Prevalence and clinical impact of incidental findings on the unenhanced CT images of PET/CT scan in patients with multiple myeloma: the value of radiological reporting in the multimodal hybrid imaging.

OBJECTIVE: In the hybrid Positron Emission Tomography/Computed Tomography (PET/CT) method, the functional evaluation is integrated with the morphological information provided by co-registered CT, still performed for attenuation correction and lesion localization. However, co-registered CT images could provide additional diagnostic information that PET alone could underestimate. To optimize the diagnostic potential of this hybrid examination, we evaluated the prevalence and the clinical significance of incidental findings detected on co-registered CT images in a cohort of multiple myeloma (MM) patients. PATIENTS AND METHODS: We evaluated 112 MM patients (mean age 65.8 y), who underwent [18F]FDG-PET/CT during their regular workup. All co-registered CT images were retrospectively reviewed by two expert radiologists and each non-myelomatous incidental finding (nM-IF) was collected and clinically graded according to a nM-IF Reporting and Data System (nM-RADS). In addition, nM-IFs were classified according to anatomic localization (skull, lung, mediastinum, abdomen, breast, gastrointestinal, genitourinary and cardiovascular system and muscle/soft tissue). RESULTS: 163 nM-IFs were detected in 94/112 patients (83.9%) (mean value: 1.5 IFs per patient). The most interested anatomic districts were the lung (n=33; 20.2%), genitourinary (n=33; 20.2%) and gastrointestinal (n=30; 18.4%) systems. Focusing on the clinically significant findings (nM3+nM4), 92/163 (56.4%) IFs could have been required further investigations, of which 38/163 (23.3%) were potentially important and detected in 33/112 (29.5%) patients. CONCLUSIONS: The high percentage of potentially clinically significant IFs detected in MM patients emphasizes that co-registered CT images hold precious information often missed. Giving more relevance to co-registered CT with tailored acquisition and reconstruction protocols and dedicated reporting could optimize the potentiality of this multimodality imaging method with impact on clinical management.

Infection prevention in endoscopy practice: comparative evaluation of re-usable vs single-use endoscopic valves.

Re-usable air/water and suction valves used in endoscopes often demonstrate risk of infection. To the authors' knowledge, the safety and efficacy of re-usable and single-use valves have not been compared to date. As such, a laboratory investigation was undertaken to compare the safety and efficacy of re-usable and single-use valves at 11 Italian endoscopy sites. Safety was evaluated by analysing the rinse liquid of reprocessed re-usable valves ready for use, and efficacy was assessed based on the completion of endoscopic procedures without valve malfunction. This study found significantly lower contamination of single-use valves compared with re-usable valves (0 vs 29.1%, respectively; P=0.007) and similar efficacy (97.6 vs 98.8%, respectively; P=ns). Microbiological analysis of the rinse liquid of reprocessed re-usable valves identified various surviving micro-organisms and highlighted their potential pathogenicity. Such data suggest that sterile single-use valves may be safer than re-usable valves, and have comparable performance.

Rescue of striatal long-term depression by chronic mGlu5 receptor negative allosteric modulation in distinct dystonia models.

An impairment of long-term synaptic plasticity is considered as a peculiar endophenotype of distinct forms of dystonia, a common, disabling movement disorder. Among the few therapeutic options, broad-spectrum antimuscarinic drugs are utilized, aimed at counteracting abnormal striatal acetylcholine-mediated transmission, which plays a crucial role in dystonia pathophysiology. We previously demonstrated a complete loss of long-term synaptic depression (LTD) at corticostriatal synapses in rodent models of two distinct forms of isolated dystonia, resulting from mutations in the TOR1A (DYT1), and GNAL (DYT25) genes. In addition to anticholinergic agents, the aberrant excitability of striatal cholinergic cells can be modulated by group I metabotropic glutamate receptor subtypes (mGlu1 and 5). Here, we tested the efficacy of the negative allosteric modulator (NAM) of metabotropic glutamate 5 (mGlu) receptor, dipraglurant (ADX48621) on striatal LTD. We show that, whereas acute treatment failed to rescue LTD, chronic dipraglurant rescued this form of synaptic plasticity both in DYT1 mice and GNAL rats. Our analysis of the pharmacokinetic profile of dipraglurant revealed a relatively short half-life, which led us to uncover a peculiar time-course of recovery based on the timing from last dipraglurant injection. Indeed, striatal spiny projection neurons (SPNs) recorded within 2 h from last administration showed full expression of synaptic plasticity, whilst the extent of recovery progressively diminished when SPNs were recorded 4-6 h after treatment. Our findings suggest that distinct dystonia genes may share common signaling pathway dysfunction. More importantly, they indicate that dipraglurant might be a potential novel therapeutic agent for this disabling disorder.

