Continuing Challenges in the Definitive Diagnosis of Cushing's Disease: A Structured Review Focusing on Molecular Imaging and a Proposal for Diagnostic Work-Up.

The definitive diagnosis of Cushing's disease (CD) in the presence of pituitary microadenoma remains a continuous challenge. Novel available pituitary imaging techniques are emerging. This study aimed to provide a structured analysis of the diagnostic accuracy as well as the clinical use of molecular imaging in patients with ACTH-dependent Cushing's syndrome (CS). We also discuss the role of multidisciplinary counseling in decision making. Additionally, we propose a complementary diagnostic algorithm for both de novo and recurrent or persistent CD. A structured literature search was conducted and two illustrative CD cases discussed at our Pituitary Center are presented. A total of 14 CD (n = 201) and 30 ectopic CS (n = 301) articles were included. MRI was negative or inconclusive in a quarter of CD patients. 11C-Met showed higher pituitary adenoma detection than 18F-FDG PET-CT (87% versus 49%). Up to 100% detection rates were found for 18F-FET, 68Ga-DOTA-TATE, and 68Ga-DOTA-CRH, but were based on single studies. The use of molecular imaging modalities in the detection of pituitary microadenoma in ACTH-dependent CS is of added and complementary value, serving as one of the available tools in the diagnostic work-up. In selected CD cases, it seems justified to even refrain from IPSS.

The Fast Gray Matter Acquisition T1 Inversion Recovery Sequence in Deep Brain Stimulation: Introducing the Rubral Wing for Dentato-Rubro-Thalamic Tract Depiction and Tremor Control.

BACKGROUND: The dentato-rubro-thalamic tract (DRT) is currently considered as a potential target in deep brain stimulation (DBS) for various types of tremor. However, tractography depiction can vary depending on the included brain regions. The fast gray matter acquisition T1 inversion recovery (FGATIR) sequence, with excellent delineation of gray and white matter, possibly provides anatomical identification of rubro-thalamic DRT fibers. OBJECTIVE: This study aimed to evaluate the FGATIR sequence by comparison with DRT depiction, electrode localization, and effectiveness of DBS therapy. MATERIALS AND METHODS: In patients with DBS therapy because of medication-refractory tremor, the FGATIR sequence was evaluated for depiction of the thalamus, red nucleus (RN), and rubro-thalamic connections. Deterministic tractography of the DRT, electrode localization, and tremor control were compared. The essential tremor rating scale was used to assess (hand) tremor. Tremor control was considered successful when complete tremor suppression (grade 0) or almost complete suppression (grade 1) was observed. RESULTS: In the postoperative phase, we evaluated 14 patients who underwent DRT-guided DBS: 12 patients with essential tremor, one with tremor-dominant Parkinson disease, and one with multiple sclerosis, representing 24 trajectories. Mean follow-up was 11.3 months (range 6-19 months). The FGATIR sequence provided a clear delineation of a hypointense white matter tract within the hyperintense thalamus. In coronal plane, this tract was most readily recognizable as a "rubral wing," with the round RN as base and lateral triangular convergence. The deterministic DRT depiction was consistently situated within the rubral wing. The number of active contacts located within the DRT (and rubral wing) was 22 (92%), of which 16 (73%) showed successful tremor control. CONCLUSIONS: The FGATIR sequence offers visualization of the rubro-thalamic connections that form the DRT, most readily recognizable as a "rubral wing" in coronal plane. This sequence contributes to tractographic depiction of DRT and provides a direct anatomical DBS target area for tremor control.

Natural Course of Mild Graves Orbitopathy: Increase of Orbital Fat But Decrease of Muscle Volume With Increased Muscle Fatty Degeneration During a 4-Year Follow-Up.

