Fundamental mechanistic insights from rare but paradigmatic neuroimmunological diseases.

The pathophysiology of complex neuroimmunological diseases, such as multiple sclerosis and autoimmune encephalitis, remains puzzling - various mechanisms that are difficult to dissect seem to contribute, hampering the understanding of the processes involved. Some rare neuroimmunological diseases are easier to study because their presentation and pathogenesis are more homogeneous. The investigation of these diseases can provide fundamental insights into neuroimmunological pathomechanisms that can in turn be applied to more complex diseases. In this Review, we summarize key mechanistic insights into three such rare but paradigmatic neuroimmunological diseases - Susac syndrome, Rasmussen encephalitis and narcolepsy type 1 - and consider the implications of these insights for the study of other neuroimmunological diseases. In these diseases, the combination of findings in humans, different modalities of investigation and animal models has enabled the triangulation of evidence to validate and consolidate the pathomechanistic features and to develop diagnostic and therapeutic strategies; this approach has provided insights that are directly relevant to other neuroimmunological diseases and applicable in other contexts. We also outline how next-generation technologies and refined animal models can further improve our understanding of pathomechanisms, including cell-specific and antigen-specific CNS immune responses, thereby paving the way for the development of targeted therapeutic approaches.

Impact of systemic immune-mediated diseases on clinical features and prognosis of patients with biopsy-proved myocarditis.

INTRODUCTION: Myocarditis has been described in association with many systemic immune-mediated diseases (SIDs). However, the role of SIDs in influencing clinical presentation and outcome of patients with a new diagnosis of biopsy-proved myocarditis, has never been investigated so far. METHODS: We enrolled 25 consecutive cases with biopsy-proved myocarditis in the context of SIDs, and controls with isolated myocarditis, matched 1:1 by age, gender, ethnicity and clinical presentation. All of the patients presented with acute symptoms, normal coronary arteries, and no previous history of myocarditis. Detailed diagnostic workup, including blood exams, echocardiogram, arrhythmia monitoring and cardiac magnetic resonance (CMR) were obtained at baseline and at defined time points, up to 12-month follow-up (FU). RESULTS: At presentation, patients with SIDs had more commonly inflammatory biomarkers elevation, signs of associated pericarditis, and replacement fibrosis at histology, as compared to controls (18 vs. 6, 20 vs. 12, and 21 vs. 11, respectively; all p < 0.05). The Lake Louise criteria at CMR were negative in 19 vs. 10 patients with and without underlying SIDs, respectively (p = 0.021). Baseline ECG, in-hospital arrhythmia telemonitoring and echocardiographic findings were not significantly different between groups (all p = n.s.). At 12-month FU, the composite major endpoint of cardiac death, end-stage heart failure or malignant ventricular arrhythmias was significantly more common in cases than in controls (7 vs. 1, respectively, p = 0.049). CONCLUSION: In patients with a new diagnosis of myocarditis, the presence of underlying SIDs is associated with distinct baseline clinical features and a significantly worse 1-year outcome.

Prenatal Bowel Findings in Male Siblings With a Confirmed FOXP3 Mutation.

There are multiple etiologies for fetal dilated bowel loops on ultrasonography (US), and we present a unique case of male siblings with a forkhead box P3 (FOXP3) mutation. Both children presented with fetal bowel anomalies on prenatal US. Family histories of cystic fibrosis and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome were reported. Amniocentesis in both pregnancies identified a normal male karyotype and the familial mutation associated with IPEX syndrome. IPEX syndrome is one of a group of conditions known as congenital diarrhea disorders. Other congenital diarrhea disorder cases have presented with similar prenatal US findings. As a result of these associations, we suggest considering IPEX syndrome as a potential cause of fetal bowel anomalies, particularly with a known family history. However, continued research into the phenotypic and genotypic correlations for IPEX syndrome is likely needed to better understand this possible prenatal presentation.

The value of 18F-FDG-PET/CT in identifying the cause of fever of unknown origin (FUO) and inflammation of unknown origin (IUO): data from a prospective study.

