevated ADC value and Glx/Cr and decreased mI/CI and Ch/Cr in patients with minHE compared to no minHE and control group. There was significant difference between minHE, no minHE, and control group in the ADC value (P=0.001 for all groups), GLx/Cr (P=0.001 for all groups), mI/Cr (P=0.004, 0.001, and 0.001, respectively), Ch/Cr (P=0.001 for all groups), and full-scale IQ of NPT (P =0.001, 0.001, and 0.143, respectively). The NPT of minHE had negative correlation with ADC value (r=−0.872, P=0.001) and GLx/Cr (r=−0.812, P=0.001) and positive correlation with mI/Cr (r=0.732, P=0.001).
A. A. K. A. Razek (*) : A. Ezzat Department of Diagnostic Radiology, Mansoura Faculty of Medicine, Mansoura University Hospital, Mansoura 13551, Egypt e-mail: [email protected] A. Abdalla : A. Megahed : T. Barakat Gastroenterology and Hepatology Unit, Mansoura Faculty of Medicine, Mansoura Children Hospital, Mansoura, Egypt
Conclusion DWI and 1H-MRS are imaging modalities that can detect minHE in children with liver cirrhosis and correlate well with parameters of NPT. Keywords Hepatic . Encephalopathy . Children . Diffusion . MR spectroscopy Abbreviations Cho Choline Cr Creatine DWI Diffusion-weighted MR imaging HE Hepatic encephalopathy mI Myoinositol minHE Minimal hepatic encephalopathy NAA N-acetylaspartate NPT Neuropsychological tests OHE Overt hepatic encephalopathy H-MRS Proton magnetic resonance spectroscopy Glx Glutamate or glutamine IQ Intelligence quotient
Introduction Minimal hepatic encephalopathy (minHE) is a subclinical complication of liver cirrhosis in which the patients have subtle cognitive and psychomotor disturbances that are not obvious at neurological examination and detected at neuropsychological test (NPT). The minHE found in up to 70 % of adult cirrhotic patients. The incidence of minHE in children with liver cirrhosis is still unknown [1–7]. Early diagnosis and treatment of minHE in children is important for the preservation of brain function in which brain experiencing maturation and cognitive development as well as about 50 % of cirrhotic children with minHE present with overt HE (OHE) after
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3 years as opposed to 8 % of the patients without minHE [2–4]. In addition, abnormal cognitive functions interfere significantly with the daily activities. Early detection of minHE may be helpful in mitigating the neurocognitive declines seen in children with liver disease by consideration of liver transplantation before obvious end-stage liver disease [8–11]. MinHE characterized by mild cognitive and psychomotor deficits that detected with NPT [6–10]. There is a consensus and standardization in using the NPT battery to assess the presence of minHE [2–5]. Abnormal NPT is sufficient to establish diagnosis of minHE. However, the tests are not specific and affected by patient age, anxiety, mood disorders, educational effects, and linguistic abilities [13–16]. Magnetic resonance (MR) imaging studies [17–22] including proton magnetic resonance spectroscopy spectroscopy (1H-MRS) [23–30], magnetization transfer ratios [31], voxel-based morphometry [32], and diffusion tensor imaging [33–37] have been used to understand cerebral alterations of hepatic encephalopathy (HE). There are few studies that discuss the role of MR imaging in children with minHE [8], HE with extrahepatic portal vein obstruction [9–11], and acute liver failure [38]. The aim of this work was to detect minHE in children with DWI and 1H-MRS and to correlate DWI and 1H-MRS findings with NPT results.
Material and methods Patient selection Prospective study conducted upon 40 consecutive children with liver cirrhosis. Ten patients were excluded from the study due to OHE (n=7) and recent gastrointestinal bleeding (n=3). The final included patients were 30 children with age range, 6–16 years; mean age was 12.5 years, 21 boys/9 girls. All patients had established liver cirrhosis that diagnosed at liver biopsy. The causes of cirrhosis were autoimmune hepatitis (n=22), viral hepatitis (n=3), alpha one antitrypsin deficiency (n = 3), and cryptogenic (n = 2). Fifteen age-, sex-, and education-matched healthy children (with age range, 7– 15 years; mean age was 11 years, 10 boys/5 girls) were included as controls. The mean number of education years of patients was 7.2 years and of controls was 6.9 years. All patients and controls underwent NPT, conventional MR, DWI, and 1H-MRS of the brain. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee. Approval of ethics committee was obtained and informed consent obtained from legal guardian of children and controls before they participated in the study.
