Opioid dependence: brain structure and function : a magnetic resonance imaging, neuropsychological, and electromagnetic study

Background: Opiod dependence is a chronic severe brain disorder associated with enormous health and social problems. The relapse back to opioid abuse is very high especially in early abstinence, but neuropsychological and neurophysiological deficits during opioid abuse or soon after cessation of opioids are scarcely investigated. Also the structural brain changes and their correlations with the length of opioid abuse or abuse onset age are not known. In this study the cognitive functions, neural basis of cognitive dysfunction, and brain structural changes was studied in opioid-dependent patients and in age and sex matched healthy controls. Materials and methods: All subjects participating in the study, 23 opioid dependents of whom, 15 were also benzodiazepine and five cannabis co-dependent and 18 healthy age and sex matched controls went through Structured Clinical Interviews (SCID) to obtain DSM-IV axis I and II diagnosis and to exclude psychiatric illness not related to opioid dependence or personality disorders. Simultaneous magnetoencephalography (MEG) and electroencephalography (EEG) measurements were done on 21 opioid-dependent individuals on the day of hospitalization for withdrawal therapy. The neural basis of auditory processing was studied and pre-attentive attention and sensory memory were investigated. During the withdrawal 15 opioid-dependent patients participated in neuropsychological tests, measuring fluid intelligence, attention and working memory, verbal and visual memory, and executive functions. Fifteen healthy subjects served as controls for the MEG-EEG measurements and neuropsychological assessment. The brain magnetic resonance imaging (MRI) was obtained from 17 patients after approximately two weeks abstinence, and from 17 controls. The areas of different brain structures and the absolute and relative volumes of cerebrum, cerebral white and gray matter, and cerebrospinal fluid (CSF) spaces were measured and the Sylvian fissure ratio (SFR) and bifrontal ratio were calculated. Also correlation between the cerebral measures and neuropsychological performance was done. Results: MEG-EEG measurements showed that compared to controls the opioid-dependent patients had delayed mismatch negativity (MMN) response to novel sounds in the EEG and P3am on the contralateral hemisphere to the stimulated ear in MEG. The equivalent current dipole (ECD) of N1m response was stronger in patients with benzodiazepine co-dependence than those without benzodiazepine co-dependence or controls. In early abstinence the opioid dependents performed poorer than the controls in tests measuring attention and working memory, executive function and fluid intelligence. Test results of the Culture Fair Intelligence Test (CFIT), testing fluid intelligence, and Paced Auditory Serial Addition Test (PASAT), measuring attention and working memory correlated positively with the days of abstinence. MRI measurements showed that the relative volume of CSF was significantly larger in opioid dependents, which could also be seen in visual analysis. Also Sylvian fissures, expressed by SFR were wider in patients, which correlated negatively with the age of opioid abuse onset. In controls the relative gray matter volume had a positive correlation with composite cognitive performance, but this correlation was not found in opioid dependents in early abstinence. Conclusions: Opioid dependents had wide Sylvian fissures and CSF spaces indicating frontotemporal atrophy. Dilatation of Sylvian fissures correlated with the abuse onset age. During early withdrawal cognitive performance of opioid dependents was impaired. While intoxicated the pre-attentive attention to novel stimulus was delayed and benzodiazepine co-dependence impaired sound detection. All