Stefan M. Weiner

Diagnosis and monitoring of central nervous system involvement in systemic lupus erythematosus: value of F-18 fluorodeoxyglucose PET

OBJECTIVE To investigate prospectively abnormalities of brain glucose utilisation in relation to major or minor neuropsychiatric symptoms in systemic lupus erythematosus (SLE). METHODS Positron emission tomography (PET) using F-18-labelled fluorodeoxyglucose was performed in 28 patients with SLE. Patients were classified as having severe neuropsychiatric manifestations (seizures, focal neurological deficits, acute confusional states, mood disorders) (n=12), or mild neuropsychiatric manifestations (headache, reactive depression, cognitive dysfunction, anxiety disorders) (n=11) and five patients without signs of central nervous system (CNS) involvement. Ten clinically and neurologically healthy volunteers served as controls. In 26 patients magnetic resonance imaging (MRI) was performed and autoantibodies against CNS tissue, ribosomal P protein and cardiolipin were measured. In 14 patients follow up PET scans were performed after a mean (SD) period of 11.6 (9.5) months. RESULTS PET scans showed hypometabolism in at least one brain region in all patients with severe or mild CNS symptoms (100%) as compared with patients without cerebral symptoms (40%) (p<0.0025). Parieto-occipital regions were most commonly affected (96%), followed by parietal regions (32%). In contrast, MRI images were abnormal in only 11 of 22 patients (50%) with neuropsychiatric symptoms and in one of four patients (25%) without symptoms. In 12 of 14 patients examined in follow up PET scans persistence, improvement or worsening of cerebral symptoms were associated with unchanged, decreased or increased brain hypometabolism, respectively. No significant correlation was found between PET or MRI findings and autoantibody profiles. CONCLUSIONS PET imaging represents a sensitive tool to detect manifest or subclinical CNS involvement in SLE and PET findings correlate well with the clinical course of disease.

High-dose cholecalciferol to correct vitamin D deficiency in haemodialysis patients

BACKGROUND Vitamin D has emerged as an important survival factor in patients with chronic kidney disease. Non-activated vitamin D may also have beneficial effects on bone, cardiovascular and immune functions. Cholecalciferol is the prevalent non-activated vitamin D in Europe, but there is no valid prospective data available about its use in haemodialysis patients. Thus, we initiated a prospective study to evaluate dosing, safety and tolerability of cholecalciferol supplementation in haemodialysis patients. METHODS The prospective study included 64 haemodialysis patients. During replenishment phase patients received 20 000 IU cholecalciferol/week for 9 months. In the open maintenance phase (15 months), patients were randomized to a treated group (20 000 IU cholecalciferol/month) and an untreated group, which did not receive cholecalciferol. RESULTS Calcidiol [25(OH)D] deficiency (<37.5 nmol/l; <15 microg/l) was detected in 61/64 patients (95%). During the replenishment phase, calcidiol increased significantly from 16.65 +/- 9.6 to 79.48 +/- 27.15 nmol/l (6.66 +/- 3.84 microug/l to 31.79 +/- 10.86 microg/l) (P < 0.001). Recommended levels (>75 nmol/l; >30 microg/l; K/DOQI) were achieved in 57% of patients. Calcium increased from 2.28 +/- 0.17 to 2.37 +/- 0.19 mmol/l (9.1 +/- 0.69 mg/dl to 9.49 +/- 0.75 mg/dl) (P<0.01). Phosphorus, calcium-phosphorus product and parathyroid hormone showed no significant changes. Fifty-nine patients progressed to the maintenance phase. Analysis per protocol showed a significant drop of calcidiol in the treated [83.98 +/- 31.73 versus 78.5 +/- 38.75 nmol/l (33.59 +/- 12.69 versus 31.4 +/- 15.5 microg/l) (P < 0.001)] and untreated groups [86.35 +/- 40.75 versus 53.4 +/- 26.2 nmol/l (34.54 +/- 16.3 versus 21.36 +/- 10.48 microg/l) (P < 0.001)]. The comparison of the treated and the untreated groups showed no significant differences at the beginning of the maintenance phase: 83.98 +/- 31.73 versus 86.35 +/- 40.75 nmol/l (33.59 +/- 12.69 versus 34.54 +/- 16.3 microg/l). At the end they differed significantly: 78.5 +/- 38.75 versus 53.4 +/- 26.2 nmol/l (31.4 +/- 15.5 versus 21.36 +/- 10.48 microg/l) (P < 0.001). CONCLUSION Vitamin D deficiency is present in a majority of haemodialysis patients. Supplementation with cholecalciferol is safe, well tolerated and reasonable to replenish vitamin D stores in haemodialysis patients. However, only 57% of patients achieved recommended calcidiol levels, thus favouring additional dose-finding studies.

Mycophenolate sodium for subacute cutaneous lupus erythematosus resistant to standard therapy

Background  Approximately 75–95% of patients with cutaneous lupus erythematosus respond to antimalarial therapy and/or topical glucocorticosteroids. Immunosuppressive agents are usually considered a second‐line approach in patients with resistant disease.