Neuropsychological test The NPT was done using well-established Egyptian version of Wechsler intelligence tests. These tests were quoted from the original version of Wechsler Intelligence Scale for ChildrenIII (WISC-III) [39]. The test battery includes six verbal subtests (information, digit span, vocabulary, arithmetic, comprehension, and similarity) and six performance subtests (picture completion, picture arrangement, block design, object assembly, digit symbol, and symbol search). Individual subtests scaled scores; verbal IQ, performance IQ, and full-scale IQ were the parameters of interest. The time taken for completing the NP test battery ranged from 35 to 45 min. Test scores considered abnormal if patients’ values lay beyond mean±2 SD, from normal established in age-, gender-, and education-matched healthy controls. MinHE diagnosed if ≥2NPTs were abnormal. Based on NP test results, patients grouped into minHE and no minHE [33]. Conventional magnetic resonance imaging MR imaging performed using a 1.5-Tesla scanner equipped with echoplanar capabilities (Symphony, Siemens, Erlangen, Germany). The machine was equipped with a self-shielding gradient set (30 mT/m maximum gradient strength and 120 T/ m/s slew rate) and a commercially available circularly polarized head coil. MR imaging consisted of transverse T1- and T2-weighted imaging. The imaging parameters were TR/TE= 500/14 ms for T1-weighted images and 5,000/86 ms for T2weighted images, field of view (FOV)=240×240 mm, section thickness=5 mm, and intersection gap=0.5 mm. The brain MR imaging was reviewed to exclude other pathologic processes. Diffusion magnetic resonance imaging Diffusion-weighted MR imaging conducted by using singleshot spin-echo echoplanar imaging. The diffusion-weighting gradients were applied on each of the three physical axes x, y, and z with b factor values of 0, 500, and 1,000 mm2/s. The scanning parameters were TR/TE=4,000/100 ms, number of averages=1, FOV=240×240 mm, slice thickness=5 mm, interslice gap=0.5 mm, and matrix=96×128 pixels. After application of diffusion-weighted sequence, we obtained a set of images corresponding to each b value applied. The apparent diffusion coefficient (ADC) map automatically was calculated from the data set obtained at three b values by commercially available software (Leonardo, version 2.0; Siemens AG Medical systems, Forchheim, Germany). The data acquisition time for the diffusion-weighted MR images was 1 min. The mean ADC was determined in manually drawn regions of interest placed in the right basal ganglia.
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The ADC value was calculated according to the following formula: ADC_−(lnSb2−lnSb1)/(b2−b1), where ln is the natural log, and Sb1 and Sb2 are the signal intensities in the ROI placed on sections corresponding to the two different b values (b1 and b2) [40, 41]. The ADC value automatically calculated in 10–3 mm2/s.
of the possibility of retrospective voxel shifting. The integrals of Glx, mI, Cho, and Cr were calculated. The ratios of integrals of various metabolites calculated with respect to Cr included Glx/Cr, mI/Cr, Cho/Cr, and NAA/Cr.
Proton magnetic resonance spectroscopy
The statistical analysis of data was done by using Statistical Package for Social Science version 16.0 (SPSS Inc., Chicago, IL, USA). The Kolmogorov-Smirnov (K-S) test was done for diagnosis normality of data distribution. All data were parametric with normal distribution. The mean and standard deviation (SD) of the ADC; Glx/Cr, mI/Cr, and Cho/Cr of MRS; and verbal IQ, performance IQ, and full-scale IQ of NPTs were calculated. The analysis of data was done to test statistical significant difference. Independent sample (student t test) and one-way ANOVA were done to study the difference of the ADC values, metabolites ratios, verbal IQ, performance IQ, and full-scale IQ of NPTs between patient groups (minHE, no minHE) and control group. Pearson correlation test was used to correlate the ADC value and metabolic ratios of minHE with full-scale IQ. The correlation coefficients r and P value were calculated. The P value was considered significant if ≤0.05 at confidence interval of 95 %.
