Abnormal vocal cord movement in patients with and without airway obstruction and asthma symptoms.

BACKGROUND: Abnormal vocal cord movements can cause laryngeal extrathoracic airway obstruction (often called vocal cord dysfunction - VCD) leading to asthma-like symptoms. These aberrant movements are characteristically present during inspiration and termed paradoxical vocal cord movement (PVCM). We have reported PVCM in up to 40% of severe asthmatics, but it is not known if PVCM is detectable in all patients with asthma-like symptoms and if the condition is more often associated with abnormal lung function. OBJECTIVE: We hypothesized that PVCM is frequently associated with asthma symptoms accompanied by airflow limitation. Studies examined whether PVCM is solely linked to experiencing asthma symptoms, or if PVCM is related to airflow limitation and/or other disease characteristics. METHODS: Patients with asthma symptoms were recruited from general practice and severe asthma clinics (n = 155). Pulmonary function measurements were conducted, asthma control and Nijmegen (dysfunctional breathing) questionnaires were administered and skin prick testing was carried out. PVCM was quantified using dynamic 320-slice computerized tomography of the larynx. Groups were divided into patients with FEV1 ≥ 80% predicted or FEV1 < 80% predicted and FEV1 /FVC < 0.7. ATS/ERS definitions of severity were also applied and evaluated. Detection of PVCM in the groups was compared and analyses performed to identify features associated with PVCM. RESULTS: Overall (n = 155), PVCM was detected in 42 cases (27.1%). Patients with FEV1 < 80% predicted had PVCM more often (25/68, 36.8%) than individuals with normal spirometry (17/87, 19.5%; P = 0.016). PVCM was associated with older age (P = 0.003) and with Nijmegen scores > 20 (P = 0.04). Patients with FEV1 < 80% predicted plus Nijmegen scores > 20 were more likely to have PVCM (OR = 9.3, P = 0.02). CONCLUSIONS AND CLINICAL RELEVANCE: Paradoxical vocal cord movement is more often associated with asthma symptoms accompanied by airflow limitation and dysfunctional breathing. Further studies are needed to determine whether PVCM is induced by dysfunctional breathing practices and/or airway obstruction. How PVCM links with symptomatic asthma and VCD also requires evaluation.

What's in a name? Expiratory tracheal narrowing in adults explained.

Tracheomalacia, tracheobronchomalacia, and excessive dynamic airway collapse are all terms used to describe tracheal narrowing in expiration. The first two describe luminal reduction from cartilage softening and the latter refers to luminal reduction from exaggerated posterior membrane movement. Expiratory tracheal narrowing is a frequent occurrence that can cause symptoms of airway obstruction, such as dyspnoea, wheeze, and exercise intolerance. The accurate diagnosis and quantification of expiratory tracheal narrowing has important aetiological, therapeutic, and prognostic implications. The reference standard for diagnosis has traditionally been bronchoscopy; however, this method has significant limitations. Expiratory tracheal disorders are readily detected by four-dimensional dynamic volume multidetector computed tomography (4D-CT), an emerging, non-invasive method that will potentially enable detection and quantification of these conditions. This review discusses the morphological forms of expiratory tracheal narrowing and demonstrates the utility of 4D-CT in the diagnosis, quantification, and treatment of these important conditions.

Long-term safety of fluticasone furoate nasal spray in adults and adolescents with perennial allergic rhinitis.

BACKGROUND: Fluticasone furoate is a novel-enhanced affinity glucocorticoid and its long-term safety must be assessed. This study was designed to assess the safety and tolerability of 12-month intranasal administration of fluticasone furoate in adult and adolescent patients with perennial allergic rhinitis (PAR). METHODS: In this randomized, double-blind, placebo-controlled, parallel-group study, 806 patients with PAR were randomized to once daily (od) fluticasone furoate nasal spray 110 microg (n = 605) or vehicle placebo nasal spray (n = 201) for 12 months, following a 7- to 14-day screening period. Safety was assessed by monitoring adverse events (AEs), 24-h urinary cortisol excretion, nasal and ophthalmic examinations, electrocardiograms and clinical laboratory tests. Plasma concentrations of fluticasone furoate were determined from blood samples. RESULTS: Fluticasone furoate was well tolerated. The incidence of most AEs was similar to that observed with placebo, with the exception of epistaxis, which was more frequently reported on active treatment. There were no clinically meaningful differences between fluticasone furoate and placebo in terms of safety assessments, including mean changes in ophthalmic parameters and 24-h urine cortisol excretion. Plasma concentrations of fluticasone furoate were not quantifiable in the majority of patients following intranasal administration. CONCLUSIONS: Long-term (12-month) administration of fluticasone furoate 110 microg od revealed an AE profile typical of the intranasal corticosteroid class in both adult and adolescent patients with PAR, with no evidence of clinically relevant systemic corticosteroid exposure.