BACKGROUND: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are diagnostically challenging conditions. Diagnosis of underlying disease may be improved by 18F-fluorodesoxyglucose positron emission tomography (18F-FDG-PET). METHODS: Prospective study to test diagnostic utility of 18F-FDG-PET/CT in a large cohort of patients with FUO or IUO and to define parameters that increase the likelihood of diagnostic 18F-FDG-PET/CT. Patients with FUO or IUO received 18F-FDG-PET/CT scanning in addition to standard diagnostic work-up. 18F-FDG-PET/CT results were classified as helpful or non-helpful in establishing final diagnosis. Binary logistic regression was used to identify clinical parameters associated with a diagnostic 18F-FDG-PET/CT. RESULTS: 240 patients were enrolled, 72 with FUO, 142 with IUO and 26 had FUO or IUO previously (exFUO/IUO). Diagnosis was established in 190 patients (79.2%). The leading diagnoses were adult-onset Still's disease (15.3%) in the FUO group, large vessel vasculitis (21.1%) and polymyalgia rheumatica (18.3%) in the IUO group and IgG4-related disease (15.4%) in the exFUO/IUO group. In 136 patients (56.7% of all patients and 71.6% of patients with a diagnosis), 18F-FDG-PET/CT was positive and helpful in finding the diagnosis. Predictive markers for a diagnostic 18F-FDG-PET/CT were age over 50 years (p=0.019), C-reactive protein (CRP) level over 30 mg/L (p=0.002) and absence of fever (p=0.001). CONCLUSION: 18F-FDG-PET/CT scanning is helpful in ascertaining the correct diagnosis in more than 50% of the cases presenting with FUO and IUO. Absence of intermittent fever, higher age and elevated CRP level increase the likelihood for a diagnostic 18F-FDG-PET/CT.

Imaging findings in systemic childhood diseases presenting with dermatologic manifestations.

PURPOSE: Many childhood diseases often present with skin abnormalities with which radiologists are largely unfamiliar. Knowledge of associated dermatologic manifestations may aid the radiologist in confirming the diagnosis and recommending targeted imaging of affected organs. METHODS: We review the imaging findings in childhood diseases associated with dermatologic manifestations. FINDINGS: Diseases include dermatologic findings which herald underlying malignancy (Neuroblastoma, leukemia/lymphoma, Langerhans cell histiocytosis),are associated with risk of malignancy (Epidermolysis Bullosa, basal cell nevus syndrome, Cowden's syndrome, Tuberous Sclerosis),or indicate a systemic inflammatory/immune disorder (Kawasaki's disease, Henoch Schonlein Purpura, systemic lupus erythematosus, scleroderma, sarcoidosis, dermatomyositis and immune thrombocytopenic purpura). CONCLUSION: Familiarity with pertinent findings in childhood diseases presenting with dermatologic manifestations in childhood diseases aids the radiologist in confirming the diagnosis and guiding imaging workup.

Quantitative measurement of 18F-FDG PET/CT uptake reflects the expansion of circulating plasmablasts in IgG4-related disease.