PURPOSE: To describe the natural course of orbital fat volume and extraocular muscle volume in mild Graves orbitopathy during a 4-year follow-up. To describe fatty changes within the extraocular muscles. PATIENTS: Twenty-five patients with mild Graves orbitopathy, who did not require any therapeutic intervention other than supportive therapy, were followed for 4 years. METHODS: CT scans were performed in all patients at baseline and follow-up. A validated technique using Mimics (Materialise) was used to calculate fat and muscle volumes. Outcomes were compared with previously collected data. The amount of intramuscular fat was assessed on CT scans in a semi-quantitative way by two blinded observers according to a four-point scale. RESULTS: After a median follow-up of 4.3 years, the median fat to orbital volume ratio increased with 0.08 from 0.57 to 0.65 (p = 0.000), whereas the median muscle volume to orbital volume ratio decreased with 0.03 from 0.17 to 0.14 (p = 0.000). In this control group in patients between 49 and 54 years old, the changes were 0.01 and -0.002, respectively. The Clinical Activity Score decreased to zero (p = 0.000), and the median eyelid aperture decreased from 12 to 10 mm (p = 0.007). A significant increase of intramuscular fat was found in patients with Graves orbitopathy. CONCLUSIONS: The natural course of mild Graves orbitopathy, as observed over 4 years, is characterized by an increase of orbital fat volume, a decrease in muscle volume, and an increased intramuscular fatty degeneration.

AMORE treatment as salvage treatment in children and young adults with relapsed head-neck rhabdomyosarcoma.

BACKGROUND AND PURPOSE: Survival after relapse of head and neck rhabdomyosarcoma (HNRMS) after prior external beam radiotherapy (EBRT) is poor, since options for adequate local treatment are often lacking. In this study we describe our experience with salvage AMORE in patients with relapsed HNRMS after prior EBRT. MATERIALS AND METHODS: Patients with relapsed HNRMS after prior EBRT in which salvage AMORE treatment was considered feasible were analysed; this includes patients with parameningeal, head and neck non-parameningeal and orbital localization. AMORE treatment consisted of Ablative surgery, MOuld technique brachytherapy and surgical REconstruction. RESULTS: In total 18 patients received salvage AMORE treatment; nine patients had relapsed parameningeal (PM) RMS, two patients had relapsed head and neck non-parameningeal RMS (HN-nonPM) and seven patients had relapsed orbital RMS. Local control rate was 67% and 5-year overall survival was 54% (95% confidence interval: 31-78%); 3/9 patients with PM RMS, 0/2 patients with HN-nonPM RMS and 6/7 patients with orbital RMS were alive after a median follow-up of 8.6 years. One patient with PM RMS survived more than 5 years after which he died from a secondary cancer. Six patients developed a local relapse (of which one patient also developed a distant metastasis) and two patients developed distant metastases. CONCLUSIONS: Salvage AMORE treatment is a feasible and effective local therapy approach even after prior EBRT. Since salvage AMORE treatment is sometimes the only curative option in patient with relapsed HNRMS, we encourage physicians to consider salvage AMORE treatment for patients with relapsed HNRMS after prior EBRT.

Crossing muscle fibers of the human tongue resolved in vivo using constrained spherical deconvolution.

