26 years of LDL--apheresis: a review of experience.

Since 1981, when LDL-Apheresis was introduced into the clinical routine at the University of Cologne as the first and so far only Apoprotein B specific LDL-cholesterol elimination technique, considerable experience has since then accumulated and has changed not only the operational technique but also extended the indications, the optimation of the target values, the introduction of supportive cholesterol lowering drug therapy, considerations of the potential pleiotropic mechanisms and the introduction of a quality control supported electronic data processing. Mild to moderate side effects range between 3% and 4.5%, whereas serious undesired reactions did not occur within 26 years with more than 80,000 treatments performed at Cologne and considerably more world wide. As cholesterol can nowadays be widely eliminated in patients with familial hypercholesterolaemia (FH), the focus of consideration should be more directed to the treatment of additional risk factors. Thus, centres of competence, providing for more than the ability to technically reduce cholesterol may be desirable. Whereas numerous diagnostic procedures exist to demonstrate the value of cholesterol lowering therapies, the prolongation of survival as demonstrated in 7 homozygous and 29 heterozygous FH patients and in 5 patients with end stage disease appears to be the most convincing evidence for the value of LDL-Apheresis. Due to the repetitive cycling and re-use LDL-Apheresis is furthermore not only the most efficient but also the most economic approach to extracorporeal LDL-elimination therapy.

Small-scale extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma: a report of 3 cases.

Extracorporeal photopheresis is an accepted method for the treatment of cutaneous T-cell lymphoma and much progress has recently been achieved in therapy and understanding of its mechanism. In general large numbers of white blood cells are collected by a cell separator and irradiated in the presence of 8-MOP. In contrast to this practice, data from an animal model showed that as few as 0.2% of the body's blood volume irradiated are sufficient to achieve an immune response after photopheresis. Based on these data we developed a small-scale photopheresis procedure and applied the method in 3 end-stage T-cell lymphoma patients who were not eligible for apheresis. The mononuclear cells from 50 ml of blood were separated by density gradient centrifugation, irradiated with UV-light in the presence of 8-Methoxy-Psoralen (MOP) with 2J/cm(2) and reinjected. 2-3 treatments per week were conducted. The three patients-2 male and 1 female, age 63-86, Sezary syndrome (1x) and mycosis fungoides in tumour stage (2x)-showed no side effects on cell injection. The two patients with mycosis fungoides showed a prompt regression and softening of the tumours. The patient with Sezary syndrome developed numerous necrotic spots on the skin after 6 weeks of therapy that turned normal within a few days. Patient 1 died of pneumonia 4 weeks after the start of therapy and patient 3 died of heart failure 8 weeks after start of therapy, both during regression of the tumours. Patient 2 was treated over a period of 11 months, with an initial regression in the first weeks followed by a slow progression of the tumours after she rejected any form of further treatment. The small-scale extracorporeal photopheresis therapy presented is effective in cutaneous T-cell lymphoma. But questions regarding the optimal number of cells irradiated per treatment, the conditions of cell incubation after irradiation and the number of treatment cycles are still open. Therefore further studies are required to establish a method that is effective and circumvents the use of apheresis technology.

Standardized ultrasound as a new method to induce platelet aggregation: evaluation, influence of lipoproteins and of glycoprotein IIb/IIIa antagonist tirofiban.

Most of the published studies concerning platelet aggregation were performed with chemical stimulation procedures, however, mechanical stimulation might be a better simulation of physiological activation of platelets. In order to evaluate the influence of ultrasound on platelet aggregation in vitro, we developed an ultrasound device in a standardized set-up, and we evaluated the influence of lipoproteins and the glycoprotein IIb/IIIa inhibitor tirofiban on ultrasound induced platelet aggregation. A cylindrical shaped plastic test tube with 1 ml of platelet-rich plasma was placed in an ultrasound bath (35 kHz) for 5 s. The ultrasound energy transfer into the sample (Delta W=3.77 J) was calculated using the average temperature increase (averaged by 0.935 degrees C) of the sample. Platelet aggregation was quantified immediately after stimulation with ultrasound or adenosine diphosphate (ADP 2.1 and 4.2 microM) by the Myrenne Aggregometer PA2 at low (40 s(-1)) and afterwards at high (2500 s(-1)) shear. To evaluate the influence of lipoproteins, seven healthy male volunteers were investigated before and after a fat load (50 g fat per m(2) body surface), and 11 patients suffering from hypercholesterolemia and atherosclerotic disease before and after a single low-density lipoprotein (LDL) apheresis. Platelet aggregation after ultrasound stimulation was well correlated with platelet aggregation after ADP (r between 0.50 and 0.95). However, when exposed to high shear, the low shear-induced platelet aggregates were more stable after ultrasound stimulation compared with ADP stimulation either with or without tirofiban. After the fat load triglyceride concentration increased from 0.86+/-0.39 to 2.10+/-1.10 mmol l(-1) (P<0.05) resulting in a reduced formation of platelet aggregates after weak (ADP 2.1 microM) but not after strong (ADP 4.2 microM or ultrasound) stimuli. After a single LDL apheresis LDL cholesterol dropped from 3.99+/-0.90 to 1.06+/-0.55 mmol l(-1) (P<0.005). No changes in platelet aggregation were observed with the exception of a lower aggregation when exposed to high shear after stimulation with 2.1 microM ADP. In conclusion, we found the ultrasound stimulation of platelet-rich plasma easy to perform. The platelet aggregation after ultrasound stimulation correlated well with stimulation after ADP. While a reduction in LDL cholesterol concentration had only slight effects on platelet aggregation, an increase in triglyceride concentration resulted in a reduced formation of platelet aggregates after weak stimulation.