Endovenous radiofrequency for chronic superficial venous insufficiency: Clinical outcomes and impact in quality of life.

BACKGROUND: Endovenous treatment of lower limb varicose veins is progressively replacing conventional surgery. The authors are investigating radiofrequency (RFA) results in terms of vein occlusion, complications, patient's satisfaction and quality of life in a single centre. METHODS AND MATERIALS: A retrospective analysis of medical charts with a prospective follow-up was performed on data about patients undergoing RFA for insufficiency of great saphenous vein (GSV). RESULTS: A total number of 135 patients (164 limbs) (63% n 85 female; 37% n 50 male; mean age of 53.9 years, range 24-85 years; mean VCSS score (Venous Clinical Severity Score) 6, range 4-22) were included. Complete obliteration of GSV was obtained in 98.2% of the cases. No device- or procedure-related adverse events occurred. No deep venous thromboses, pulmonary embolism, phlebitis, major bleeding, paraesthesia nor skin burn were detected. Patients returned to normal activities in a mean of 8 days (range 5-10). One-month postoperatively, the mean quality of life scores 6 (range 5-9) and mean satisfaction score was 6 (range 4-8) in a scale from 0 to 8. At a median follow-up of 11 months (range 2-18), mean VCSS was 3.9 (range 2-8). CONCLUSIONS: Radiofrequency guarantees good functional outcomes and low rate of complications. It is associated with high satisfaction rate and quality of life score.

EAN consensus statement for management of patients with neurological diseases during the COVID-19 pandemic.

BACKGROUND AND PURPOSE: The recent SARS-CoV-2 pandemic has posed multiple challenges to the practice of clinical neurology including recognition of emerging neurological complications and management of coexistent neurological diseases. In a fast-evolving pandemic, evidence-based studies are lacking in many areas. This paper presents European Academy of Neurology (EAN) expert consensus statements to guide neurologists caring for patients with COVID-19. METHODS: A refined Delphi methodology was applied. In round 1, statements were provided by EAN scientific panels (SPs). In round 2, these statements were circulated to SP members not involved in writing them, asking for agreement/disagreement. Items with agreement >70% were retained for round 3, in which SP co-chairs rated importance on a five-point Likert scale. Results were graded by importance and reported as consensus statements. RESULTS: In round one, 70 statements were provided by 23 SPs. In round two, 259/1061 SP member responses were received. Fifty-nine statements obtained >70% agreement and were retained. In round three, responses were received from 55 co-chairs of 29 SPs. Whilst general recommendations related to prevention of COVID-19 transmission had high levels of agreement and importance, opinion was more varied concerning statements related to therapy. CONCLUSION: This is the first structured consensus statement on good clinical practice in patients with neurological disease during the COVID-19 pandemic that provides immediate guidance for neurologists. In this fast-evolving pandemic, a rapid response using refined Delphi methodology is possible, but guidance may be subject to change as further evidence emerges.

Infective endocarditis following transcatheter aortic valve implantation.

Trans-catheter aortic valve implantation (TAVI) has recently emerged as a less invasive alternative to surgical aortic valve replacement (SAVR) in high risk patients. Although several procedures have been performed worldwide, infective endocarditis (IE) has been reported to be a rare TAVI complication, nevertheless if IE occurs it represents a life-threatening condition and treatment is challenging. TAVI-IE are thus normally treated conservatively by targeted antibiotic therapy with a high reported mortality (40%). Surgical explant represent the definitive strategy but, the intervention is at a high risk (risk of complication 87%, with an in hospital mortality of about 47%). In the present paper, we report the case of a 71-year-old patient affected by an early endocarditis after TAVI (TAVI-IE) treated at our Institution by surgical explant. The case highlights a paradox: if TAVI procedures are indicated over traditional surgical valve replacement in treatment of high surgical risk patients, what should be the best management when TAVI-IE occurs in these same population of patients?