BACKGROUND: Surgical resection of tongue cancer may impair swallowing and speech. Knowledge of tongue muscle architecture affected by the resection could aid in patient counseling. Diffusion tensor imaging (DTI) enables reconstructions of muscle architecture in vivo. Reconstructing crossing fibers in the tongue requires a higher-order diffusion model. PURPOSE: To develop a clinically feasible diffusion imaging protocol, which facilitates both DTI and constrained spherical deconvolution (CSD) reconstructions of tongue muscle architecture in vivo. STUDY TYPE: Cross-sectional study. SUBJECTS/SPECIMEN: One ex vivo bovine tongue resected en bloc from mandible to hyoid bone. Ten healthy volunteers (mean age 25.5 years; range 21-34 years; four female). FIELD STRENGTH/SEQUENCE: Diffusion-weighted echo planar imaging at 3 T using a high-angular resolution diffusion imaging scheme acquired twice with opposing phase-encoding for B0 -field inhomogeneity correction. The scan of the healthy volunteers was divided into four parts, in between which the volunteers were allowed to swallow, resulting in a total acquisition time of 10 minutes. ASSESSMENT: The ability of resolving crossing muscle fibers using CSD was determined on the bovine tongue specimen. A reproducible response function was estimated and the optimal peak threshold was determined for the in vivo tongue. The quality of tractography of the in vivo tongue was graded by three experts. STATISTICAL TESTS: The within-subject coefficient of variance was calculated for the response function. The qualitative results of the grading of DTI and CSD tractography were analyzed using a multilevel proportional odds model. RESULTS: Fiber orientation distributions in the bovine tongue specimen showed that CSD was able to resolve crossing muscle fibers. The response function could be determined reproducibly in vivo. CSD tractography displayed significantly improved tractography compared with DTI tractography (P = 0.015). DATA CONCLUSION: The 10-minute diffusion imaging protocol facilitates CSD fiber tracking with improved reconstructions of crossing tongue muscle fibers compared with DTI. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:96-105.

Impact of superior ophthalmic vein thrombosis: a case series and literature review.

Purpose: To present nine new cases of superior ophthalmic vein thrombosis (SOVT) and compare these with the literature, and to assess the impact of SOVT for the clinician. Methods: Using the data bases of the Department of Ophthalmology of the AMC, we searched for patients with radiologically evidenced SOVT between January 2006 and December 2014. In addition, a PubMed search, using the mesh term 'superior ophthalmic vein thrombosis', was done. Results: We found nine patients with SOVT. In three patients, SOVT was related to dural arteriovenous fistulae. In one patient, it was caused by the acute reversal of warfarin by vitamin K. In two patients, an infectious cause was found. In three patients, the cause of SOVT was not found despite screening for coagulation and other disorders. All patients presented with eyelid swelling, proptosis, and/or motility impairment. We found complete recovery in four patients. Three patients had mild sequelae and two patients had severe visual impairment. In the literature, we found 60 cases reporting on SOVT with various aetiologies. Clinical presentation, treatment modalities, and outcomes were comparable to our findings. Conclusion: Our case series and literature review show that SOVT can occur simultaneously with cavernous sinus thrombosis (CST) but can also be a separate entity. Clinical presentation can mimic orbital cellulitis (OC) or CST and when no signs of OC can be found, an alternative cause for SOVT should be sought. When timely and adequate treatment is conducted, the prognosis is predominantly favourable.

Prognosis of septic cavernous sinus thrombosis remarkably improved: a case series of 12 patients and literature review.

PURPOSE: Septic cavernous sinus thrombosis (CST) is a rare complication of infections in the head and neck area. CST is notorious for its bad prognosis, with high mortality and morbidity rates described in literature. However, these rates are based on old series. We question whether the prognosis of CST is currently still as devastating. The primary purpose of this study is to assess the mortality and morbidity of CST. METHODS: Using the databases of all relevant specialties in our tertiary referral hospital, we collected all the patients treated for CST in the period 2005-2017. In addition, a PubMed search, using the mesh term 'cavernous sinus thrombosis', was performed. RESULTS: We found 12 patients with CST in the study period. Of the 12 patients, 11 survived and 9 recovered without any permanent deficits. Seven patients were treated with anticoagulation, and in none of the patients we saw hemorrhagic complications. In literature, older articles describe higher mortality rates (14-80%), but more recent articles report mortality and morbidity rates similar to our results. CONCLUSIONS: The prognosis of CST nowadays is more favorable than previously described. Anticoagulation seems to be a safe addition to antibiotic and surgical treatment, at least in patients without central nervous system infection.

The development of hypothalamic obesity in craniopharyngioma patients: A risk factor analysis in a well-defined cohort.

