Haemophagocytic lymphohistiocytosis after intravesical BCG administration for bladder cancer presenting with multiorgan failure.

Bacillus Calmette-Guérin (BCG), is administered intravesically as an adjuvant immunotherapy for the treatment of non-muscle invasive bladder cancer. While mild non-infectious problems can occur in up to 85 % of cases, significant local and systemic complications have been reported in 1-5 % of cases. We report the case of a patient with superficial bladder cancer who developed multiorgan failure after intravesical BCG instillation including the kidney and liver with subsequent haemophagocytic lymphohistiocytosis. Our case illustrates the first reported combination of secondary haemophagocytic lymphohistiocytosis with severe renal and liver failure after BCG immunotherapy for bladder carcinoma. Treatment strategy is discussed.

Outcome of refractory to conventional and/or biologic treatment adult Still's disease following canakinumab treatment: Countrywide data in 50 patients.

OBJECTIVE: To assess the efficacy and safety of the IL-1b inhibitor canakinumab in all adults with refractory Still's disease identified from the National Organization For Medicines for off-label drug use. METHODS: In a retrospective longitudinal multicenter cohort of 50 patients (median age 39 years) with active Still's disease despite treatment with corticosteroids (n = 11), conventional and synthetic (n = 34) and/or biologic disease modifying anti-rheumatic drugs (n = 30), we assessed the efficacy of canakinumab 150-300 mg administered every 4 (n = 47) or 8 weeks (n = 3) as combination therapy or monotherapy (n = 7) during a median follow-up of 27 (3-84) months. RESULTS: Α complete response was initially observed in 78% of patients within 3 months (median), irrespective of age at disease onset. A partial response was evident in 20%. One patient had resistant disease. Treatment de-escalation was attempted in 15 of 39 complete responders and a complete drug discontinuation in 21 patients for 8 months (median). Eleven patients (22%) relapsed during treatment, one during de-escalation process, and 11 after treatment discontinuation. Overall, 9 of 11 relapses were successfully treated with canakinumab treatment intensification or re-introduction. At last visit, 18% of patients were off treatment due to remission and 26% due to disease activity. Canakinumab had a significant corticosteroid sparing effect allowing weaning in 21 of 41 cases. Infections (20%, severe 4%) and leucopenia (6%) led to treatment cessation in one patient. CONCLUSION: High rates of sustained remission were observed in this, largest so far, real-life cohort of adult patients with refractory Still's disease treated with canakinumab.

Treatment modalities and drug survival in a systemic sclerosis real-life patient cohort.

BACKGROUND: European data indicate that systemic sclerosis (SSc)-related death rates are increasing, thus raising concerns about SSc's optimal management. Herein, we describe current treatment modalities and drug survival in a real-life SSc cohort. METHODS: Details on immunosuppressive/antiproliferative (methotrexate, mycophenolate, cyclophosphamide, azathioprine, rituximab, tocilizumab) and vasoactive agent [(endothelin receptor antagonists (ERAs), sildenafil, iloprost, and calcium channel blockers (CCB)] administration during the disease course (11.8 ± 8.4 years, mean + SD) of 497 consecutive patients examined between 2016 and 2018 were retrospectively recorded. Drug survival was assessed by Kaplan-Meier analysis. RESULTS: Methotrexate was the most frequently administered immunosuppressive/antiproliferative agent (53% of patients), followed by cyclophosphamide (26%), mycophenolate (12%), and azathioprine (11%). Regarding vasoactive agents, CCB had been ever administered in 68%, ERAs in 38%, iloprost in 7%, and sildenafil in 7% of patients; 23% of patients with pulmonary fibrosis had never received immunosuppressive/antiproliferative agents, 33% of those with digital ulcers had never received ERAs, iloprost, or sildenafil, whereas 19% of all patients had never received either immunosuppressive/antiproliferative or other than CCB vasoactive agents. Survival rates of methotrexate, cyclophosphamide, and mycophenolate differed significantly, being 84/75%, 59/43%, and 74/63% at 12/24 months, respectively, with inefficacy being the most frequent discontinuation cause. Conversely, CCB, ERAs, and sildenafil had high and comparable retention rates of 97/91%, 88/86%, and 80/80%, respectively. CONCLUSIONS: Existing therapeutic limitations indicate that more evidence-based treatment is warranted for successful management of SSc. Vasculopathy seems to be managed more rigorously, but the low retention rates of immunosuppressive/antiproliferative drugs suggest that effective and targeted disease-modifying agents are warranted.