Objective: [18F]Fluorodeoxyglucose (18F-FDG) PET/CT is increasingly used to assess organ involvement and response to treatment in IgG4-related disease (IgG4-RD), but clear correlations between 18F-FDG uptake and disease activity have not been established yet. We aimed to correlate the intensity and distribution of 18F-FDG uptake with validated clinical, serological and immunological parameters of IgG4-RD activity. Methods: Twenty patients with active IgG4-RD underwent a baseline 18F-FDG PET/CT. Ten patients repeated 18F-FDG PET/CT after immunosuppressive treatments. 18F-FDG tissue uptake was measured using the standardized uptake value corrected for the partial volume effect (PVC-SUV) and the total lesion glycolysis (TLG) with (TLGtot+ln) and without (TLGtot-ln) lymph nodes. Disease activity was assessed by means of clinical parameters [IgG4-RD Responder Index (RI)], serological (ESR and CRP) and immunological (serum IgG4 and circulating plasmablasts) biomarkers. The enhanced liver fibrosis score was exploited as a biomarker for fibroblast activation. Results: Thirteen (65%) patients had two or more organs affected by IgG4-RD. All patients had active IgG4-RD as defined by a median IgG4-RD RI value of 9 (range 6-15; normal < 3). Serum IgG4 and plasmablasts were elevated in 85% of patients. Circulating plasmablasts positively correlated with PVC-SUV (P = 0.027), inversely correlated with TLGtot-ln (P = 0.023) and did not correlate with TLGtot+ln (P > 0.05). No statistically significant correlation was found between PVC-SUV or TLG and IgG4-RD RI, ESR, CRP, serum IgG4 or enhanced liver fibrosis score (P > 0.05). Clinical response to immunosuppressive therapies was associated with a consensual reduction of circulating plasmablasts, PVC-SUV, TLGtot+ln and TLGtot-ln values (P < 0.05 for all comparisons). Conclusions: 18F-FDG uptake of IgG4-RD lesions reflects immunological perturbations of the B cell compartment rather than fibroblast activation and extracellular matrix deposition. Conventional biomarkers of disease activity, namely IgG4-RD RI, ESR, CRP and serum IgG4 levels, do not appear to correlate with the radiometabolic activity of IgG4-RD lesions. In light of our results PET/CT represents a reliable instrument for assessing IgG4-RD activity, although lymph-node uptake deserves careful interpretation.

IgG4-related disease of the lung: a rare differential diagnosis to lung cancer after positive positron emission tomography and biopsy.

Immunoglobulin G4-related disease is a rare immune-mediated condition that often causes serious diagnostic problems. Symptoms are unspecific, and several organs can be involved. To date, IgG4-related lung disease has seldom been reported in literature. Nevertheless, a variety of pulmonary involvement has been described, which can mimic malignancy. The gold standard for the diagnosis is the identification of typical histopathological features, even if diagnostic biomarker such as serum IgG4 concentration can be an indicator for a more aggressive course of the disease.

Viruses, Immunity and Unusual Lymphoproliferative Disorders of the Chest: Integrating Imaging With Pathogenesis and Clinical Presentations.

Unusual lymphoproliferative diseases result from the stimulation of intrathoracic lymphoid tissue by viruses and immune dysfunction, ranging from benign hyperplasia to malignant transformation. We review the clinical, radiological, and histopathological findings of unusual lymphoproliferative disorders, which have been linked to viruses or immune dysfunction, focusing on thoracic manifestations. Understanding these advances in science enhances the radiologist's skills in integrating the imaging findings to the clinical scenario to suggest the correct diagnosis.

A case of immunogammaglobulin 4-related disease.

An 81-year-old woman with history of thyroiditis and a putative diagnosis of retroperitoneal fibrosis presented with abdominal pain, progressive shoulder pain, back pain, and lower extremity weakness. Abdominal and pelvic MRI revealed periaortic inflammation and a left renal mass, which were F-FDG avid on PET/CT. Renal biopsy was compatible with immunogammaglobulin 4 (IgG4)-related disease. Total spine MRI revealed postcontrast meningeal enhancement, correlating with FDG activity. Epidural biopsy showed chronic inflammation and scattered but not abnormal IgG4-positive cells, possibly related to posttreatment changes. This case exemplifies multiorgan involvement in IgG4-related disease.

Whole-body gallium-67 scintigraphic findings in IgG4-related disease.