BACKGROUND: Hypothalamic obesity (HO) is a major concern in patients treated for craniopharyngioma (CP). The influence of degree of resection on development of HO, event-free survival (EFS), and neuroendocrine sequelae is an issue of debate. PROCEDURE: A retrospective cohort consisting of all CP patients treated between 2002 and 2012 in two university hospitals was identified. Multivariable logistic regression was used to study the associations between preoperative BMI, age at diagnosis, tumor volume, performed surgical resection, and presence of HO at follow-up. RESULTS: Thirty-five patients (21 children and 14 adults) were included. Median follow-up time was 35.6 months (4.1-114.7). Four patients were obese at diagnosis. HO was present in 19 (54.3%) patients at last follow-up of whom eight were morbidly obese. Thirteen (37.1%) patients underwent partial resection (PR) and 22 (62.9%) gross total resection (GTR). GTR was related to HO (OR 9.19, 95% CI 1.43-59.01), but for morbid HO, obesity at diagnosis was the only risk factor (OR 12.92, 95% CI 1.05-158.73). EFS in patients after GTR was 86%, compared to 42% after PR (log-rank 9.2, P = 0.003). Adjuvant radiotherapy after PR improved EFS (log-rank 8.2, P = 0.004). Panhypopituitarism, present in 15 patients, was mainly seen after GTR. CONCLUSIONS: HO is less frequent after PR than after GTR, but PR cannot always prevent the development of morbid obesity in patients with obesity at diagnosis. PR reduces the occurrence of panhypopituitarism. When developing a treatment algorithm, all these factors should be considered.

True abscess formation is rare in bacterial orbital cellulitis; consequences for treatment.

BACKGROUND: Pre- or retroseptal bacterial orbital cellulitis (pOC/rOC) is not an uncommon orbital disease. Treatment consists of antibiotics with or without surgical drainage. Several questions regarding course, complications and outcome of treatment are unanswered and the indication for surgery is not well defined. The aim of this study is to: 1. describe the outcome of orbital cellulitis (OC) in a large cohort, 2. assess the significance of Chandler's classification, 3. assess the incidence of abscess formation in OC, and 4. redefine criteria for surgery. METHODS: Retrospective case series of patients with OC seen between 1-1-2007 and 1-1-2014 in a tertiary referral center. RESULTS: Sixty-eight patients presented with (presumed) bacterial pOC. Two out of these 68 developed rOC. All 68 patients had a full recovery. Forty-eight patients presented with rOC. Four out of 48 (8%) had intracranial extension of the infection at the time of admission. No admitted patient developed distant seeding. Only four (8%) patients with rOC had a true orbital abscess. In the other 92% we found a diffuse orbital inflammation or a subperiosteal empyema. Forty-four (92%) patients with rOC had a full recovery. CONCLUSIONS: 1. The prognosis of both pOC and rOC nowadays is generally favorable. 2. Chandler's classification is of little use. 3. True abscess formation in OC is rare. 4. The indication for surgical intervention must be based on the clinical presentation and the assessment of true orbital abscess formation.

The effect of Ecstasy on memory is moderated by a functional polymorphism in the cathechol-O-methyltransferase (COMT) gene.

There is ample evidence for decreased verbal memory in heavy Ecstasy users. However, findings on the presence of a dose-response relation are inconsistent, possibly due to individual differences in genetic vulnerability. Catechol-O-methyltransferase (COMT) is involved in the catabolism of Ecstasy. Therefore, COMT gene polymorphisms may moderate this vulnerability. We prospectively assessed verbal memory in subjects with a high risk for future Ecstasy use, and compared 59 subjects after first Ecstasy use with 60 subjects that remained Ecstasy-naive. In addition, we tested the interaction effect of Ecstasy and the functional val (158)met polymorphism on verbal memory. Met-allele carriers were somewhat more sensitive to the effects of Ecstasy on verbal learning than homozygous val-subjects. After correction for the use of other substances this effect was no longer statistically significant. The findings suggest that the COMT gene moderates the negative effect of Ecstasy on memory, but also other drug use seems to play a role.