Treatment of lower limb arterial disease by Dardik graft: It takes one to know one.

OBJECTIVE: To perform a comprehensive literature review on outcomes achieved with the historical Dardik graft, illustrated with a case report of a patient with 13-years primary patency and limb salvage. METHODS: A comprehensive literature review was performed through MedLine (PubMed.gov, U.S. National Library of Medicine, National Institute of Health) from 1976 to 2018 using search terms (Umbilical Vein Graft), (Dardik graft), (Glutaraldehyde stabilized human umbilical vein [HUV]) and (HUV) to collected data on clinical use of HUV. Only papers in English and reporting adequate information about indication for surgery, short- and long-term patency and complication rate were included. RESULTS: Data about a total of 899 patients (977 limbs) were available. Overall, 45% of patients (438 limbs) underwent HUV implantation for critical limb ischemia (rest pain or tissue loss) or for disabling claudication in 12.2% of cases (120 limbs). Others indication for surgery were acute onset limb ischemia, popliteal aneurysms or aneurysmal degeneration of a previously implanted synthetic graft. At a mean follow-up of 4.3 years (range 3-6 years), primary patency and secondary patency were 61.3% and 61%, respectively. Aneurisms formation was detected in 3% of cases (21 limbs), graft's infection in 24.4% of cases (31 limbs) and graft's thrombosis in 25.5% of cases (193 limbs). CONCLUSION: This article provide a historical review of the use, outcomes and complications of HUV. Even though it is no longer commercially available, the knowledge of this type of substitute still remains inspirational for the development of innovative vascular conduits and fundamental for the new generations of physician both in diagnostics and in the management of complications.

The international European Academy of Neurology survey on neurological symptoms in patients with COVID-19 infection.

BACKGROUND AND PURPOSE: Although the main clinical features of COVID-19 infection are pulmonary, several associated neurological signs, symptoms and diseases are emerging. The incidence and characteristics of neurological complications are unclear. For this reason, the European Academy of Neurology (EAN) core COVID-19 Task Force initiated a survey on neurological symptoms observed in patients with COVID-19 infection. METHODS: A 17-question online survey was made available on the EAN website and distributed to EAN members and other worldwide physicians starting on 9 April 2020. RESULTS: By 27 April 2020, proper data were collected from 2343 responders (out of 4199), of whom 82.0% were neurologists, mostly from Europe. Most responders (74.7%) consulted patients with COVID-19 mainly in emergency rooms and in COVID-19 units. The majority (67.0%) had evaluated fewer than 10 patients with neurological manifestations of COVID-19 (neuro COVID-19). The most frequently reported neurological findings were headache (61.9%), myalgia (50.4%), anosmia (49.2%), ageusia (39.8%), impaired consciousness (29.3%) and psychomotor agitation (26.7%). Encephalopathy and acute cerebrovascular disorders were reported at 21.0%. Neurological manifestations were generally interpreted as being possibly related to COVID-19; they were most commonly recognized in patients with multiple general symptoms and occurred at any time during infection. CONCLUSION: Neurologists are currently and actively involved in the management of neurological issues related to the COVID-19 pandemic. This survey justifies setting up a prospective registry to better capture the prevalence of patients with neuro COVID-19, neurological disease characteristics and the contribution of neurological manifestations to outcome.

Models of dystonia: an update.

Although dystonia represents the third most common movement disorder, its pathophysiology remains still poorly understood. In the past two decades, multiple models have been generated, improving our knowledge on the molecular and cellular bases of this heterogeneous group of movement disorders. In this short survey, we will focus on recently generated novel models of DYT1 dystonia, the most common form of genetic, "isolated" dystonia. These models clearly indicate the existence of multiple signaling pathways affected by the protein mutation causative of DYT1 dystonia, torsinA, paving the way for potentially multiple, novel targets for pharmacological intervention.

Does SARS-Cov-2 invade the brain? Translational lessons from animal models.

