Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies

OBJECTIVE: To evaluate the effect of intravenous high dose human immunoglobulin (IVIg) therapy on the clinical course and autoantibody titres of patients with neurological paraneoplastic syndromes. METHODS: Twenty two patients with paraneoplastic encephalomyelitis and sensory neuronopathy syndrome associated with anti-Hu antibodies (18) or paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies (four), were treated with 1-26 (mean 5.8) cycles of IVIg. The Rankin scale was used to evaluate the response. RESULTS: The only serious toxicity was one case of haemolytic anaemia. Twenty one patients were evaluable for therapeutic response. One patient, with subacute sensory neuronopathy (SSN), improved for at least 15 months, 10 remained stable (eight with anti-Hu and two with anti-Yo antibodies), and 10 deteriorated (eight with anti-Hu and two with anti-Yo antibodies). In seven of the 10 patients who stabilised, the syndrome had already made a plateau when the treatment was started but three patients (one with anti-Hu and two with anti-Yo antibodies) who had still been progressing stabilised for six, eight, and more than 48 months, including one patient with SSN who achieved stabilisation when the neurological dysfunction was only moderate (Rankin scale = 3). Another patient with SSN and initial stable response worsened when IVIg was reduced and improved when it was increased. No significant predictive factors of outcome could be identified but improvement or stabilisation was more frequent in patients with isolated involvement of the peripheral nervous system (62%) than in patients with evidence of CNS damage (37%) at the onset of treatment. Stabilisation in patients with CNS involvement was only achieved when the neurological dysfunction was already severe (Rankin scale > 3). The titres of autoantibodies did not change significantly. CONCLUSION: Treatment with IVIg at the doses given in the present protocol was not effective in paraneoplastic CNS syndromes associated with antineuronal antibodies. The role of this regime in the treatment of SSN should be further evaluated.     

Anti-CD4 activity of normal human immunoglobulin G for therapeutic use. (Intravenous immunoglobulin, IVIg)

The effects of intravenously administered normal immunoglobulin G (IVIg) in autoimmune diseases are dependent on the ability of IVIg to interact with surface molecules of lymphocytes. In the present study, we demonstrate the presence of anti-CD4 activity in IVIg by showing the ability of IVIg to bind to CD4 and to inhibit CD4-dependent cellular functions. Binding of IVIg to recombinant soluble human CD4 was assessed by ELISA, immunoblotting and real time analysis of complex formation. Anti-CD4 antibodies isolated from IVIg by affinity-chromatography bound to human CD4+ T cells. These anti-CD4 antibodies inhibited proliferative responses in MLR and infection of CD4+ human T cells with HIV. These results indicate that IVIg contains antibodies reactive with human CD4 and that these anti-CD4 antibodies exhibit biological functions. The presence of anti-CD4 antibodies in IVIg may be relevant to the immunoregulatory effects of normal polyspecific immunoglobulin G.     

Intravenous immunoglobulin therapy for recurrent spontaneous abortion: a meta-analysis

The aim of this paper was to identify the mechanism/s responsible of the antimetastatic effect of a single low dose of cyclophosphamide (Cy), previously demonstrated by us in the rat lymphoma LTACB. No direct cytotoxic antimetastatic activity of Cy could be proved. In vitro treatment of L-TACB cells with mafosfamide did not alter their invasiveness or their motility. The adoptive transfer of splenocytes from Cy-treated tumor-bearing rats, together with L-TACB cells inhibited their metastatic growth. The single low dose Cy treatment of T-immunodeficient nude mice did not show the antimetastatic effect on L-TACB observed in immunocompetent mice. An inhibition of the metastatic ability due to immunomodulation by Cy is proposed.     