Striatal dopamine transporter availability associated with polymorphisms in the dopamine transporter gene SLC6A3.

UNLABELLED: Polymorphisms in the dopamine transporter (DAT) gene SLC6A3 are associated with human striatal DAT expression, but the exact effects on DAT expression are not clear. A variable number of tandem repeats (VNTR) in the 3' untranslated region of the DAT gene was previously investigated in relation to striatal DAT availability, but the results were inconclusive. Other polymorphisms in the DAT gene were not extensively studied. Therefore, we investigated whether polymorphisms in both 3' and 5' ends of the DAT gene show association with in vivo striatal DAT expression. METHODS: The subjects were an ethnically homogeneous group of 79 healthy young adults. Striatal DAT availability was measured with 123I-(2-beta-carbomethoxy-3-beta(4-iodophenyl)-tropane) (123I-beta-CIT) SPECT. The 40-base-pair VNTR in the 3' untranslated region of the DAT gene and the 2 single nucleotide polymorphisms (SNPs) rs2652511 and rs2937639 in the 5' end of the DAT gene were genotyped. Multiple-regression analysis was performed for each of the 3 polymorphisms. Analysis of the combination of the polymorphisms (haplotype analysis) was conducted for the triad rs2652511-rs2937639-VNTR. RESULTS: For the VNTR, the 9-repeat (9R) allele was associated with significantly higher striatal DAT expression than was the 10-repeat (10R) allele (P=0.002). Subanalysis suggested a dominant effect for the 9R allele. Neither SNP rs2652511 nor SNP rs2937639 was associated with striatal DAT availability. The haplotype T-A-9R (rs2652511-rs2937639-VNTR) was significantly more associated with higher striatal DAT expression than were the other haplotypes (P=0.009). CONCLUSION: The DAT VNTR 9R carriers have higher striatal DAT availability than do 10R homozygotes. This finding replicates former studies that included healthy subjects and also used 123I-beta-CIT SPECT. Our haplotype analysis identified a subgroup of 9R carriers, the T-A-9R, which appears to be mainly responsible for the association with higher striatal DAT availability. Thus, a combination of polymorphisms in both the 3' and the 5' ends of the DAT gene is associated with in vivo striatal DAT expression. This finding in healthy subjects may contribute to research on DAT availability and genotype in neuropsychiatric disorders.

Sustained effects of ecstasy on the human brain: a prospective neuroimaging study in novel users.

Previous studies have suggested toxic effects of recreational ecstasy use on the serotonin system of the brain. However, it cannot be excluded that observed differences between users and non-users are the cause rather than the consequence of ecstasy use. As part of the Netherlands XTC Toxicity (NeXT) study, we prospectively assessed sustained effects of ecstasy use on the brain in novel ecstasy users using repeated measurements with a combination of different neuroimaging parameters of neurotoxicity. At baseline, 188 ecstasy-naive volunteers with high probability of first ecstasy use were examined. After a mean period of 17 months follow-up, neuroimaging was repeated in 59 incident ecstasy users and 56 matched persistent ecstasy-naives and their outcomes were compared. Neuroimaging included [(123)I]beta-carbomethoxy-3beta-(4-iodophenyl)tropane (CIT) SPECT to measure serotonin transporter densities as indicators of serotonergic function; (1)H-MR spectroscopy ((1)H-MRS) to measure brain metabolites as indicators of neuronal damage; diffusion tensor imaging (DTI) to measure the apparent diffusion coefficient and fractional anisotropy (FA) of the diffusional motion of water molecules in the brain as indicators of axonal integrity; and perfusion weighted imaging (PWI) to measure regional relative cerebral blood volume (rrCBV) which indicates brain perfusion. With this approach, both structural ((1)H-MRS and DTI) and functional ([(123)I]beta-CIT SPECT and PWI) aspects of neurotoxicity were combined. Compared to persistent ecstasy-naives, novel low-dose ecstasy users (mean 6.0, median 2.0 tablets) showed decreased rrCBV in the globus pallidus and putamen; decreased FA in thalamus and frontoparietal white matter; increased FA in globus pallidus; and increased apparent diffusion coefficient in the thalamus. No changes in serotonin transporter densities and brain metabolites were observed. These findings suggest sustained effects of ecstasy on brain microvasculature, white matter maturation and possibly axonal damage due to low dosages of ecstasy. Although we do not know yet whether these effects are reversible or not, we cannot exclude that ecstasy even in low doses is neurotoxic to the brain.