The effect of TNF-a antagonists on aortic stiffness and wave reflections: a meta-analysis.

Patients with rheumatoid arthritis (RA) have higher aortic stiffness and cardiovascular risk. Tumor necrosis factor alpha (TNF-a) antagonists reduce inflammation in RA and are indicated for the treatment of patients with severe active rheumatoid disease. However, it is debatable if they have favorable effects on cardiovascular health. The present meta-analysis evaluates the effect of TNF-a antagonists on aortic stiffness and wave reflections, predictors of cardiovascular events and mortality, in RA patients. A search of PubMed, Cohrane, and Embase databases was conducted to identify studies into the effect of TNF-a antagonists on aortic stiffness in RA patients. Aortic stiffness and wave reflections were assessed by aortic (carotid-femoral [cf]) pulse wave velocity (PWV) and augmentation index (AIx), respectively. cfPWV significantly improved following TNF-a antagonist treatment (mean change: -0.53 m/s, 95% CI: -0.833 to -0.218, p = 0.001), independently of age and clinical response to treatment. A more prominent reduction in cfPWV was associated with etanercept/adalimumab (mean difference: -0.62 m/s, 95% CI: -0.968 to -0.272 m/s, p < 0.001) versus infliximab (mean difference: -0.193 m/s, 95% CI: -0.847 to 0.462 m/s, p = 0.564). TNF-a antagonist treatment induced a significant improvement in AIx (mean change: -1.48%, 95% CI: -2.89 to -0.078%, p = 0.039), but this reduction was influenced by age and clinical response to treatment. The balance of evidence suggests that TNF-a antagonists may have a beneficial effect on aortic stiffness and, therefore, on cardiovascular risk. However, larger, longitudinal studies are warranted to confirm such findings.

Clinical and financial burden of active lupus in Greece: a nationwide study.

Analyses of the medical and economic burden of chronic disorders such as systemic lupus erythematosus (SLE) are valuable for clinical and health policy decisions. We performed a chart-based review of 215 adult SLE patients with active autoantibody-positive disease at the predefined ratio of 30% severe (involvement of major organs requiring treatment) and 70% non-severe, followed at seven hospital centres in Greece. We reviewed 318 patients consecutively registered over three months (sub-study). Disease activity, organ damage, flares and healthcare resource utilization were recorded. Costs were assessed from the third-party payer perspective. Severe SLE patients had chronic active disease more frequently (22.4% vs 4.7%), higher average SLE disease activity index (SLEDAI) (10.5 vs 6.1) and systemic lupus international collaborating clinics (SLICC) damage index (1.1 vs 0.6) than non-severe patients. The mean annual direct medical cost was €3741 for severe vs €1225 for non-severe patients. Severe flares, active renal disease and organ damage were independent cost predictors. In the sub-study, 19% of unselected patients were classified as severe SLE, and 30% of them had chronic active disease. In conclusion, this is the first study to demonstrate the significant clinical and financial burden of Greek SLE patients with active major organ disease. Among them, 30% display chronic activity, in spite of standard care, which represents a significant unmet medical need.

The three last years of Manuel II Palaeologus' reign between two stroke attacks: aphasia or not?

The authors attempt to solve the enigma about the possible aphasia of the Byzantine Emperor Manuel II Palaeologus (1391-1425) in the 3-year period between his first and his second and fatal stroke. The texts of historians and chroniclers reveal that Manuel remained semi-paralyzed at bed and his motor disability alienated him from the state affairs and condemned him to isolation from all embassies and contact with others, except his family. Only the funeral oration of the Bishop Bessarion raises the suspicion of a speechless emperor. All testimonies referring to this infirmity are examined.

High levels of HCV core+1 antibodies in HCV patients with hepatocellular carcinoma.

The core region of the hepatitis C virus (HCV) genome possesses an overlapping ORF that has been shown to encode a protein, known as the alternate reading frame protein (ARFP), F or core+1. The biological role of this protein remains elusive, as it appears to be non-essential for virus replication. However, a number of independent studies have shown that the ARFP/F/core+1 protein elicits humoral and cellular immune responses in HCV-infected individuals and interacts with important cellular proteins. To assess the significance of the core+1 humoral response in HCV-infected patients, we examined the prevalence of anti-core+1 antibodies in sera from patients with hepatocellular carcinoma (HCC) in comparison with chronically HCV-infected individuals without HCC. We produced two HCV core+1 histidine-tagged recombinant proteins for genotypes 1a (aa 11-160) and 1b (aa 11-144), as well as a non-tagged highly purified recombinant core+1/S protein (aa 85-144) of HCV-1b. Using an in-house ELISA, we tested the prevalence of core+1 antibodies in 45 patients with HCC in comparison with 47 chronically HCV-infected patients without HCC and 77 negative-control sera. More than 50 % of the serum samples from HCC patients reacted with all core+1 antigens, whereas <26 % of the sera from the non-HCC HCV-infected individuals tested positive. No core+1-specific reactivity was detected in any of the control samples. In conclusion, the high occurrence of anti-core+1 antibodies in the serum of HCC patients suggests a role for the ARFP/F/core+1 protein in the pathogenesis of HCC.