these changes point to disturbances on frontotemporal areas.Huumeriippuvuus on krooninen aivosairaus, joka johtaa aineen jatkuvaan käyttöön huolimatta käytön aiheuttamista vakavista haitoista kaikilla elämän alueilla. Huumeriippuvuuteen liittyy myös huomattava huumeidenkäytön uusiutumisriski erityisesti varhaisen vieroituksen aikana, mutta vielä pitkänkin päihteettömän ajanjakson jälkeen. Tutkimuksen tavoitteena oli selvittää pitkäaikaisen opioidien (heroiini ja buprenorfiini) väärinkäytön vaikutusta aivojen rakenteeseen magneettikuvauksella ja toimintaan aivojen sähköisiä vasteita mittaavilla elektroenkefalografia (EEG) - ja magnetoenkefalografiatutkimuksilla (MEG). Lisäksi kognitiivista suoriutumista selvitettiin varhaisen vieroitushoidon aikana neuropsykologisilla testeillä. Tutkimukseen osallistui 23 opioidiriippuvaista henkilöä, joista 15 oli myös bentsodiatsepiiniriippuvaisia. Tutkittavilla oli vakava pitkäaikainen opioidiriippuvuus. Tutkittavien tuloksia verrattiin iältään ja sukupuoleltaan vastaavien terveiden henkilöiden tutkimustuloksiin. Kaikille tutkittaville tehtiin strukturoidut psykiatriset haastattelut, joilla pois suljettiin sellaiset psykiatriset sairaudet, jotka eivät liity päihteiden käyttöön tai persoonallisuushäiriöihin. Kaikilla opioidiriippuvaisilla oli persoonallisuushäiriöitä, mutta verro-keilla ei niitä todettu. Vieroitushoitoon tulopäivänä opioidiriippuvaisille tehtiin samanaikainen EEG-MEG mittaus, jossa tutkittiin kuulovasteita. Tahatonta tarkkavaisuutta tutkittiin ns. poikkeavuusnegatiivisuus vasteella (mismatch negativity, MMN) ja P3a vasteella. MEG-EEG mittauksessa potilailla olivat MMN vaste EEG mittauksessa ja P3a vaste MEG mittauksessa viivästyneet viitaten tahattoman tarkkaavaisuuden muutokseen. Näitä vasteita pidetään kognitiivisina, alkeellista työmuistia edustavina vasteina. Potilailla, joilla oli myös bentsodiatsepiiniriippuvuus, oli kuuloärsykkeen aiheuttama vaste voimistunut. Aineiden sekakäyttö siis lisäsi kuulovasteen muutoksia. Vieroitushoidon aikana 15 opioidiriippuvaiselle tehtiin laaja neuropsykologinen tutkimus, jolla selvitettiin joustavaa älykkyyttä, muistin eri osa-alueita ja toiminnan ohjausta. Neuro-psykologisessa testissä potilaat menestyivät verrokeita huonommin tarkkavaisuutta ja työmuistia (PASAT) sekä toiminnan ohjausta (RFFT) ja joustavaa älykkyyttä mittaavissa tes-teissä (CFIT). PASAT ja CFIT testien tulokset korreloivat positiivisesti vieroitushoidon kestoon. Opioidiriipuvaisten kokonaissuoriutuminen neuropsykologisissa testeissä vieroitusvaiheessa oli verrokeita vaatimattomampi. Kahden viikon vieroitushoitojakson lopussa 17 opioidiriippuvaista kävi aivojen 1,5 T magneettiikuvauksessa. Kuvista analysoitiin valkean ja harmaan aineen sekä aivoselkäydin-nestetilojen tilavuudet sekä tehtiin aivorakenteiden pinta-ala mittauksia ja laskettiin rakenteiden suhteita. Myös korrelaatiot eri tutkimustulosten ja päihdehistorian välille laskettiin. Aivojen magneettiikuvauksessa todettiin, että aivojen sivukammiot olivat laajemmat kuin verrokeilla. Opioidiriipuvaisilla Sylvian uurteet oli leveämmät suhteessa aivojen poikkimittaan kuin verrokeilla ja tämä suhde korreloi opioidien käytön aloitusikään. Löydös viittaa aivojen otsa- ja ohimolohkojen surkastumiseen. Aivojen tilavuusmittauksissa todettiin aivojen kokonaisvolyymin olevan verrokeita pienempi ja suhteellisen aivoselkäydinnestemäärän olevan tutkittavilla merkittävästi verrokeita suurempi. Verrokeilla neuropsykologinen kokonaissuoriutuminen korreloi positiivisesti harmaan aineen määrään, mutta opioidirippuvaisilla henkilöillä tällaista korrelaatiota ei havaittu, voidaan siis ajatella vieroitusvaiheen muutosten heikentävän opioidiriippuvaisten suoriutumista ehkä pysyvämpiä muutoksia enemmän. Kaikissa eri tutkimuksissa saadut tulokset viittaavat pääosin otsa- ja ohimolohkojen toiminnan ja rakenteen muutoksiin opioidiriippuvaisilla