The homogeneity of the magnetic field over the volume of interest was optimized by shimming. Suppression of the water signal was performed by using three preceding Gaussian pulses (60-Hz bandwidth). Single voxel point-resolved spectroscopy pulse sequence (PRESS) technique (Fig. 1) was applied using the following parameters: TR/ TE =1,500/ 35 ms, voxel size=8 cm3, and number of averages=128. Voxel of 2×2×2 cm3was located in the right basal ganglia according to previous study [9]. A standard software package (Syngo; Siemens) was used for postprocessing MR spectroscopic data. The peaks fitted included 3.75 ppm for glutamate or glutamine (Glx), 3.5 ppm for myoinositol (mI), 3.22 ppm for choline (Cho), 3.03 ppm for creatine (Cr), and 2.00 ppm for N-acetylaspartate (NAA). By using standardized postprocessing protocols, the raw data processed automatically, allowing for operator-independent quantifications. To minimize the amount of arbitrary operator input, no use was made
Statistical analysis
Results Among the 30 patients with liver cirrhosis included in this study, minHE was detected in 17 patients (56.7 %) and was absent in 13 (43.3 %; no minHE group) based on NPT results. Table 1 shows the ADC value, MRS metabolite ratios, and NPT in minHE, no minHE, and control groups. Neuropsychological test At NPT, both verbal IQ and performance IQ were significantly different in minHE group compared with healthy controls (P= 0.001, respectively), with consecutive affection of the fullscale IQ (P=0.001) while the no CHE group was insignificantly affected regarding verbal IQ, performance IQ, and fullscale IQ (P=0.988, P=0.070, and P=0.143, respectively) compared with healthy controls. The full-scale IQ had negative correlation with ADC value (r=−0.872, P=0.001) and GLx/Cr (r=−0.812, P=0.001) and positive correlation with mI/Cr (r=0.732, P=0.001). Conventional and diffusion magnetic resonance imaging
Fig. 1 Localization for 1H-MRS. Axial T2-weighted image shows that the voxel of interest is located in the right basal ganglion region
There are no areas of abnormal signal intensity that could be detected at T1- and T2-weighted images. The mean ADC value of the right basal ganglion in cirrhotic patients with minHE was 87.58±2.3×10−3 mm2/s, in patients with no
Neuroradiology Table 1 The mean and standard deviation of ADC value, MRS metabolites, and NPT in minHE, no minHE, and control groups minHE group (n=17) ADC (10−3 mm2/s) MRS Glx/Cr mI/Cr Cho/Cr NAA/Cr NPT Verbal IQ Performance IQ Full-scale IQ
No minHE group (n=13)
Control group (n=15)
P value a
b
c
87.58±2.30
73.66±2.02
69.65±2.28
0.001
0.001
0.001
2.85±0.40 0.30±0.08 0.62±0.05 2.54±0.43
2.14±0.44 0.48±0.12 0.71±0.04 2.62±0.32
1.69±0.37 0.60±0.24 0.85±0.02 2.75±0.15
0.001 0.004 0.001 0.886
0.001 0.001 0.001 0.535
0.001 0.001 0.001 0.659
94.24±8.4 78.06±10.8 85.47±9.5
108.69±6.05 88.76±12.09 98.62±6.09
108.73±5.56 95.40±2.67 102.60±3.73
0.001 0.004 0.001
0.001 0.001 0.001
0.988 0.070 0.143
a minHE versus no minHE, b minHE versus control, c no minHE versus control
minHE was 73.66±2.020×10−3 mm2/s, and in the control group was 69.65±2.28×10−3 mm2/s. The ADC values were significantly higher in minHE group compared to no minHE (P=0.001) and control groups (P=0.001). Proton magnetic resonance spectroscopy At 1H-MRS, the Glx/Cr was higher in patients with minHE and no minHE than control group. On the other hand, the mI/ Cr and Cho/Cr were lower in patients with minHE and no minHE than control group (Fig. 2). There was no significant difference in NAA/Cr between patients with minHE and no minHE. There was significant different between minHE versus no minHE, minHE versus control, and no minHE versus control in Glx/Cr (P=0.001, 0.001, and 0.001, respectively) and significant decrease in mI/Cr (P=0.001, 0.004, and 0.001, respectively) and Cho/Cr (P=0.001, 0.001, and 0.001, respectively) (Table 1).