First experience with a ready-for-use rheohemapheresis system.

Rheohemapheresis is increasingly being used for the improvement of microcirculation in numerous diseases. The method is based on the constant-flow separation of plasma by a cell separator and the secondary filtration of plasma through a hollow-fiber membrane. A new CE-marked system has recently been launched for an improved continuous flow blood separator (dideco Excel Pro) that contains a connection kit between the cell separator and a secondary filter and software which includes differential filtration as a standard protocol. The new system was used in our center using ethylenevinylalcohol secondary filters (Evaflux LA4 or LA5). 99 procedures were completed in 47 patients. A median of 2.7 (1.6-4.2) 1 of plasma were processed via the secondary filter in 109 (41-218) min. The values in peripheral blood before and after the treatment were total protein 6.7 (5.8-8.9)/ 5.3 (4.4-6.7) g/dl, fibrinogen 215 (118-480)/110 (37-275) mg/dl and cholesterol 200 (134-254)/92 (69 149) mg/dl. A median platelet loss of 30% in the peripheral blood of the patients was observed partly by platelet content of the separated plasma of 30 g/l after 500 ml of treatment and 10 g/l after 2,500 ml. Major side effects in the patients were not observed. The new differential filtration system already fulfills the demands of a ready-to-use CE-marked rheohemapheresis system but improvements in the details of the treatment protocol are still required and under way.

The current state of extracorporeal haemorheotherapy: from haemodilution via cascadefiltration to rheohaemapheresis.

Rheological therapy aims at an improvement of organ perfusion however, it has to be stressed that the tonus of the blood vessels also plays an important role for both the blood distribution and the rheology in the micro- and the macrocirculation. Conventional rheotherapy consists of attempts to influence nutrition and life style, to apply drugs such as purin derivatives, vasodilatating or defibrinising substances and hypervolaemic (using infusion therapy), hypovolaemic, e.g., blood letting, erythrocytapheresis and--the most widely distributed- -isovolaemic haemodilution. With the introduction of centrifugal devices, and approximately 10 years later with the introduction of hollow fibre and flat sheet membrane techniques, a considerable increase of therapeutical efficacy was achieved. These technologies were successfully applied for the treatment of cellular and plasmatic hyperviscosity syndromes. The treatment of less severe diseases of the micro- and macrocirculation, vessel stenosis, vessel wall sclerosis, malformation of the blood vessel architecture, pathological clinical-chemical blood parameters and maldistribution have hardly been taken into consideration. Our group at Köln investigated different plasma differential separation techniques and demonstrated, that adsorption as well as filtration could be applied. These different techniques being 6-10 times more effective as conventional haemodilution techniques have in common high molecular weight proteins determining the viscosity of plasma and thus whole blood viscosity is removed, however differences among the different elimination techniques do exist. The rheological and clinical importance of such differences has to be determined. Applying filtration techniques for both primary and secondary separations, the concept of Rheohaemapheresis was developed. A corresponding quality program was also introduced into our clinical routine. Rheohaemapheresis is supported from the currently introduced concept of the synergetic consideration of the microcirculation. Age related macular degeneration, so far without generally accepted therapy, is a most advanced indication based on several pilot studies and a prospective, randomised controlled trial. Other diseases of the microcirculation have also successfully been treated.

The role of rheology in hemapheresis.