Huntington's disease in Greece: the experience of 14 years.

A large scale genetic and epidemiological study of Huntington's disease (HD) was carried out in Greece from January 1995 to December 2008. Diagnostic testing was carried out in 461 symptomatic individuals, while 256 were tested for presymptomatic purposes. The diagnosis of HD with a CAG expansion ≥ 36 was confirmed in 278 symptomatic individuals. The prevalence of HD in Greece was estimated at approximately 2.5 to 5.4:100,000, while the mean minimum incidence was estimated at 2.2 to 4.4 per million per year. The molecular diagnosis of HD was confirmed in the majority of patients (84.4%) sent for confirmation. The false-positive cases 15.6% were characterized by the absence of a family history of HD and the presence of an atypical clinical picture. The uptake of predictive testing for HD was 8.6%. A prenatal test was requested in six pregnancies. The findings of our study do not differ significantly from those of similar studies from other European countries despite the relative genetic isolation of Greece. Of interest is the identification of clusters of HD in Greece. The presence or absence of a family history of HD should be interpreted cautiously, during the diagnostic process.

Churg-Strauss syndrome complicated by neuropathy: a clinicopathological study of nine cases.

OBJECTIVE: The purpose of this study was to investigate the clinical, electrophysiological and pathological features of Churg Strauss syndrome (CSS) neuropathy. METHODS: Biopsies were selected from over 700 sural nerve biopsies. The diagnosis of vasculitis was based on established clinicopathological criteria. Complete laboratory, clinical, electrophysiological and pathological studies were performed in all cases. RESULTS: Nerve biopsies of 9 patients were diagnosed as Churg-Strauss syndrome. The pathological features were vasculitis with predominant axonal degeneration and a varying pattern of myelinated fiber loss. The vasculitic changes were found mainly in small epineural blood vessels. Mononeuritis multiplex and distal symmetrical and asymmetrical sensorimotor neuropathy, were equally frequent. CONCLUSION: We conclude that, Churg-Strauss syndrome complicated frequently with polyneuropathy, and as remission depends on immunosuppressive therapy, it is important to recognize it in the early stage. The diagnosis of polyneuropathy is based on clinical and electrophysiologic studies, but precise histology, immunolohistochemistry and morphometric study of the peripheral nerve biopsy may be decisive in establishing the diagnosis.

The onset of multiple sclerosis in Greece: a single-center study of 1,034 consecutive patients.

BACKGROUND/AIMS: The onset of multiple sclerosis (MS) in Greece has not been systematically studied. We sought to provide data on the onset of MS in Greece with detailed information regarding initial symptoms, and to confirm the prognostic significance of demographic and clinical factors at onset. METHODS: We studied 1,034 consecutive patients with MS and independently assessed 265 patients 'seen at onset'. We used the MS severity score and survival analysis (time to reach an Expanded Disability Status Scale score of 4.0) to evaluate the prognostic significance of factors at onset. RESULTS: Female-to-male ratio was 1.9:1 and mean age at onset was 30.7 +/- 9.9 years. MS was primary progressive in 9.6%. Initial symptoms were optic neuritis in 20.1%, brainstem dysfunction in 14.7%, dysfunction of long tracts in 49.3%, cerebral dysfunction in 1% and a combination of symptoms in 14.9%. In 'seen at onset' patients, detailed data on initial symptoms are presented. Female gender, earlier age at onset, 'bout onset' and onset with optic neuritis were associated with less severe disease and longer time to disability. CONCLUSION: The onset of MS in Greece is similar to Western populations. Initial symptoms are within the expected spectrum. Prognostic significance of factors at onset is as previously identified.

Long-term safety of anti-TNF treatment in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection.