PURPOSE: To clarify the features of gallium-67 (Ga-67) imaging typical of IgG4-related disease. METHODS: We retrospectively investigated 14 patients diagnosed with IgG4-related disease who underwent Ga-67 scintigraphy in our hospital between January 2005 and May 2010. Of these, 13 patients who underwent gallium scintigraphy before steroid therapy were enrolled in this study. The patient population comprised 11 men and 2 women with age ranging from 47 to 76 years (mean age, 61.9 years). RESULTS: Among the 13 patients, significant accumulation of Ga-67 was detected in the bilateral pulmonary hila in 10 patients (77%), pancreas in 10 (77%), salivary glands in 7 (54%), lacrimal glands in 7 (54%), periaortic lesions in 2 (15%), and lung parenchyma in 1 (8%) patient. High accumulation of Ga-67 in the salivary glands was observed in the parotid glands in 3 cases and in the submandibular glands in 6 cases, with the following pattern: normal parotid gland uptake and symmetrical submandibular gland uptake in 2 cases; symmetrical high accumulation in both parotid and submandibular glands in 1 case; symmetrical high accumulation in parotid glands and normal submandibular gland uptake in 1 case; symmetrical uptake by parotid glands and asymmetric uptake by submandibular glands in 1 case; normal parotid gland uptake and asymmetric submandibular gland uptake in 1 case; and asymmetric parotid gland uptake and symmetrical parotid gland uptake in 1 case. CONCLUSION: Characteristic patterns of gallium uptake would be helpful for diagnosis, detection of involved lesions, and differential diagnosis in patients with IgG4-related disease to avoid unnecessary surgery.

Future clinical prospects in somatostatin/cortistatin/somatostatin receptor field.

Somatostatin receptors (sst), somatostatin (SS) and cortistatin (CST) are widely expressed in the various systems in the human and rodent organisms and are "responsible" for maintaining homeostasis, which is essential for survival. Because of their broad expression pattern sst, SS and CST interactions may play regulatory roles in both physiology and pathophysiology in mammalian organisms. SS analogue treatment strategies as well as the use of SS analogues for diagnostic purposes have been established in diseases of different origins. This review focuses on the currently determined role for SS analogues in today's clinical practice and the potential clinical prospects for SS, CST and sst interactions in the future, with a focus on neuroendocrine and non-neuroendocrine tumours and immune-mediated diseases. Moreover, the role of new SS analogues and new insights in sst physiology will be discussed.

[Radiographic presentation of the bronchial and pulmonary changes in children with selected primary immunodeficiencies]. / Obraz radiologiczny przewleklych zmian oskrzelowych i plucnych u dzieci z wybranymi pierwotnymi niedoborami odpornosci.

In the paper authors presented issues concerning clinical manifestation of primary immunodeficiency diseases in children. Considering the frequently recognized changes in the respiratory tract in this group of disorders, particular attention was paid to the chronic bronchopulmonary disease taking into consideration it's clinical course and radiographic presentation in selected cases.

Imaging features of pulmonary Kaposi sarcoma-associated immune reconstitution syndrome.

OBJECTIVE: The purpose of this study was to analyze the radiologic features of pulmonary Kaposi sarcoma-associated immune reconstitution syndrome. The syndrome is a phenomenon characterized by clinical deterioration of the condition of HIV-positive patients after initiation of highly active antiretroviral therapy. MATERIALS AND METHODS: The study included four patients at our institution who fulfilled the diagnostic criteria for pulmonary Kaposi sarcoma-associated immune reconstitution syndrome from 2001 to 2006. All patients were men (mean age, 43 years; range, 31-59 years). Images reviewed included chest radiographs obtained before highly active antiretroviral therapy, radiographs and chest CT scans obtained at appearance of the symptoms of Kaposi sarcoma-associated immune reconstitution syndrome, and follow-up radiographs and chest CT scans during immune reconstitution syndrome. RESULTS: The radiographic findings of Kaposi sarcoma-associated immune reconstitution syndrome included reticular and reticulonodular opacities (n = 4), areas of consolidation (n = 3), septal lines (n = 3), and pleural effusion (n = 3). The CT findings in all four patients were ill-defined pulmonary nodules and interlobular septal thickening. Three of the patients had a CT halo sign, areas of consolidation, ground-glass opacities, lymphadenopathy, and pleural effusion. The areas of consolidation in three subjects who did not receive chemotherapy increased markedly after 14-20 days. CT performed during the initial symptoms of immune reconstitution syndrome in these three subjects showed less than 5% parenchymal involvement. Follow-up CT showed 26-50% involvement in two patients and more than 50% involvement in one patient. CONCLUSION: The radiologic findings of pulmonary Kaposi sarcoma-associated immune reconstitution syndrome are similar to the findings described in patients with Kaposi sarcoma without the syndrome, but the extent of abnormalities tends to increase with the development of the syndrome.