Risk factors and outcomes of tapering surgery for small intestinal dilatation in pediatric short bowel syndrome

Background: In remains unclear why in some short bowel syndrome (SBS) patients, the remaining small bowel (SB) dilates excessively leading to requirement of tapering surgery. Methods: Among SBS children, we retrospectively analyzed risk factors for tapering surgery with logistic regression and compared the outcome of operated patients (n = 16) to those managed conservatively (n = 44) with Cox proportional hazards regression. Results: SBS was caused by necrotizing enterocolitis (NEC) (n = 31), SB atresia (SBA) (n = 13), midgut volvulus (n = 12), or gastroschisis (n = 4). Patients with spontaneous symptomatic SB dilatation unable to wean parenteral nutrition (PN) underwent tapering surgery at median age of 1.04 (interquartile range 0.70-3.27) years. Missing ICV was related to an 8-fold (p = 0.003) increased risk while SBA diagnosis was related to a 13-fold risk of tapering surgery (p <0.001). Increasing SB length and NEC diagnosis were protective of tapering (p = 0.027-0.004). Of operated patients, 75% reached enteral autonomy during follow-up and their postoperative adjusted PN weaning rate was similar to nonoperated children (p = 0.842). Conclusion: SBS children with short remaining SB, missing ICV, and SBA etiology are more likely while NEC patients are less likely than others to necessitate tapering surgery. Postoperative PN weaning rates were comparable to patients who initially had more favorable intestinal anatomy and adapted without surgery. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe

Small Bowel Dilatation Predicts Prolonged Parenteral Nutrition and Decreased Survival in Pediatric Short Bowel Syndrome

Objective: To analyze risk factors and prognostic significance of small bowel (SB) dilatation in children with short bowel syndrome (SBS). Background: In SBS, the remaining SB may dilate as part of intestinal adaptation. The impact of dilatation on parenteral nutrition (PN) dependence and survival has not been studied systematically. Methods: SB diameter of SBS children (n = 61) was measured in contrast SB series (n = 169, median age 0.94, range 0.32-2.7 years) during 2002 to 2015, and expressed as millimeters (SB width) and as ratio to L5 vertebra height (SB diameter ratio). Linear regression was used to examine risk factors for dilatation. PN weaning and survival were analyzed with Cox proportional hazards regression. Results: Maximal SB diameter ratio during follow-up was predicted by PN dependence and SB atresia, while maximal absolute SB width by birth weight, age, PN duration, and remaining bowel length. Weaning off PN was 14-fold more likely in patients with maximal SB diameter ratio 3.00 (P = 0.005), and 5.4-fold more likely when maximal SB width was 30mm (P = 0.023). After adjustment for age, remaining SB length, and the presence of ileocecal valve, both estimates of maximal SB dilatation remained significant independent predictors for weaning off PN. When all measurements were included, the cumulative survival was worse if SB diameter ratio exceeded 2.00 (P = 0.002-0.042). Conclusions: SB dilatation predicts prolonged PN duration and decreased survival in SBS children. Measurement of maximal SB diameter standardized to L5 vertebra height may be a valuable objective tool for patient follow-up and assessment of prognosis.Peer reviewe

Metabolic profile of liver damage in non-cirrhotic virus C and autoimmune hepatitis : A proton decoupled P-31-MRS study