The current coronavirus disease (COVID-19) outbreak, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has raised the possibility of potential neurotropic properties of this virus. Indeed, neurological sequelae of SARS-CoV-2 infection have already been reported and highlight the relevance of considering the neurological impact of coronavirus (CoV) from a translational perspective. Animal models of SARS and Middle East respiratory syndrome, caused by structurally similar CoVs during the 2002 and 2012 epidemics, have provided valuable data on nervous system involvement by CoVs and the potential for central nervous system spread of SARS-CoV-2. One key finding that may unify these pathogens is that all require angiotensin-converting enzyme 2 as a cell entry receptor. The CoV spike glycoprotein, by which SARS-CoV-2 binds to cell membranes, binds angiotensin-converting enzyme 2 with a higher affinity compared with SARS-CoV. The expression of this receptor in neurons and endothelial cells hints that SARS-CoV-2 may have higher neuroinvasive potential compared with previous CoVs. However, it remains to be determined how such invasiveness might contribute to respiratory failure or cause direct neurological damage. Both direct and indirect mechanisms may be of relevance. Clinical heterogeneity potentially driven by differential host immune-mediated responses will require extensive investigation. Development of disease models to anticipate emerging neurological complications and to explore mechanisms of direct or immune-mediated pathogenicity in the short and medium term is therefore of great importance. In this brief review, we describe the current knowledge from models of previous CoV infections and discuss their potential relevance to COVID-19.

Use of amyloid PET/CT with 18F-Florbetaben in the management of patients with Alzheimer's disease.

INTRODUCTION AND AIM: Amyloid PET/CT is an "in vivo" imaging that may radically change management of Alzheimer's disease (AD) thanks to its ability to identify AD at the earliest stage. A diagnosis of dementia is currently made in terms of probability and is based on clinical evaluation (neuropsycological tests) as well as on the results of morphological imaging investigations (MRI) that can be supported by biohumoral (CSF analysis), and functional imaging only in the case of uncertain diagnosis of disease. The present study aimed to evaluate the role of amyloid PET/CT in the management of patients with suspicion of AD, through comparison with instrumental and clinical evaluation. METHODS: 38 consecutive patients with suspicion of AD (23 female, 15 male; median age 63 years old, range 46-72), who performed 18F-florbetaben PET/CT, were retrospectively reviewed. All of them performed a previous instrumental evaluation. A subgroup of patients (24/38) were evaluated with Mini Mental State Examination (MMSE). Cohen's K test was used as a measure of agreement between previous instrumental examinations/clinical evaluation and beta-amyloid PET results. RESULTS: Twenty-five/38 (65.8%) amyloid PET/CT scans resulted positive for amyloid deposition. Among the four target regions, precuneus was the most frequently involved. Previous instrumental evaluation was: MRI in 26/38 patients (24/26 positive for atrophy), CT in 9/38 (8/9 positive for atrophy), perfusion SPECT in 12/38 (8/12 areas of hypo-perfusion), 18F-FDG PET/CT in 2/38 (1/2 hypometabolism in frontal cortex). The agreement between previous instrumental examinations and beta-amyloid PET results was low (K= 0.084). In the subgroup of 24/38 patients, MMSE was scored positive (MMSE<24) in 14/24 (58.4%) and negative (MMSE>24) in 10/24 (41.6%). The agreement between clinical evaluation (MMSE) and beta-amyloid PET results was fair (K= 0.217). CONCLUSION: The low agreement between amyloid PET/CT and previous clinical and instrumental assessments that we found in our study suggests that the amyloid PET/CT provides additional and early information. To perform an early and differential diagnosis of AD could have a great impact on the patient's management and cost of care in order to perform the correct therapeutic interventions and to allow family members to manage adequately the patient's demanding care.

Nutritional management in renal transplant recipients: A transplant team opportunity to improve graft survival.

AIMS: The nutritional management of renal transplant recipients (RTR) represents a complex problem either because the recovery of renal function is not complete and for the appearance of "unavoidable" metabolic side effects of immunosuppressive drugs. Nevertheless, it remains a neglected problem, whereas an appropriate dietary intervention could favorably affect graft survival. DATA SYNTHESIS: Renal transplantation is associated with steroids and calcineurin inhibitors administration, liberalization of diet after dialysis restrictions, and patients' better quality of life. These factors predispose, from the first months after surgery, to body weight gain, enhanced post transplant diabetes, hyperlipidemia, metabolic syndrome, with negative consequences on graft outcome. Unfortunately, specific guidelines about this topic and nutritional counseling are scarce; moreover, beyond the low adherence of patients to any dietary plan, there is a dangerous underestimation of the problem by physicians, sometimes with inadequate interventions. A prompt and specific nutritional management of RTR can help prevent or minimize these metabolic alterations, mostly when associated with careful and repeated counseling. CONCLUSIONS: A correct nutritional management, possibly tailored to enhance patients' motivation and adherence, represents the best preventive maneuver to increase patients' life and probably improve graft survival, at no cost and with no side effects.