The radiology of IRIS (immune reconstitution inflammatory syndrome) in patients with mycobacterial tuberculosis and HIV co-infection: Appearances in 11 patients.

AIM: To determine the radiological manifestations of IRIS (immune reconstitution inflammatory syndrome) in patients with HIV and mycobacterium tuberculosis co-infection, in the context of their demographic and clinical data. MATERIALS AND METHODS: The radiological imaging, demographic and clinical data of 11 patients diagnosed with IRIS associated with HIV and mycobacterial tuberculosis co-infection were studied retrospectively. Where available, follow-up imaging studies were also reviewed. RESULTS: The most common radiological feature of IRIS was lymph node enlargement (73%), with central low attenuation centres, in keeping with necrosis, present in most of these cases (88%). Most commonly affected were intra-abdominal nodes (70%), followed by axillary (40%) and mediastinal lymph nodes (36%). Within the lung parenchyma, diffuse, bilateral pulmonary nodules were seen in 55% of cases. Unilateral small volume pleural effusions were seen in two cases with associated parenchymal changes seen in only one. Small volume ascites was seen in two cases. Thirty-six percent of cases presented with new or worsening abscesses despite treatment. In this context, image-guided radiological drainage proved a useful adjunct to the conventional medical therapy for IRIS. The most common clinical signs of IRIS included fever (64%), abdominal pain (36%) and cough (27%). CONCLUSION: We have described the radiological features that are characteristic in IRIS and the importance of putting these into context with the clinical and pathological findings as part of a multidisciplinary approach in making the diagnosis. The role of the radiologist is central in diagnosis, monitoring of disease progression and management of complications in patients with IRIS.

Immune dysfunction in the presence of residual splenic tissue.

Immunological function was examined in children who had undergone splenectomy, in 8 for trauma, and in 11 for haematologic/oncologic reasons. Particular emphasis was placed on the effects of residual splenic tissue on immune function. Children in the elective group had no evidence of splenosis but 6 of the 8 trauma patients showed residual splenic activity. A general trend indicated that immunological dysfunction was associated with the presence of residual splenic tissue. Three patients with significant post-traumatic splenosis showed low IgM levels, one also had a low IgG level and another a low IgA and impaired lymphocyte response to mitogens. The trauma patients with little or no splenic tissue had normal immune functions. Immunological abnormalities were found in 8 of the 11 haematologic/oncologic patients with no splenosis suggesting the abnormalities were possibly due to the primary disease. In contrast to the popular belief that splenosis confers protection against overwhelming sepsis, the present findings suggest that patients with residual splenic tissue are at a greater risk of infection because of a lower level of immune response.

Acroosteolysis. Problems of diagnosis--report of four cases.

Four cases of idiopathic acroosteolysis are reported. The first is a common phalangeal type, the second, the Hozay variety. The third case was diagnosed after a mumps infection, and marked regress of the changes was noted in the following years. The fourth case shows skin changes, periostitis, mild osteosclerosis, and skull changes as well as acroosteolysis.

Radiographic findings of immunoblastic lymphadenopathy and related immunoblastic proliferations.

Immunoblastic lymphadenopathy is a recently recognized disorder of unknown etiology accompanied by clinical manifestations similar to lymphoma. Radiographic examinations of nine patients revealed multisystemic involvement and findings similar to those of lymphomatous processes. The diagnosis of immunoblastic lymphadenopathy should be considered when lung involvement accompanies mediastinal adenopathy and when the anterior mediastinal nodes are spared. One of the patients developed allergic pneumonitis which is interesting in light of recognition of immunoblastic lymphadenopathy as a hyperimmune phenomenon.