Purpose: To study liver P-31 MRS, histology, transient elastography, and liver function tests in patients with virus C hepatitis (HCV) or autoimmune hepatitis (AIH) to test the hypothesis that P-31 MR metabolic profile of these diseases differ. Materials and methods: 25 patients with HCV (n = 12) or AIH (n = 13) underwent proton decoupled P-31 MRS spectroscopy performed on a 3.0 T MR imager. Intensities of phosphomonoesters (PME) of phosphoethanolamine (PE) and phosphocholine (PC), phosphodiesters (PDE) of glycerophosphoethanolamine( GPE) and glycerophosphocholine (GPC), and gamma, alpha and beta resonances of adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide phosphate (NADPH) were determined. Liver stiffness was measured by transient elastography. Inflammation and fibrosis were staged according to METAVIR from biopsy samples. Activities of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALT) and thromboplastin time (TT) were determined from serum samples. Results: PME had a stronger correlation with AST (z = 1.73, p = 0.04) and ALT (z = 1.77, p = 0.04) in HCV than in AIH patients. PME, PME/PDE, PE/GPE correlated positively and PDE negatively with inflammatory activity. PE, PC and PME correlated positively with liver function tests. Conclusion: P-31-MRS suggests a more serious liver damage in HCV than in AIH with similar histopathological findings. P-31-MRS is more sensitive in detecting inflammation than fibrosis in the liver. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Outcome after pin fixation of supracondylar humerus fractures in children : postoperative radiographic examinations are unnecessary A retrospective study of 252 Gartland-III and 12 flexion-type supracondylar humerus fractures

Background and purpose - The quality of pin fixation of displaced supracondylar humerus fractures in children has not been assessed, and the clinical value of radiographic examinations after pin fixation is unclear. We evaluated pin configuration, quality of osteosynthesis, and outcome in 264 supracondylar fractures. The clinical significance of postoperative radiographs was analyzed. Patients and methods - 252 Gartland-III and 12 flexion-type supracondylar humerus fractures were pin-fixed in the periods 2002-2006 and 2012-2014. During 2012-2014, staff were intructed that postoperative radiographs should not be taken. Quality of reduction was assessed by measuring Baumann and lateral capitellohumeral angles (LCHA) and also by recording the crossing point of the anterior humeral line (AHL) with bony capitellum. Rotatory alignment was registered as normal or abnormal. Pin configuration and quality of osteosynthesis were evaluated. The clinical significance of postoperative radiographs was analyzed. Results - Postoperatively, Baumann angle was normal in 66% of the fractures, AHL crossed the capitellum in 84%, and no malrotation was evident in 85% of the fractures. Crossed pins were used in 89% of the cases. 2 or more pins fixed both fracture fragments in 66%. Radiographic examinations were inadequate for assessment of LCHA in 13%, of Bauman angle in 8%, of AHL in 2%, of rotation in 1%, and of pin fixation in 2% of the cases. Postoperative radiographs did not give useful information except in 1 patient who had corrective osteotomy. All 94 patients with follow-up (97%) who were treated during 2012-2014 were satisfied with the outcome. Interpretation - Despite pin fixation being deemed unsatisfactory in one-third of the cases, significant malunion was rare. Postoperative radiography did not alter management or outcome.Peer reviewe

Noninvasive Evaluation of Liver Fibrosis and Portal Hypertension After Successful Portoenterostomy for Biliary Atresia

We investigated noninvasive follow-up markers for histologic liver fibrosis and portal hypertension (PH) in patients with biliary atresia after successful portoenterostomy (PE). Among children with bilirubin 11 mu mol/L in the youngest tertile (AUROC, 0.91; P 80 mu mol/L in the middle tertile (AUROC, 0.81; P = 0.009), and liver stiffness was >24 kPa in the oldest age tertile (AUROC, 0.96; P = 0.002). Conclusion: After successful PE, development of PH associates with progression of liver fibrosis and can be accurately detected by APRI and stiffness. Liver stiffness most accurately identified cirrhosis in older children, whereas biochemical markers of cholestasis closely reflected histologic cirrhosis in younger children.Peer reviewe

(31)Phosphorus magnetic resonance spectroscopy of the liver for evaluating inflammation and fibrosis in autoimmune hepatitis