Neurotoxic effects of ecstasy on the thalamus.

BACKGROUND: Neurotoxic effects of ecstasy have been reported, although it remains unclear whether effects can be attributed to ecstasy, other recreational drugs or a combination of these. AIMS: To assess specific/independent neurotoxic effects of heavy ecstasy use and contributions of amphetamine, cocaine and cannabis as part of The Netherlands XTC Toxicity (NeXT) study. METHOD: Effects of ecstasy and other substances were assessed with (1)H-magnetic resonance spectroscopy, diffusion tensor imaging, perfusion weighted imaging and [(123)I]2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane ([(123)I]beta-CIT) single photon emission computed tomography (serotonin transporters) in a sample (n=71) with broad variation in drug use, using multiple regression analyses. RESULTS: Ecstasy showed specific effects in the thalamus with decreased [(123)I]beta-CIT binding, suggesting serotonergic axonal damage; decreased fractional anisotropy, suggesting axonal loss; and increased cerebral blood volume probably caused by serotonin depletion. Ecstasy had no effect on brain metabolites and apparent diffusion coefficients. CONCLUSIONS: Converging evidence was found for a specific toxic effect of ecstasy on serotonergic axons in the thalamus.

Assessment of cognitive brain function in ecstasy users and contributions of other drugs of abuse: results from an FMRI study.

Heavy ecstasy use has been associated with neurocognitive deficits in various behavioral and brain imaging studies. However, this association is not conclusive owing to the unavoidable confounding factor of polysubstance use. The present study, as part of the Netherlands XTC Toxicity study, investigated specific effects of ecstasy on working memory, attention, and associative memory, using functional magnetic resonance imaging (fMRI). A large sample (n=71) was carefully composed based on variation in the amount and type of drugs that were used. The sample included 33 heavy ecstasy users (mean 322 pills lifetime). Neurocognitive brain function in three domains: working memory, attention, and associative memory, was assessed with performance measures and fMRI. Independent effects of the use of ecstasy, amphetamine, cocaine, cannabis, alcohol, tobacco, and of gender and IQ were assessed and separated by means of multiple regression analyses. Use of ecstasy had no effect on working memory and attention, but drug use was associated with reduced associative memory performance. Multiple regression analysis showed that associative memory performance was affected by amphetamine much more than by ecstasy. Both drugs affected associative memory-related brain activity, but the effects were consistently in opposite directions, suggesting that different mechanisms are at play. This could be related to the different neurotransmitter systems these drugs predominantly act upon, that is, serotonin (ecstasy) vs dopamine (amphetamine) systems.

Cognition in novice ecstasy users with minimal exposure to other drugs: a prospective cohort study.