OBJECTIVES: The aim of this prospective study was to examine the safety of anti-tumour necrosis factor (TNF) therapy in patients with rheumatic disease and hepatitis B virus (HBV) infection. METHODS: 14 patients with chronic HBV infection, 19 HBV-vaccinated patients and 19 patients with resolved HBV infection were included in the study. All HBV-infected patients received combination therapy with oral antivirals and anti-TNF agents. During treatment the levels of hepatitis B surface antibodies (anti-HBs) in HBV-vaccinated patients and of serum HBV DNA in patients with chronic or resolved HBV infection were monitored. RESULTS: No viral reactivation was observed in patients with resolved HBV infection while anti-HBs titres decreased during anti-TNF treatment in vaccinated patients, similarly to patients treated with methotrexate alone. None of the HBV-infected patients developed liver decompensation or a significant increase in alanine aminotransferase levels. One patient (7%) treated with lamivudine and etanercept showed viral reactivation due to the emergence of a lamivudine-resistant mutant strain. CONCLUSIONS: Anti-TNF agents represent a safe option for patients with chronic HBV infection when combined with antiviral therapy, as well as in patients previously exposed to HBV receiving no HBV prophylaxis. Resistant HBV strains may arise in patients with chronic hepatitis B, necessitating the initial use of anti-HBV agents with a low risk of resistance.

Incidence of rotational vertigo in supratentorial stroke: a prospective analysis of 112 consecutive patients.

BACKGROUND: Single cases with hemispheric, cortical or subcortical, ischemic lesions presenting with rotational vertigo (RV), that challenge the notion of infratentorial or peripheral generation of RV have been published, but the incidence of this symptom in a larger series is unknown. The aim of this study was to investigate whether acute hemispheric cerebrovascular lesions cause vertiginous sensations with particular emphasis on RV. METHODS: A total of 112 consecutive stroke patients were assessed in a prospective single-center study over a 22-month inclusion period. Rotational or other vertiginous sensations were assessed using a structured 5-item questionnaire and patients with vertigo were further evaluated with Yardley's Vertigo Symptom Scale. All subjects underwent standard clinical neuro-ophthalmological and neuro-otological testing and data were correlated to imaging findings. RESULTS: RV was absent among our patients. Few subjects reported non-rotational vertiginous sensations with stroke onset. These were mainly right-hemispheric strokes with concomitant subcortical leukoaraiosis. CONCLUSION: In this case series we did not find any patients with spinning sensations which is supportive of the dogma that supratenotrial lesions do not cause RV. Certain hemispheric stroke patterns, however, may be related to non-rotational dizziness.

Time-frequency analysis methods to quantify the time-varying microstructure of sleep EEG spindles: possibility for dementia biomarkers?

The time-varying microstructure of sleep EEG spindles may have clinical significance in dementia studies and can be quantified with a number of techniques. In this paper, real and simulated sleep spindles were regarded as AM/FM signals modeled by six parameters that define the instantaneous envelope (IE) and instantaneous frequency (IF) waveforms for a sleep spindle. These parameters were estimated using four different methods, namely the Hilbert transform (HT), complex demodulation (CD), matching pursuit (MP) and wavelet transform (WT). The average error in estimating these parameters was lowest for HT, higher but still less than 10% for CD and MP, and highest (greater than 10%) for WT. The signal distortion induced by the use of a given method was greatest in the case of HT and MP. These two techniques would necessitate the removal of about 0.4s from the spindle data, which is an important limitation for the case of spindles with duration less than 1s. Although the CD method may lead to a higher error than HT and MP, it requires a removal of only about 0.23s of data. An application of this sleep spindle parameterization via the CD method is proposed, in search of efficient EEG-based biomarkers in dementia. Preliminary results indicate that the proposed parameterization may be promising, since it can quantify specific differences in IE and IF characteristics between sleep spindles from dementia subjects and those from aged controls.

The epidemiology of primary systemic vasculitides involving small vessels in Crete (southern Greece): a comparison of older versus younger adult patients.