Dystonia: Are animal models relevant in therapeutics?

Dystonia refers to a heterogeneous group of movement disorders characterized by involuntary, sustained muscle contractions leading to repetitive twisting movements and abnormal postures. A better understanding of the etiology, pathogenesis and molecular mechanisms underlying dystonia may be obtained from animal models. Indeed, while studies in vitro using cell and tissue models are helpful for investigating molecular pathways, animal models remain essential for studying the pathogenesis of these disorders and exploring new potential treatment strategies. To date, the mouse is the most common choice for mammalian models in most laboratories, particularly when manipulations of the genome are planned. Dystonia animal models can be classified into two categories, etiological and symptomatic, although neither is able to recapitulate all features of these disorders in humans. Nevertheless, etiological and symptomatic animal models have advantages and limitations that should be taken into consideration according to the specific proposed hypothesis and experimental goals. Etiological mouse models of inherited dystonia can reproduce the etiology of the disorder and help to reveal biochemical and cellular alterations, although a large majority of them lack motor symptoms. Conversely, symptomatic models can partially mimic the phenotype of human dystonia and test novel pharmacological agents, and also identify the anatomical and physiological processes involved, although the etiology remains unknown. Thus, our brief survey aims to review the state of the art as regards most of the commonly used animal models available for dystonia research.

Correction to: The Italian Dystonia Registry: rationale, design and preliminary findings.

In the original article, Gina Ferrazzano was affiliated to Department of Neurology and Psychiatry, Neuromed Institute IRCCS, Sapienza University of Rome, Pozzilli, Italy.The corrected affiliation should be: Neuromed Institute IRCCS, Pozzilli, IS, Italy.

Redefining the Pulvinar Sign in Fabry Disease.

BACKGROUND AND PURPOSE: The pulvinar sign refers to exclusive T1WI hyperintensity of the lateral pulvinar. Long considered a common sign of Fabry disease, the pulvinar sign has been reported in many pathologic conditions. The exact incidence of the pulvinar sign has never been tested in representative cohorts of patients with Fabry disease. The aim of this study was to assess the prevalence of the pulvinar sign in Fabry disease by analyzing T1WI in a large Fabry disease cohort, determining whether relaxometry changes could be detected in this region independent of the pulvinar sign positivity. MATERIALS AND METHODS: We retrospectively analyzed brain MR imaging of 133 patients with Fabry disease recruited through specialized care clinics. A subgroup of 26 patients underwent a scan including 2 FLASH sequences for relaxometry that were compared with MRI scans of 34 healthy controls. RESULTS: The pulvinar sign was detected in 4 of 133 patients with Fabry disease (3.0%). These 4 subjects were all adult men (4 of 53, 7.5% of the entire male population) with renal failure and under enzyme replacement therapy. When we tested for discrepancies between Fabry disease and healthy controls in quantitative susceptibility mapping and relaxometry maps, no significant difference emerged for any of the tested variables. CONCLUSIONS: The pulvinar sign has a significantly lower incidence in Fabry disease than previously described. This finding, coupled with a lack of significant differences in quantitative MR imaging, allows hypothesizing that selective involvement of the pulvinar is a rare neuroradiologic sign of Fabry disease.

Abnormal striatal plasticity in a DYT11/SGCE myoclonus dystonia mouse model is reversed by adenosine A2A receptor inhibition.