CONTEXT: Ecstasy (street name for [+/-]-3,4-methylenedioxymethamphetamine [MDMA]) use has been associated with cognitive deficits, especially in verbal memory. However, owing to the cross-sectional and retrospective nature of currently available studies, questions remain regarding the causal direction and clinical relevance of these findings. OBJECTIVE: To examine the relationship between Ecstasy use and subsequent cognitive performance. DESIGN: A prospective cohort study in Ecstasy-naive subjects with a high risk for future first Ecstasy use, as part of the Netherlands XTC Toxicity study. The initial examination took place between April 10, 2002, and April 28, 2004; follow-up was within 3 years after the initial examination. SETTING AND PARTICIPANTS: One hundred eighty-eight healthy Ecstasy-naive volunteers (mean age, 22 years) were recruited. Of these, 58 subjects started using Ecstasy (mean cumulative dose, 3.2 tablets; median cumulative dose, 1.5 tablets). They were compared with 60 persistent Ecstasy-naive subjects matched on age, sex, intelligence, and use of substances other than Ecstasy. Differences in cognition between Ecstasy users and Ecstasy-naive subjects were adjusted for differences in cannabis and other recreational drug use. MAIN OUTCOME MEASURES: Change scores between the initial examination and follow-up on neurocognitive tests measuring attention, working memory, verbal and visual memory, and visuospatial ability. RESULTS: At the initial examination, there were no statistically significant differences in any of the neuropsychological test scores between persistent Ecstasy-naive subjects and future Ecstasy users. However, at follow-up, change scores on immediate and delayed verbal recall and verbal recognition were significantly lower in the group of incident Ecstasy users compared with persistent Ecstasy-naive subjects. There were no significant differences on other test scores. CONCLUSIONS: Our findings suggest that even a first low cumulative dose of Ecstasy is associated with decline in verbal memory. Although the performance of the group of incident Ecstasy users is still within the normal range and the immediate clinical relevance of the observed deficits is limited, long-term negative consequences cannot be excluded.

Incidental use of ecstasy: no evidence for harmful effects on cognitive brain function in a prospective fMRI study.

RATIONALE: Heavy ecstasy use in humans has been associated with cognitive impairments and changes in cognitive brain function supposedly due to damage to the serotonin system. There is concern that even a single dose of 3,4-methylenedioxymethamphetamine may be neurotoxic, but very little is known about the consequences of a low dose of ecstasy for cognitive brain function. OBJECTIVES: The objective of the study was to assess the effects of a low dose of ecstasy on human cognitive brain function using functional magnetic resonance imaging (fMRI). MATERIALS AND METHOD: We prospectively studied, as part of the NeXT (Netherlands XTC toxicity) study, sustained effects of a low dose of ecstasy on brain function in 25 subjects before and after their first episode of ecstasy use (mean 2.0 +/- 1.4 ecstasy pills, on average 11.1 +/- 12.9 weeks since last ecstasy use), compared to 24 persistent ecstasy-naive controls, also measured twice and matched with the novice users on age, gender, IQ, and cannabis use. Cognitive brain function was measured in the domains of working memory, selective attention, and associative memory using fMRI. RESULTS: No significant effects were found of a low dose of ecstasy on working memory, selective attention, or associative memory neither at the behavioral level nor at the neurophysiological level. CONCLUSIONS: This study yielded no firm evidence for sustained effects of a low dose of ecstasy on human cognitive brain function. The present findings are relevant for the development of prevention and harm reduction strategies. Furthermore, the study is relevant to the discussion concerning potential therapeutic use of ecstasy.

Quantification of striatal dopamine transporters with 123I-FP-CIT SPECT is influenced by the selective serotonin reuptake inhibitor paroxetine: a double-blind, placebo-controlled, crossover study in healthy control subjects.