Discussion The pathophysiology of HE remains incompletely defined. At least three elements are reported to contribute to the pathophysiology of HE: (1) neurotransmission abnormality, (2) neuroinflammation (microglia activation), and (3) astrocytic injury. Neurotransmission abnormalities are caused by an imbalance between the inhibitory and excitatory neurotransmission systems toward an increase of the inhibitory system with an increase in intra-astrocytic glutamine due to the high ammonia levels. Neuroinflammation in HE is characterized by microglial activation with local brain production and release of proinflammatory cytokines including TNF-α and interleukins IL-1b and IL-6. The most recent theory of how
astrocytic swelling occurs includes “Trojan horse” hypothesis of glutamine being carried into mitochondria causing oxidative stress and microglial activation, which also contributes to oxidative stress [20, 24, 42, 43]. In the present study, there is significantly higher ADC in patients with minHE compared to patients with no minHE and control groups, which is associated with poor NPT score due to extracellular accumulation of water in chronic liver failure. Plausible explanation is extracellular migration of macromolecules induced by increase astrocytic glutamate or increase blood-brain barrier permeability. In addition, hyperammonemia may increase blood-brain barrier permeability that leads to capillary water influx to the brain [20–24]. Several studies reported that ADC/mean diffusivity is reliable tool for quantification of low-grade edema in patients with minHE, as mean diffusivity increases in patients with minHE compared with controls. In addition, the mean diffusivity correlates with grades of HE, NPT scores, and 1H-MRS biomarkers in patients with chronic liver failure [33–37]. One study reported that cerebral edema is more extensive, involving the cortical and deep gray matter as well as deep white matter, in minHE than in no minHE in adults [33]. Other study added that regional difference of ADC/diffusivity in patients with minHE and proposed that higher diffusivity of frontal and parietal white matter can predict further bouts of OHE [34]. These implications applied to chronic liver failure patients and not to acute or OHE patients due to time-dependent compensatory mechanism. The significance of ADC and diffusivity being high or low varies according to the clinical stage and acuity of the disease. High ADC in chronic liver failure patient may be a sign of worsening disease, while a rapid decrease in ADC in acute liver failure patients due to acute cellular injury is a poor harbinger [18–20, 24].
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Fig. 2 1H-MRS of the brain in children with minHE (a), no minHE (b), and control (c). Child with minHE (a) shows higher Glx/Cr and lower Cho/Cr and mI/Cr compared to no minHE (b) and control child (c)
1
H-MRS used for assessment of diffuse metabolic disease of the brain [44]. 1H-MRS studies provided evidence for the presence of an osmoregulatory mechanism in patients with cirrhosis with HE and chronic hyperammonemia in the form of depletion of the mI peak and elevation of the Glx peak in children [8–11] and adults [10–13]. A characteristic triad of increased glutamine with decreased mI and Cho seen on brain 1 H-MRS considered the hallmark of hepatic dysfunction. These metabolite abnormalities are reversible after liver transplantation [23–30]. In this study, there was statistically significant increase in Glx/Cr ratio and reduction in mI/Cr and Cho/Cr ratios and insignificant difference in NAA/Cr ratio in patients with minHE group compared to patients with no minHE and control groups. The increase in Glx/Cr reflects increased glutamine concentration in the brain, a finding that attributed to increased detoxification of ammonia by astrocytes into glutamine via the amidation of glutamate [23–26]. In addition, in patients with cirrhosis with or without HE, a low level of mI has been reported because there is an increase in intracellular osmolality secondary to accumulation of glutamine that compensated by a decrease in intra-cellular mI [25–27]. Lastly, the Cho reduction in patients with liver cirrhosis is likely to reflect alterations in phospholipid metabolism and membrane fluidity because glycerophosphorylcholine is itself a cerebral osmolyte [26–30]. However, a normal Cho/Cr ratio was reported in children with extrahepatic portal venous obstruction and cirrhosis with or without HE [9]. The NPTs are of value for evaluating and quantifying cognitive impairment in patients with minHE. These tools allow better evaluation of the origin of cognitive complaints and help in estimating the risk of accidents [3–6]. These tests are a valid test for diagnosis of minHE, as they directly measure cognitive functions that are directly relevant to activities of daily living. However, these tests are associated with subjectivity of the individuals involved in their assessment
[13–15]. The NPTs tend to significantly correlated with functional status [14–16]. In this study, the NPT well correlated with ADC value and metabolic change, denoting that cerebral brain edema and altered metabolic changes were responsible for abnormalities in NPTs in these patients. There are few limitations of this work. First, we applied diffusion-weighted MR imaging. Further studies with application of diffusion tensor MR imaging and new post processing methods such as non-Gaussian (diffusion kurtosis) modeling or K-means clustering algorithms will improve the results with global assessment of diffusivity of the brain [45, 46]. Second, we applied single voxel study of basal ganglion at short TE (35 ms) for better assessment of some metabolites such as glutamate or glutamine (Glx) and mI. However, further studies done at 3-Tesla scanner using multivoxel chemical shift imaging at high (270 ms) and intermediate (135 ms) with application of advanced postprocessing and quantitative assessment of metabolites will improve the results and allow detection of subtypes of glutamate. Third, there is no follow-up of these patients after therapy or prognosis for longitudinal studies.
Conclusion We concluded that DWI and 1H-MRS are imaging modalities that can detect minHE of the children with cirrhosis and correlate well with parameters of NPT.
Ethical standards and patient consent We declare that all human studies have been approved by the local ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. We declare that all patients gave informed consent prior to inclusion in this study. Conflict of interest We declare that we have no conflict of interest.
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