Rheological therapy attempts to favorably influence the blood flow mechanics for the treatment of diseases, mainly of the microcirculation but also of the macrocirculation. Hemapheresis, originally used only for the elimination of an excess of cellular or plasmatic components, was shown to also influence the hemorheology favorably. As extracorporeal therapy affects the rheology much more than conventional hemorheotherapy, not only cellular or plasmatic hyperviscosity syndromes but also many more diseases associated with organ perfusion problems due to diseases of the micro- and macrocirculation, especially in the elderly, were and are increasingly considered to be indicated. Technical progress led away from plasma exchange as an unspecific and unselective procedure to plasma differential separation using precipitation. adsorption, and filtration. With our recent development, we demonstrated that rheohemapheresis is the most advanced technical procedure. The mechanism of action can well be related to a synergetic consideration of rheology. However. one has to keep in mind that the elimination of blood components such as lipids, immunoglobulins, and endothelial factors may well contribute to the explanation and understanding of the positive clinical effects observed. These speculative aspects need further investigation.

Improvement of macular function by membrane differential filtration in diabetic retinopathy.

BACKGROUND: Alterations of blood rheology are assumed to substantially contribute to the pathogenesis of diabetic retinopathy. Membrane differential filtration (MDF) is an extracorporeal treatment which is able to optimize rheological parameters by eliminating high molecular weight proteins and lipoproteins from the blood. The present study was designed to investigate the effects of repetitive MDF on visual function in diabetic retinopathy. METHODS: 11 patients (11 eyes) with nonproliferative or inactive proliferative diabetic retinopathy underwent three treatment cycles during a mean period of 18 weeks. The best corrected visual acuity served as the main parameter of the study. The measurement of visual acuity, visual field, biochemical and rheological parameters was carried out 24 hours pre and post each treatment cycle and at follow up. The mean follow up time was 9 weeks during the post treatment period. RESULTS: Compared to baseline examination the visual acuity improved stepwise by a mean value of 1.4 lines (p = 0.02) after the last treatment and remained stable at follow up (1.3 lines, p < 0.001). The mean defect of the visual field was reduced by 2.8 dB (p = 0.13) after the treatment period and by 2.5 dB (p = 0.016) at follow up, respectively. CONCLUSIONS: Repetitive treatment with membrane differential filtration is able to improve visual function in patients with diabetic retinopathy. The present study suggests that repetitive membrane differential filtration treatment could be a useful adjunct along with laser treatment to influence the clinical course of diabetic maculopathy.

Influence of membrane differential filtration on the natural course of age-related macular degeneration: a randomized trial.

PURPOSE: Membrane differential filtration is able to optimize rheologic parameters by eliminating high molecular weight proteins and lipoproteins from the blood. Following the hypothesis that these changes result in an improvement of the microcirculation, the authors tested the efficacy of membrane differential filtration in improving visual function in patients with age-related macular degeneration (ARMD). METHODS: Forty patients (40 eyes) were randomized into two groups. The treatment group was treated five times over a period of 21 weeks. In both groups, 9/20 of the eyes showed subfoveolar subretinal neovascularization. The main parameter of the study was visual acuity (VA). Electroretinogram (ERG), electrooculogram, and macular visual evoked potentials were also recorded. Plasma and whole blood viscosity and erythrocyte aggregation were measured. RESULTS: The 20 patients treated repeatedly over a period of 21 weeks showed a mean improvement of 0.63 lines (SD 1.8) of VA on Early Treatment Diabetic Retinopathy Study charts. The control group showed a deterioration of 0.94 lines (SD 1.7) compared to VA at baseline examination. The amplitude of the ERG photopic a-wave and the flicker ERG was significantly increased. The rheologic parameters were lowered in all treated patients. CONCLUSION: Repetitive treatment with membrane differential filtration is able to improve visual acuity of patients with ARMD and the natural course of this disease. Several questions arise from the results of this study. Further research will show if it is possible to optimize the selection of patients for subgroups with predictive responses through morphologic and functional tests and how to create an optimized and individual treatment strategy determined by the quality, intensity, and frequency of treatment sessions.

[Modification of vision by change in rheologic parameters in senile macular degeneration through membrane differential filtration--initial results of a randomized study]. / Beeinflussung des Visus durch Anderung rheologischer Parameter bei der altersabhängigen Makuladegeneration (AMD) durch die Membrandifferentialfiltration--Erste Ergebnisse einer randomisierten Studie.