Intravenous immunoglobulin treatment in multiple sclerosis

In in vivo tumor growth experiments it is common to report the tumor measurement time at which the volume distributions of the treatment groups become significantly different. This method of analysis, as commonly practiced, is deficient in that its type I error rate exceeds the usual nominal rate of 5%, unless one specifically corrects for multiple comparisons. A second problem is that many investigators evidently interpret the time of first significance as a statistical parameter--i.e., a fixed but unknown property of the model that one can estimate by experimentation. In fact the time until first significance, like the power of the test, depends both on true model parameters (such as mean growth curves and experimental variability) and on features of the experimental design, such as the sample size and the spacing of the measurement times. We argue that investigators would do better to compare treatment groups by modeling tumor growth curves or estimating volume doubling times.     

Intravenous immunoglobulin in oncology nursing practice

Phenylalanine dehydrogenase from Thermoactinomyces intermedius and leucine dehydrogenase from Bacillus stearothermophilus show a 59% sequence similarity in their substrate-binding domains, although their substrate specificities are different. We prepared a phenylalanine dehydrogenase mutant enzyme whose inherent hexapeptide segment (124F-V-H-A-A-129R) in the substrate-binding domain was replaced by the corresponding part of leucine dehydrogenase (M-D-I-I-Y-Q) in order to investigate the mechanism of substrate recognition by phenylalanine dehydrogenase. The catalytic efficiencies (kcat/Km) of the mutant enzyme with aliphatic amino acids and aliphatic keto acids as substrates were 0.5 to 2% of those of the wild-type enzyme. In contrast, the efficiencies for L-phenylalanine and phenylpyruvate decreased to 0.008 and 0.035% of those of the wild-type enzyme, respectively. These results suggest that the hexapeptide segment plays an important role in the substrate recognition by phenylalanine dehydrogenase.     

Intravenous immunoglobulin administration to a patient with systemic lupus erythematosus and pneumococcal septicemia

A case history is presented of a woman with systemic lupus erythematosus, sepsis and pneumonia caused by Streptococcus pneumoniae. Conventional treatment was supplemented with intravenous human immunoglobulin with remarkable effect. The treatment is discussed.     

Intravenous immunoglobulin as sole therapy for systemic vasculitis

High-dose, pooled, i.v. immunoglobulin (IVIg) is a potential, alternative treatment for Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) which has shown promise in the treatment of refractory disease when administered with continuing immunosuppression. This study of six new patients with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis and early disease, without threatened vital organ function, examined the therapeutic response to treatment with IVIg alone. IVIg was well tolerated and all six patients had early reductions in disease activity. Four entered full, clinical remission which lasted for at least 1 yr, while in two the responses were partial and transient, and they subsequently required conventional treatment. After 16-48 months of follow-up, two of the four patients in full remission relapsed, but the other two have remained well.     

Intravenous immunoglobulin therapy in POEMS syndrome: a case report

One course of intravenous immunoglobulin was tried on a patient with the syndrome of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin lesions and Castleman's disease. No effect was noted.     

Intravenous immunoglobulin prophylaxis in neonates on artificial ventilation

The efficacy of the prophylactic use of intravenous immunoglobulin (Ig) was evaluated in a double-blind placebo-controlled trial of 21 pairs of ventilated neonates weighing more than 1,500 g. Each infant received 0.4 g/kg/day of intravenous Ig or a similar volume of placebo daily for 5 days. Criteria used to assess the efficacy of intravenous Ig were the number of infections, the duration of ventilation therapy and time to clinical recovery. There were no significant differences in the treated and placebo groups with regard to the frequency of positive blood cultures (28.6% and 14.3%), endotracheal cultures (57.1% and 66.7%) and abnormal white cell counts (52.4% and 57.1%). On entry to the study there was no significant difference in IgG levels between the treated (974.5 mg/dl; SD 575.3) and placebo groups (818 mg/dl; SD 516.9). However, on day 6 the treated group had a mean level of 1,400.3 mg/dl (SD 426.7) versus 710.9 mg/dl (SD 377.4) in the placebo group (P < 0.05). Clinical improvement occurred within 3 days in both groups. Ventilatory support was required for 11.8 days (SD 8.3) in the treated and 11.8 days (SD 7.3) in the placebo group. Both groups required 3-4 antibiotic treatments over a period of 14-15 days. Two patients died in the treated and 4 in the placebo group, with 1 infant in each group developing bronchopulmonary dysplasia. The patients who recovered did so within 14 days. Analyses of subgroups of patients with different diagnoses revealed no differences except a trend suggesting fewer infections in term babies treated with intravenous Ig. The organisms cultured in the intravenous Ig groups were Pseudomonas, Klebsiella, Escherichia coli and Staphylococcus and in the placebo group Pseudomonas, Klebsiella and Enterobacter. The above has shown that, except for a trend in the older neonates, intravenous Ig is not of prophylactic benefit in ventilated neonates. Newer adjuncts in immunotherapy such as hyperimmune gammaglobulin or monoclonal antibodies may prove of greater value in the treatment of neonatal sepsis.     