BACKGROUND: The frequency of primary systemic small vessel vasculitides (PSV) varies among different geographic regions and age categories. We studied PSV in patients from middle-eastern Crete (Greece), and compared clinical characteristics in younger (<65 years) versus older (> or = 65 years) adult patients. METHODS: The records of 67 patients (33 younger, 34 older adults) diagnosed with PSV during 1995-2003 who were referred to a mixed secondary/tertiary care University Hospital in Crete were reviewed. Data on clinical manifestations, diagnosis, therapy, and adverse outcomes (end stage renal disease, death) during a median follow-up of 6 (range 0-12) years were recorded. Multivariate regression analysis was applied to identify independent predictors for adverse outcomes. RESULTS: The overall annual incidence of PSV was 19.5/million (95% confidence interval [CI] 15.7-23.4), 48.9/million (95% CI 33.8-63.9) in older and 12.4/million (95% CI 7.7-17) in younger adults. Microscopic polyangiitis was more prevalent in older patients (65%) and Wegener's Granulomatosis in younger patients (52%). Thirty-one percent of older patients developed end-stage renal disease as compared to 11% of younger patients (p=0.103). Mortality rates were 60% in older patients and 19% in younger patients (p=0.001). In multivariate regression analysis age (Beta=0.33 per 1-year, p=0.005), serum creatinine (Beta=0.29 per 1-mg/dL, p=0.011), and lung involvement (Beta=0.36, p=0.002) at the time of diagnosis were independent predictors for end stage renal disease and/or death. CONCLUSION: This study documents increased frequency and significant mortality of PSV among older people in Crete, with MPA being the most prevalent type. Age, serum creatinine, and lung involvement are important predictors for adverse outcome in these patients.

Stereoanesthesia or astereognosia?

This case attempts to explicit the importance of clinical examination in the differential diagnosis of two similar clinical entities namely astereognosia and stereoanesthesia. The patient presented below involves a multiple sclerosis patient whose symptoms were considered at first to be a case of astereognosia since she mainly complained of an inability to recognize and name the form and nature of objects by touch. However, a thorough clinical examination and the results of neurophysiological and neuroimaging testing demonstrated that it involved a case of stereoanesthesia due to a demyelinating lesion at the cervical region of the spinal cord.

CSF biomarker profile and diagnostic value in vascular dementia.

BACKGROUND AND PURPOSE: The differential diagnosis between vascular dementia (VD) and Alzheimer's disease (AD) or mixed dementia (MD) is not always easy in clinical practice. The purpose of the present study was to evaluate the cerebrospinal fluid (CSF) biomarkers tau protein in its total (tau(T)) or hyperphosphorylated at threonin-181(tau(P-181)) form and beta amyloid peptide 1-42 (A beta 42) alone and their combinations to investigate their diagnostic value in the discrimination between VD and AD or MD. METHODS: The above CSF biomarkers were determined in duplicate and blind to the clinical diagnosis by double sandwich, enzyme-linked immunosorbent assay (ELISA) commercial kits (Innogenetics, Gent, Belgium) in 92 AD patients, 23 VD patients, 17 patients with MD and 68 controls. RESULTS: Alzheimer's disease and MD showed increased levels of tau(T), tau(P) and reduced levels of A beta 42 as compared with the controls. The best discrimination between VD and AD or MD was achieved by the combination of all three biomarkers, correctly classifying >or=85% of patients, either in the form of a discriminant function or in the form of the tau(T) x tau(P-181)/A beta 42 formula. CONCLUSIONS: Cerebrospinal fluid biomarkers may be a useful adjunct for the discrimination between AD/ MD and VD in every day clinical practice.

Dietary lipids and geriatric depression scale score among elders: the EPIC-Greece cohort.

In a prospective epidemiological investigation aiming to identify dietary lipids potentially associated with affective state and depression, 610 healthy men and women aged 60 years or older, participating in the EPIC-Greece cohort and residing in the Attika region had dietary, sociodemographic, anthropometric, medical and lifestyle variables ascertained at enrollment. Six to 13 years later, affective state was evaluated through the 15-point geriatric depression scale (GDS) score along with cognitive function and medical variables. In multivariate linear regression analysis, while adjusting for potential confounders, GDS score was negatively associated with dietary intake of monounsaturated lipids (MUFA) and their main source, olive oil, and positively associated with intake of polyunsaturated lipids (PUFA) and one of their principal sources, seed oils. Intake of calories, total lipids, fish and seafood or saturated lipids did not exhibit significant association with GDS. Potential non-linearities were assessed by quantile multivariate regression analysis: The median GDS score was positively associated with PUFA and seed oils intake, while other lipid groups showed no appreciable associations. The 90th percentile of the GDS score (towards the high end) exhibited significant negative associations with MUFA and olive oil, weaker positive associations with PUFA and seed oils and no appreciable association with other lipid group dietary intakes. We conclude that among Attika elders, lower intake of seed oils and higher intake of olive oil prospectively predict a healthier affective state. Olive oil intake, in particular, predicts a lower chance of scoring in the highest part of the GDS.