UNLABELLED: Dopamine transporter (DAT) imaging with (123)I-FP-CIT ((123)I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane) SPECT is frequently used to detect loss of nigrostriatal cells in parkinsonism. Recent (123)I-beta-CIT ((123)I-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane) studies have shown a significant increase in striatal-to-nonspecific beta-CIT binding ratios after treatment with selective serotonin reuptake inhibitors (SSRIs). Due to similarities between (123)I-beta-CIT and (123)I-FP-CIT (both are derived from cocaine and show relatively high affinity for the DAT and the serotonin transporter [SERT]), we hypothesized that quantification of striatal (123)I-FP-CIT binding may be influenced by SSRIs. Moreover, we hypothesized that (123)I-FP-CIT in humans binds not only to DATs but also to central and peripheral SERTs. METHODS: To study the influence of the SSRI paroxetine on (123)I-FP-CIT binding to DATs in the striatum, we conducted a double-blind, placebo-controlled, crossover study with paroxetine in 8 healthy young male control subjects. In addition, we studied whether paroxetine was able to block (123)I-FP-CIT binding in SERT-rich brain areas and in lung tissue, as lung tissue contains a considerable amount of SERTs. Participants were pretreated for 2 d with paroxetine (20 mg/d) or placebo at 2 sessions (crossover design), and brain SPECT was performed 1 and 3 h after (123)I-FP-CIT injection, whereas lung uptake was measured 2 h after injection. RESULTS: Compared with placebo pretreatment, we found after paroxetine pretreatment a statistically significant increase (approximately 10%) in specific striatal-to-nonspecific (123)I-FP-CIT binding ratios at 3 h after injection, a time point at which striatal (123)I-FP-CIT binding ratios are stable. In addition, after paroxetine treatment, statistically significantly lower binding ratios were found in SERT-rich brain areas (e.g., at 1 h after injection, midbrain-to-cerebellar ratios were approximately 90% lower) as well as significantly lower uptake in lung tissue was found (approximately 40% lower after paroxetine). CONCLUSION: In this study we show that the quantification of striatal (123)I-FP-CIT binding to DAT is significantly increased by the SSRI paroxetine in humans. To our knowledge, this is the first study which shows that (123)I-FP-CIT binds in vivo in humans not only to DATs but also to central SERTs and SERTs in lung tissue.

A prospective cohort study on sustained effects of low-dose ecstasy use on the brain in new ecstasy users.

It is debated whether ecstasy use has neurotoxic effects on the human brain and what the effects are of a low dose of ecstasy use. We prospectively studied sustained effects (>2 weeks abstinence) of a low dose of ecstasy on the brain in ecstasy-naive volunteers using a combination of advanced MR techniques and self-report questionnaires on psychopathology as part of the NeXT (Netherlands XTC Toxicity) study. Outcomes of proton magnetic resonance spectroscopy (1H-MRS), diffusion tensor imaging (DTI), perfusion-weighted imaging (PWI), and questionnaires on depression, impulsivity, and sensation seeking were compared in 30 subjects (12M, 21.8+/-3.1 years) in two sessions before and after first ecstasy use (1.8+/-1.3 tablets). Interval between baseline and follow-up was on average 8.1+/-6.5 months and time between last ecstasy use and follow-up was 7.7+/-4.4 weeks. Using 1H-MRS, no significant changes were observed in metabolite concentrations of N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), and creatine (Cr), nor in ratios of NAA, Cho, and mI relative to Cr. However, ecstasy use was followed by a sustained 0.9% increase in fractional anisotropy (FA) in frontoparietal white matter, a 3.4% decrease in apparent diffusion (ADC) in the thalamus and a sustained decrease in relative regional cerebral blood volume (rrCBV) in the thalamus (-6.2%), dorsolateral frontal cortex (-4.0%), and superior parietal cortex (-3.0%) (all significant at p<0.05, paired t-tests). After correction for multiple comparisons, only the rrCBV decrease in the dorsolateral frontal cortex remained significant. We also observed increased impulsivity (+3.7% on the Barratt Impulsiveness Scale) and decreased depression (-28.0% on the Beck Depression Inventory) in novel ecstasy users, although effect sizes were limited and clinical relevance questionable. As no indications were found for structural neuronal damage with the currently used techniques, our data do not support the concern that incidental ecstasy use leads to extensive axonal damage. However, sustained decreases in rrCBV and ADC values may indicate that even low ecstasy doses can induce prolonged vasoconstriction in some brain areas, although it is not known whether this effect is permanent. Additional studies are needed to replicate these findings.