Intravenous immunoglobulin inhibits IgE production in human B lymphocytes

This study sought to determine the prevalence of spontaneous reperfusion of an infarct-related artery (IRA) and associated myocardial salvage in the absence of thrombolysis or angioplasty. Twenty-one patients with acute myocardial infarction received only heparin and aspirin. At a median of 18 hours after presentation, 12 patients (57%) had angiographic patency of the IRA. Technetium-99m sestamibi was injected acutely on presentation and again at hospital discharge. Acute and final perfusion defect sizes were measured. Their difference, myocardial salvage, was calculated along with salvage index (myocardial salvage/acute defect). Comparing patients with a patent versus occluded IRA, myocardium at risk was similar (16% +/- 12% vs 12% +/- 9% left ventricle, p = NS); however, myocardial salvage (9% +/- 9% vs -2% +/- 7% left ventricle, p = 0.01), and salvage index (0.62 +/- 0.37 vs 0.19 +/- 0.33, p = 0.01) were greater in patients with spontaneous reperfusion. Resolution of chest pain was greater in patients with a patent IRA (100% vs 55%, p = 0.003). Spontaneous reperfusion of the IRA occurs frequently in patients with acute myocardial infarction and is associated with significant myocardial salvage.     

Pharmacologic modulation of autonomic tone: implications for the diabetic patient

The inhibitory effects of nitroglycerin (NTG) on platelet function and the mechanisms of inhibition have been studied in vitro, but not in vivo. Therefore, we have investigated the effects of NTG on platelet function in eight patients undergoing orthopaedic surgery. Simultaneous measurements of platelet aggregation and change in intracellular calcium concentrations were performed in Fura-2 loaded platelets using thrombin as a stimulator. Intraplatelet concentrations of cyclic 3',5'-guanine monophosphate (cGMP) were measured by radioimmunoassay, and the concentration of nitrite ion was also measured. Continuous i.v. infusion of NTG 4-8 micrograms kg-1 min-1 significantly inhibited platelet aggregation and the increase in intracellular Ca2+ concentration (first phase, mean 439.9 (SEM 68.7) vs 210.6 (38.7) nmol litre-1; second phase, 154.4 (19.8) vs 106.7 (18.0) nmol litre-1). The concentration of cGMP (from 0.633 (0.098) to 1.764 (0.578) pmol/10(9) platelets) and the concentration of nitrite ion (from 532.6 (17.6) to 724.4 (34.8) nmol litre-1) also increased significantly after infusion of NTG. The NTG concentration in plasma was of the order of 10(-8) mol litre-1. We have demonstrated that in vivo, NTG increased intraplatelet cGMP concentrations and inhibited platelet function; one mechanisms of this effect is likely to be related to nitric oxide liberation from NTG bioconversion.     