Striatal dysfunction is implicated in many movement disorders. However, the precise nature of defects often remains uncharacterized, which hinders therapy development. Here we examined striatal function in a mouse model of the incurable movement disorder, myoclonus dystonia, caused by SGCE mutations. Using RNAseq we found surprisingly normal gene expression, including normal levels of neuronal subclass markers to strongly suggest that striatal microcircuitry is spared by the disease insult. We then functionally characterized Sgce mutant medium spiny projection neurons (MSNs) and cholinergic interneurons (ChIs). This revealed normal intrinsic electrophysiological properties and normal responses to basic excitatory and inhibitory neurotransmission. Nevertheless, high-frequency stimulation in Sgce mutants failed to induce normal long-term depression (LTD) at corticostriatal glutamatergic synapses. We also found that pharmacological manipulation of MSNs by inhibiting adenosine 2A receptors (A2AR) restores LTD, again pointing to structurally intact striatal circuitry. The fact that Sgce loss specifically inhibits LTD implicates this neurophysiological defect in myoclonus dystonia, and emphasizes that neurophysiological changes can occur in the absence of broad striatal dysfunction. Further, the positive effect of A2AR antagonists indicates that this drug class be tested in DYT11/SGCE dystonia.

Home infusion program with enzyme replacement therapy for Fabry disease: The experience of a large Italian collaborative group.

Fabry disease (FD) [OMIM 301500] is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in progressive multisystem accumulation of globotriaosylceramide (Gb3). Although the introduction of Enzyme Replacement Therapy (ERT) resulted in a variety of clinical benefits, life-long intravenous (IV) treatment with ERT with an every other week schedule, may interfere with daily life activities and impact on QoL. We report here a multicentric, observational, longitudinal data analysis on a large cohort of 85 Italian FD patients (45 males, 40 females) from 11 out of 20 Italian regions, who received a cumulative number of 4269 home infusions of agalsidase alfa. For the whole cohort, the average duration of home therapy was 1 year and 11 months (range 3 months-4 years and 6 months), and during this period, compliance to treatment (number of infusions performed vs scheduled) reached 100%. The EQ-5 VAS scale was administered to patients to evaluate the self-reported QoL, 58% of patients showing an increase of EQ-5 VAS score at follow up compared to baseline (home treatment start) or remaining stable. A mild increase of average disease severity, measured through Mainz Severity Score Index (MSSI), was found during hospital treatment (p < 0,007), while it remained stable between the first home therapy infusion and last follow up. Interestingly, 4 out of 7 (57%) patients, showing an improvement in FD-related clinical status after starting home therapy, had previously a sub-optimal compliance to treatment during the period of hospital treatment management. Only 4 adverse non serious reactions (0,093%) were reported totally in 2 patients during home treatment. We conclude that home infusions in eligible patients with FD are safe, contribute to improve treatment compliance and therapeutic clinical outcomes, and may have a positive impact on self-perceived QoL.

Small intestinal bacterial overgrowth and celiac disease: A systematic review with pooled-data analysis.

BACKGROUND: A link between small intestinal bacterial overgrowth (SIBO) and celiac disease (CD) has been hypothesized. METHODS: Literature search was performed in main medical databases. Methods of analysis/inclusion criteria were based on Preferred Reporting Items for Systematic reviews and Meta-Analyses recommendations. The end-point was to estimate, by a pooled-data analysis, SIBO prevalence in CD. Proportions/percentages and their 95% confidence intervals (CI) were calculated by inverse variance method, whereas odd ratios (OR) and their 95% CI were estimated, where available, based on the Mantel-Haenszel method. Data were entered into the RevMan 5.3 software. KEY RESULTS: Eleven articles fulfilled considered criteria. The pooled mean prevalence of SIBO in CD was 20% (95% CI of 10%-30%). In comparison to asymptomatic controls, CD was associated to higher risk of SIBO, with an OR of 10.52 (95% CI 2.69-41.21, P=.0007). Jejunal aspirate culture assessed SIBO prevalence of 11% (95% CI 3%-19%) in CD, whereas breath tests detected a higher value (23%, 95% CI 10%-37%). The pooled prevalence of SIBO in CD patients who were symptomatic despite a GFD was 28% (95% CI 10%-47%), higher than in asymptomatic celiac patients (pooled prevalence of 10%, with a 95% CI of 3%-16%), despite not statistically significant (P=.06). When GFD-unresponsive CD was defined only by clinical persistence of symptoms, the prevalence of SIBO was higher than in the case of villous atrophy association (31% vs 16% P=.33). CONCLUSIONS: The heterogeneity of available studies may not support a relationship SIBO-CD. Nevertheless, SIBO could be more common in CD when symptoms do not improve after GFD.