Background: Liver biopsy is the gold standard in evaluating inflammation and fibrosis in autoimmune hepatitis.Aims: In search of non-invasive follow-up tools in autoimmune hepatitis, we evaluated (31)phosphorus magnetic resonance spectroscopy (P-31 MRS).Methods: Twelve consecutive AIH patients (mean age 42.8 years, 10 women) underwent liver biopsy, routine laboratory liver function tests, which were compared to findings in P-31 MRS and transient elastography (TE).Results: Phosphoenolpuryvate (PEP) correlated with the grade of inflammation (r=0.746, p=.005) and thromboplastin time (r=0.592, p=.043). It also differentiated patients with active inflammation from patients without (t=3.781, p=.009). There was no correlation between PEP and aminotransferase or immunoglobulin G levels.The phosphoethanolamine (PE)/phosphocholine (PC) ratio, PE/glyserophosphoethanolamine (GPE) ratio and PC/[total phosphomonoester (PME)+phosphodiester (PDE)] ratios correlated with immunoglobulin G (r=0.764, p=.006; r=0.618, p=.043; and r=-0.636, p=.035, respectively).PME/PDE and PE/GPE correlated with fibrosis (r=0.668, p=.018 and r=0.604, p=.037). PE/GPE also differentiated F3 from F0-2 patients (t=3.810, p=.003).Phosphorus metabolites did not correlate with TE results and TE did not correlate with liver histology or laboratory parameters.Conclusions: P-31 MRS seems to detect active inflammation and advanced fibrosis in AIH patients. TE was ineffective in fibrosis quantification.Peer reviewe

Liver pathology and biochemistry in patients with mutations in TRIM37 gene (Mulibrey nanism)

Background and Aims Mulibrey nanism (MUL) is a multiorgan disease caused by recessive mutations in the TRIM37 gene. Chronic heart failure and hepatopathy are major determinants of prognosis in MUL patients, which prompted us to study liver biochemistry and pathology in a national cohort of MUL patients. Methods Clinical, laboratory and imaging data were collected in a cross-sectional survey and retrospectively from hospital records. Liver histology and immunohistochemistry for 10 biomarkers were assessed. Results Twenty-one MUL patients (age 1-51 years) with tumour suspicion showed moderate congestion, steatosis and fibrosis in liver biopsies and marginally elevated levels of serum GGT, AST, ALT and AST to platelet ratio index (APRI) in 20%-66%. Similarly, GGT, AST, ALT and APRI levels were moderately elevated in 12%-69% of 17 MUL patients prior to pericardiectomy. In a cross-sectional evaluation of 36 MUL outpatients, GGT, total bilirubin and galactose half-life (Gal1/2) correlated with age (r = 0.45, p = .017; r = 0.512, p = .007; r = 0.44, p = .03 respectively). The frequency of clearly abnormal serum values of 15 parameters analysed, however, was low even in patients with signs of restrictive cardiomyopathy. Transient elastography (TE) of the liver revealed elevated levels in 50% of patients with signs of heart failure and TE levels correlated with several biochemistry parameters. Biomarkers of fibrosis, sinusoidal capillarization and hepatocyte metaplasia showed increased expression in autopsy liver samples from 15 MUL patients. Conclusion Liver disease in MUL patients was characterized by sinusoidal dilatation, steatosis and fibrosis with individual progression to cirrhosis and moderate association of histology with cardiac function, liver biochemistry and elastography.Peer reviewe

Cognitive function during early abstinence from opioid dependence: a comparison to age, gender, and verbal intelligence matched controls

BACKGROUND: Individuals with opioid dependence have cognitive deficits during abuse period in attention, working memory, episodic memory, and executive function. After protracted abstinence consistent cognitive deficit has been found only in executive function. However, few studies have explored cognitive function during first weeks of abstinence. The purpose of this study was to study cognitive function of individuals with opioid dependence during early abstinence. It was hypothesized that cognitive deficits are pronounced immediately after peak withdrawal symptoms have passed and then partially recover. METHODS: Fifteen patients with opioid dependence and fifteen controls matched for, age, gender, and verbal intelligence were tested with a cognitive test battery When patients performed worse than controls correlations between cognitive performance and days of withdrawal, duration of opioid abuse, duration of any substance abuse, or opioid withdrawal symptom inventory score (Short Opiate Withdrawal Scale) were analyzed. RESULTS: Early abstinent opioid dependent patients performed statistically significantly worse than controls in tests measuring complex working memory, executive function, and fluid intelligence. Their complex working memory and fluid intelligence performances correlated statistically significantly with days of withdrawal. CONCLUSION: The results indicate a rather general neurocognitive deficit in higher order cognition. It is suggested that cognitive deficit during early abstinence from opioid dependence is related to withdrawal induced neural dysregulation in the prefrontal cortex and is partly transient