Swallowing in neurological outpatients: use of a timed test

Swallowing was studied prospectively in a consecutive group of 90 neurology outpatients under 70 years of age. No patient had been referred primarily because of dysphagia. Patients were classified into four groups: those with (1) neurological or (2) non-neurological diagnoses possibly relevant to disordered swallowing, (3) functional disorders, and (4) definite diagnoses not likely to be relevant. They were defined as having abnormal or probably abnormal swallowing if two or more of the following were present: a complaint of swallowing problem, abnormal symptoms or signs, a slow swallowing speed (< 10 ml.s-1). Nineteen patients among the four groups (21%) were found to have abnormal/probably abnormal swallowing. Swallowing speed was significantly slower in patients who perceived a swallowing problem or who had abnormal symptoms or signs compared with those who did not, providing further evidence for the validity of a timed test of swallowing capacity. The study also provides evidence of a significant incidence of disordered swallowing in outpatients who may not have complained spontaneously but who have diagnoses potentially relevant to swallowing.     

On the specificity of assays to detect circulating immunoglobulin A-fibronectin complexes: implications for the study of serologic phenomena in patients with immunoglobulin A nephropathy

Immunoglobulin A (IgA)-fibronectin complexes have been proposed as specific serologic markers of IgA nephropathy. They have been detected by the use of ELISA composed of an immobilized antifibronectin antibody (or albumin as a negative control) and an enzyme-conjugated anti-IgA antibody (antifibronectin capture assay). By the use of this type of assay, plasma samples from 32 normal controls, 38 IgA nephropathy patients, and 81 patients with other types of glomerulonephritis were analyzed. Extinction values in IgA nephropathy patients were higher (P = 0.06) than in patients with other glomerulonephritis types and significantly higher than in normals. Markedly lower values were obtained when the plates were coated with albumin. However, when the antifibronectin antibody was replaced by normal IgG or F(ab')2 fragments, almost identical extinctions were measured. The use of different antifibronectin antibodies, IgG, ELISA plates, or blocking regimens did not modify these results. Extinction values could not be suppressed by the addition of exogenous fibronectin. Similar extinctions were observed when plasma samples were replaced by physiologic concentrations of fibronectin-free IgA. Extinction values measured in the plasma samples correlated significantly with IgA concentrations in plasma as analyzed by nephelometry. A collagen binding assay, a second type of assay used to measure IgA-fibronectin complexes, also allowed the detection of fibronectin-free IgA, and again, extinctions measured in plasma could not be suppressed by exogenous fibronectin. In conclusion, both antifibronectin capture ELISA and collagen binding assays do not specifically detect only IgA-fibronectin complexes, but also total plasma IgA, which is frequently, but nonspecifically, elevated in IgA nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peripheral effects of sex steroids: implications for patient management

Sex steroids--estrogens, progesterone, and testosterone and other androgens--have effects on the anatomy and physiology of many nonreproductive organ systems. These changes can influence the sex ratio of certain diseases. They also affect the "normal range" for certain parameters, and data from men often do not apply to normal female physiology. Sex steroids also affect the response to certain toxins, pharmacologic agents, and other therapies. Replacement sex steroid therapy and oral contraceptives may affect these processes differently than natural hormones do. The normal monthly changes of female hormones can also affect the severity of many conditions and may change the response to therapy in certain conditions, such as asthma or control of diabetes. This paper reviews the data on the effects of sex hormones on normal and pathologic human physiology and examines the therapeutic implications of these findings.     

Intravenous acyclovir treatment for extensive herpetic keratitis in a liver transplant patient

BACKGROUND: The different clinical forms of glaucoma share in common an optic nerve head neuropathy. MATERIALS AND METHODS: Review article. RESULTS: For a long time, a high intraocular pressure (IOP) has been considered to be the only risk factor associated with glaucoma. By extension it has even been considered that glaucoma was equivalent to a high IOP, and thus only an affection of the anterior segment of the eye. The fact to consider glaucoma as an affection of the posterior segment has changed our conceptual approach of this disease. It has allowed us to look for other risk factors associated with this affection. CONCLUSIONS: The existence of different potentially treatable risk factors opens new therapeutical perspectives for glaucoma.