BACKGROUND: Membrane differential filtration (MDF) is known to optimize rheological parameters by eliminating high molecular weight proteins und lipoproteins from the blood and was shown to influence ocular perfusion parameters. Following the hypothesis that these changes may influence the natural course of age-related macular degeneration (AMD) we tested their efficacy in improving visual function in these patients in a randomized trial. PATIENTS AND METHODS: 20 patients (36 eyes) were randomized into two groups. Ten patients (18 eyes) were treated with MDF and ten (18 eyes) served as controls. The first group was treated five times over a period of 21 weeks. In both groups 8/18 of the eyes showed subfoveolar subretinal neovascularisations. Main parameter of the study was visual acuity. Macular visual evoked potentials were also recorded. Plasmaviscosity, whole blood viscosity and erythrocyte aggregation were measured. RESULTS: The ten patients, treated repeatedly over a period of 21 weeks, showed a mean improvement 1.1 (SD 1.9) lines after 21 weeks, while the control group showed a deterioration of visual acuity (0.6 lines, SD 1.7). The macular visual evoked potentials showed an increase of 0.28 microV (SD 1.12) for the therapy group and a deterioration of 0.57 microV (SD 1.31) in the control group. The rheological parameters were lowered in all patients. CONCLUSIONS: We conclude that repetitive treatment with MDF is able to improve visual function in patients with AMD. Further research is necessary to show how to optimize the selection of patients and how to create an individual treatment strategy.

Improvement of visual acuity in patients suffering from diabetic retinopathy after membrane differential filtration: a pilot study.

BACKGROUND: Membrane differential filtration is an extracorporeal treatment procedure which eliminates high molecular weight proteins and lipids from the blood. This pilot study was initiated to investigate the short-term effects on blood rheology and visual function in patients suffering from diabetic retinopathy. METHODS: Six patients with non-proliferative diabetic retinopathy, clinically significant macular edema (five patients, nine eyes) and inactive proliferative diabetic retinopathy (one patient, one eye) underwent a single treatment with a hollow fiber secondary plasma filter. The main parameter measured was visual acuity prior to and after treatment. Biochemical and rheological parameters (whole blood and plasma viscosity, and erythrocyte aggregation) were also measured. The mean follow-up was 25 (range 4-90) days after treatment. RESULTS: The mean improvement of visual acuity was 1.4 lines (SD 0.8 lines, p = 0.002) 24 h after therapy. This remained stable during the follow-up period. The rheological measures were significantly lowered. A significant reduction of total protein, fibrinogen, IgG, IgM, IgA, alpha-2-macroglobulin, total cholesterol, LDL and HDL was found. CONCLUSION: This study demonstrates the rheological impact of membrane differential filtration. It was shown that rheological changes correlated with clinical improvement in patients suffering from diabetic retinopathy with clinically significant macular edema.

Results of an open, longitudinal multicenter LDL-apheresis trial.

The German Multicenter LDL-Apheresis Trial showed that a partial regression of tendon xanthomas could be obtained applying LDL-apheresis without cholesterol lowering drug therapy over a period of 3 years, whereas secondary prevention of coronary heart disease was generally observed in the mainly heterozygous patients. As there were considerably fewer homozygous patients and the average age of the heterozygous patients in this study was higher compared to the phase I trial regression may well occur with this therapy although it appears to be restricted to young patients only. If the additional information obtained from continuation of the treatment these patients and from other patients under going regular LDL-apheresis for up to 16 years is also taken into consideration the assumption appears to be well supported that interventions such as a second PTCA or a second coronary bypass operation can be avoided. LDL-apheresis increases the quality of live by decreasing the frequency of angina pectoris and also--at least in homozygous patients--is able to prolong life expectancy to a considerable extent. However, additional risk factors may play a role and have to be taken into consideration.

Changes of hemorheological and biochemical parameters after plasma perfusion using a tryptophan-polyvinyl alcohol adsorber leading to clinical improvement in patients suffering from maculopathy.

BACKGROUND: Selective adsorption is an extracorporeal treatment able to reduce high-molecular-weight proteins and lipids. We evaluated its efficacy in lowering hemorheological parameters to achieve a better microcirculation of the retina. PATIENTS AND METHODS: Ten patients suffering from maculopathies of various origin underwent a selective plasma adsorption procedure using the TR-350. Plasma and whole blood viscosity, erythrocyte aggregation and proteins and lipids were determined before and 24 h after therapy. RESULTS: Selective adsorption therapy reduced the high-molecular-weight proteins and lipids. Plasma viscosity, standardized whole blood viscosity and erythrocyte aggregation were significantly lowered to 87, 88 and 65%, respectively, of their values prior to treatment. An improvement of visual acuity was achieved in 6/10 patients. Minor side effects were noted in 2/10 patients. CONCLUSIONS: Selective adsorption using the TR-350 adsorber is a safe technique, showing a high impact on blood rheology. The changes of hemorheological parameters led to clinical improvement in 6/10 patients suffering from retinal disorders.