Renal Toxicity after Radionuclide Therapy

Abstract Lambert, B., Cybulla, M., Weiner, S. M., Van De Wiele, C., Ham, H., Dierckx, R. A. and Otte, A. Renal Toxicity after Radionuclide Therapy. Radiat. Res. 161, 607–611 (2004). During the past 10 years, a variety of radiolabeled monoclonal antibodies, antibody fragments, and low-molecular- weight oncophilic peptides have been used to deliver radioactivity to target cells for therapeutic purposes. The high and persistent localization of several of these radiolabeled molecules in the kidneys raised concern about potential renal radiation toxicity compromising therapeutic effectiveness. In particular, radiolabeled peptides, such as yttrium-90-labeled synthetic somatostatin analogues, have initiated a discussion on the safety profiles of the various somatostatin derivatives in recent clinical trials. In general, the toxicity risk seems to depend on the characteristics of the oncophilic molecule, such as the molecular weight, electric charges and clearance pathways as well as the chemical and physical characteristics of the applied radionuclide. Encouraging results for the prevention of radiation-induced renal damage by radiolabeled peptides have been obtained by co-infusion of positively charged amino acids. The available literature on nephrotoxicity after radiolabeled peptide therapy is reviewed, and therapeutic options that have become available as a result of greater insights into putative pathogenic mechanisms are discussed.

A clinical and virological study of hepatitis C virus-related cryoglobulinemia in Germany

BACKGROUND/AIMS Several reports, especially from Southern Europe, have demonstrated a close association between hepatitis C virus (HCV) infection and mixed cryoglobulinemia. In this study we have analyzed the significance of HCV-related cryoglobulinemia in Germany. METHODS Sera from 79 patients with cryoglobulinemia of type I (n=21), II (n=28) or III (n=30) were investigated for HCV markers. Furthermore, 132 consecutive patients with chronic hepatitis C were studied for the presence of cryoglobulins. Genotypes of HCV were determined according to Simmonds, and HCV-RNA concentrations were measured in patients with and without cryoglobulinemia. RESULTS In 79 patients with cryoglobulinemia we found anti-HCV antibodies in 17 (22%) and HCV-RNA in 11 patients (14%). HCV antibodies were more frequent in essential (44%) compared to secondary mixed cryoglobulinemia (15%). In 132 patients with chronic HCV infection cryoglobulins were detected in 37 patients (28%), in 21 of them at low levels. Clinical symptoms due to cryoglobulinemia were observed in eight of the 37 patients, severe vasculitis in three patients with high cryocrit-levels and cryoprecipitation at room temperature. HCV genotype 1 and subtype 1b were most prevalent, both in patients with and without cryoglobulinemia, and mean HCV-RNA levels were not different between the two groups. Comparison of HCV-RNA levels in cryoprecipitates, supernatant and native serum suggests binding of HCV-RNA to the cryoprecipitate with different affinity in individual patients. CONCLUSIONS The lower prevalence of HCV-related cryoglobulinemia in our study compared with data from Italy and France suggests a south-north gradient in the prevalence of HCV-associated cryoglobulinemia in Europe.

Brain glucose utilization in systemic lupus erythematosus with neuropsychiatric symptoms: a controlled positron emission tomography study.

In contrast to morphological imaging [such as magnetic resonance imaging (MRI) or computed tomography], functional imaging may be of advantage in the detection of brain abnormalities in cases of neuropsychiatric systemic lupus erythematosus (SLE). Therefore, we studied 13 patients (aged 40±14 years, 11 female, 2 male) with neuropsychiatric SLE who met four of the American Rheumatism Association criteria for the classification of SLE. Ten clinically and neurologically healthy volunteers served as controls (aged 40±12 years, 5 female, 5 male). Both groups were investigated using fluorine-18-labelled fluorodeoxyglucose brain positron emission tomography (PET) and cranial MRI. The normal controls and 11 of the 13 patients showed normal MRI scans. However, PET scan was abnormal in all 13 SLE patients. Significant group-to-group differences in the glucose metabolic index (GMI=region of interest uptake/global uptake at the level of the basal ganglia and thalamus) were found in the parieto-occipital region on both sides: the GMI of the parieto-occipital region on the right side was 0.922±0.045 in patients and 1.066±0.081 in controls (P<0.0001, Mann WhitneyU test), while on the left side it was 0.892±0.060 in patients and 1.034±0.051 in controls (P=0.0002). Parietooccipital hypometabolism is a conspicuous finding in mainly MRI-negative neuropsychiatric SLE. As the parieto-occipital region is located at the boundary of blood supply of all three major arteries, it could be the most vulnerable zone of the cerebrum and may be affected at an early stage of the cerebrovascular disease.