Sequential treatment of Guillain-Barré syndrome with extracorporeal elimination and intravenous immunoglobulin.

Plasma exchange and administration of intravenous immunoglobulin (IgG) are established treatments for Guillain-Barré syndrome (GBS). Elimination of postulated pathogenetic factors by plasma exchange or selective adsorption treatment using affinity-type adsorption columns and subsequent immunomodulation by intravenous IgG may provide a more effective treatment. Forty-five patients with acute GBS were prospectively examined using a clinical score. We treated 11 patients by plasma exchange, 13 patients by selective adsorption using a tryptophan-linked polyvinyl alcohol gel adsorbent, and 21 patients by selective adsorption followed by intravenous IgG. The patients treated sequentially by selective adsorption and intravenous IgG improved significantly better than the patients who received plasma treatment only. The results suggest that sequential treatment of GBS may be superior to plasma treatment alone. The higher cost of combined treatment may be offset by lower overall expenditure.

[Clinically pure motor variant of Guillain-Barré polyneuritis. Report of 3 cases]. / Klinisch rein motorische Variante der Polyneuritis Guillain -Barré. Darstellung von 3 Fällen.

We report three patients with severe Guillain-Barré syndrome (GBS). On clinical examination, no sensory deficit was elicited. Electromyography (EMG) and motor nerve conduction velocity (NCV) studies were indicative of an axonal lesion. In two patients, we found total peripheral conduction block without volitional EMG activity. Sensory NCV and cortical median nerve evoked potentials remained normal. Sural nerve biopsy revealed unequivocal alterations of sensory nerve fibers, some in the form of primary demyelination. Therefore, these cases must bei classified as combined motor-sensory syndromes despite the clinical and electrophysiological findings. Although total denervation of the extremity muscles occurred, causing tetraparalysis, this manifestation appears to be attributable to the secondary axonal variant. In contrast to positive reports in literature, immunomodulatory treatment proved ineffective in all three cases.

Clinical efficacy of haemorheological treatment using plasma exchange, selective adsorption and membrane differential filtration in maculopathy, retinal vein occlusion and uveal effusion syndrome.

The aim of the study was to test the clinical efficacy of haemorheological treatment with extracorporeal techniques in ocular diseases. We treated patients suffering from maculopathies of different origin: age-related (AMD, n = 17), uveitis-associated (n = 14) and myopia-associated maculopathy (n = 5). We also treated patients with uveal effusion syndrome (n = 3) and central retinal vein occlusion (n = 4) resistant to haemodilution or steroid therapy. The treatment consisted of plasma exchange, selective adsorption with a tryptophan-polyvinylalcohol adsorber and membrane differential filtration. Maculopathy patients underwent two treatments while the other patients received between 1 and 7 treatments. Pulsatile ocular blood flow was measured in 10 patients before and after therapy. The main parameter for evaluating clinical outcome was the change in visual acuity. Severe side-effects did not occur. The rheological parameters including plasma viscosity, whole blood viscosity and erythrocyte aggregation were statistically significantly lowered. Of 36 patients suffering from maculopathy, 25 showed an improvement of at least 1 line of visual acuity after therapy, 7/17 patients in AMD, 6/14 in uveitis and 0/5 in myopia improved 3 lines or more. All patients suffering from retinal vein occlusion improved at least 1 line and two showed an improvement of 3 lines or more. In uveal effusion syndrome, an improvement of 3 lines or more was reached in all patients. Plasma exchange, selective adsorption and membrane differential filtration are effective rheological treatment approaches to improving visual acuity in patients suffering from maculopathy except myopia-associated maculopathy. Efficacy in patients suffering from central retinal vein occlusion and uveal effusion syndrome was proven, even when the patients were resistant to previous haemodilution or steroid therapy. We conclude that a rheological approach should be considered before invasive methods such as laser coagulation, radiation therapy or surgery are applied.

Changes of haemorheological parameters when using plasma exchange, selective adsorption and membrane differential separation.

At present, conventional haemorheotherapy consists of changes in life-style, drug therapy and haemodilution. Extracorporeal therapy has been considered only for the treatment of hyperviscosity syndromes. However, a wide range of viscosity-related syndromes may be amenable to rheological therapy if appropriate techniques were available. According to our data, plasma exchange, selective adsorption and membrane differential filtration may lead to an improvement of haemorheology and clinical conditions. For reasons of economy and feasability, membrane differential filtration is favoured over other techniques of differential separation therapy.