Alterations of cerebral glucose metabolism indicate progress to severe morphological brain lesions in neuropsychiatric systemic lupus erythematosus

Neuropsychiatric systemic lupus erythematosus (SLE) is frequently associated with deficits in brain glucose metabolism, even if morphological imaging by magnetic resonance imaging (MRI) shows no abnormalities. In these patients it is unclear whether or not the changes of brain metabolism measured by F-18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) may progress to lesions of cerebral structure. We describe a 20-year-old woman with SLE who presented with depression, headache and impairment of memory. Initially, a cranial MRI was negative, but FDG-PET revealed significant hypometabolism in the frontal and parieto-temporo-occipital regions on both sides as well as hypermetabolism in the nuclei caudati. Within two months the patient developed an acute confusional state, seizures, visual disturbances and cranial MRI became positive showing hyperintensities at the basal ganglia and the temporo-occipital regions. Focal cerebral symptoms responded to treatment with high dose corticosteroids and brain lesions in MRI disappeared. However, a second FDG-PET showed persistent hypometabolism at frontal regions in accordance with the persistence of subclinical depression. To our knowledge, this is the first SLE case report showing that functional brain lesions visualized by FDG-PET may be a risk factor for subsequent structural brain damage seen in MRI. Thus, FDG-PET may help to verify cerebral involvement of SLE earlier than MRI.

Neuropsychiatric systemic lupus erythematosus before and after immunosuppressive treatment: a FDG PET study

At its inception, morphological imaging, like magnetic resonance imaging (MRI), is often not useful in neuropsychiatric systemic lupus erythematosus (NPSLE), although the disease clinically shows cerebral symptoms. Functional imaging, like positron emission tomography (PET), may be a method that offers some advantages. We report a 53-year-old white man with decreased memory and visual disturbances who met four of the American Rheumatism Association (ARA) criteria for the classification of SLE. He was investigated before and after 3 months of therapy using PET and F-18-fluoro-2-deoxy-D-glucose (FDG). Treatment consisted of prednisone (25 mg/day, tapered to 10 mg/day) and cyclophosphamide (daily 100 mg for 3 weeks followed by a drug-free interval of 1 week). For the control group, 15 clinically and neurologically healthy volunteers (5 male, 10 female, aged 48–7 years) were investigated. All study participants additionally had a cranial MRI. In both controls and the SLE patient, cranial MRI was negative. However, the patient showed a significant hypometabolism in the region parieto-occipital on both sides and the parietal region on the right side before treatment. After treatment metabolism in these regions was within normal limits. Hence, FDG-PET could help to verify brain-onset of SLE earlier and may be a powerful tool for controlling SLE treatment.

Neuro-Behçet's syndrome in a patient not fulfilling criteria for Behçet's disease: clinical features and value of brain imaging.

Abstract: Central nervous system involvement is rarely an initial presenting manifestation of Behçet’s disease (BD). We report the case of a 33-year-old man with recurrent attacks of fever, oral mucosal ulcers, deep venous thrombosis, diplopia, vertigo and headache. Sequential brain magnetic resonance imaging (MRI) scans showed fluctuating lesions of the brain stem, mesencephalon and thalamus. F-18-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) revealed hypometabolism at the parieto-occipital cortex at both sides and the brain stem. Treatment with prednisone and cyclosporine A led to a complete remission and normalisation of MRI and FDG-PET lesions. The present case illustrates the difficulty in the differential diagnosis of early neuro-BD.

The renal resistance index is increased in mild-to-moderate obstructive sleep apnoea and is reduced under continuous positive airway pressure

BACKGROUND Impaired renal function has recently been reported in obstructive sleep apnoea (OSA). The underlying mechanisms, however, are not entirely understood. This study investigated the influence of mild-to-moderate OSA and its treatment on renal haemodynamics as assessed by the renal resistance index (RRI). METHODS RRI has been measured by colour duplex ultrasound in 64 patients with newly diagnosed mild-to-moderate OSA and 61 controls without OSA at baseline and follow-up after 9.9 months. Treatment with continuous positive airway pressure was offered to all patients with OSA (apnoea/hypopnoea index ≥ 5/h). RESULTS Increased values of RRI (≥ 1 SD [8.9%] above the age-adjusted normal value) were found in 41 out of 64 (64.0%) OSA patients when compared with 20 out of 61 (32.8%) controls (P < 0.001). The corresponding mean RRI was 70.50 ± 9.01 vs 66.51 ± 8.33 (P = 0.012). In multivariate analyses, the influence of OSA on RRI was independent from hypertension, diabetes mellitus, age and baseline renal function. At follow-up, RRI decreased only in patients with effective OSA treatment but remained unchanged in ineffectively treated OSA patients and controls. CONCLUSIONS For the first time, this prospective controlled observational study demonstrates an impairment of renal haemodynamics in OSA as measured by an increased RRI. These changes of renal blood flow may identify OSA patients at high risk of declining renal function. Both parenchymal and vascular renal diseases are proposed as pathomechanisms for this association. An effective treatment of OSA resulted in a decreased RRI, suggesting an improvement in renal perfusion. Further studies are needed to elucidate the role of impaired renal haemodynamics in OSA.