Roflumilast, a phosphodiesterase 4 inhibitor, reduces airway hyperresponsiveness after allergen challenge.

BACKGROUND: Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, is currently in clinical development for the treatment of asthma. OBJECTIVES: This pilot study examined the effect of roflumilast on allergen-induced airway hyperresponsiveness (AHR) to histamine challenge and asthmatic response to allergen challenge. METHODS: In a randomized, double-blind, 2-period, crossover trial, 13 patients with mild allergic asthma [mean forced expiratory volume in 1 s (FEV(1)) % predicted = 86%] received a single dose of oral roflumilast 1,000 microg or placebo. Patients were administered roflumilast 60 min before allergen challenge, and asthmatic responses were assessed via change in FEV(1)

Case-control study of severe life threatening asthma (SLTA) in a developing community.

BACKGROUND: Distinct risk factors for asthma death have not been identified in developing communities. This study was conducted to distinguish risk factors for severe life threatening asthma (SLTA), a proxy for asthma death, in a developing country. METHODS: A case-control study was performed at a University Hospital serving developing communities in the Western Cape Province, South Africa, over the period October 1997 to April 2000. Thirty consecutive patients with SLTA admitted to the intensive care unit (ICU) were compared with 60 chronic asthmatic patients, without a history of SLTA, who had attended the hospital outpatient respiratory clinic over the same period. RESULTS: The risk of SLTA in comparison with controls increased with female sex (odds ratio (OR) 3.3, 95% CI 1.2 to 9.6, p = 0.02), rural residence (OR 8.1, 95% CI 2.6 to 25.3, p = 0.0005), and absence of a formal income (OR 5.7, 95% CI 2 to 16.6, p = 0.002). Cases were more likely to have had more than one hospital admission in the previous year (OR 8, 95% CI 2.5 to 25.2, p = 0.0009) and more than one emergency room visit in the previous year (OR 4.4, 95% CI 1.19 to 16.4, p = 0.04). Patients with SLTA were less likely to use inhaled corticosteroids (OR 5.6, 95% CI 1.9 to 16.5, p = 0.003) and more likely to use inhaled fenoterol (OR 6, 95% CI 2.2 to 16.2, p = 0.0004). Patients with SLTA also had lower mean (SE) forced expiratory volume in 1 second (FEV(1)) measurements (66.9 (9.5)% predicted v 82.5 (4.0)% predicted; p = 0.03) and lower FEV1/FVC ratios (60.7 (4.1)% predicted v 69.6 (1.9)% predicted; p = 0.05) documented before the episode of SLTA. CONCLUSIONS: Risk factors for SLTA that are mainly analogous to those distinguished in other environments have been identified in a geographical area characterised by a third world socioeconomic context. Rural residence and poverty may increase the risk of SLTA.

Comparison of Australian and international guidelines for grading severity of chronic obstructive pulmonary disease.

AIM: To compare grading of chronic obstructive pulmonary disease (COPD) using Australian guidelines Confirm diagnosis, Optimize function, Prevent deterioration, Develop a self-management plan and manage eXacerbations (COPD-X) versus Global initiative for Obstructive Lung Disease (GOLD) guidelines and to assess whether this is associated with differences in other health domains affected by COPD. Adult outpatients (n = 61) with COPD were studied using lung function measurements, six-minute walk test and body composition assessments. Subjects also completed self-rated dyspnoea scores and health-related quality-of-life scales. For each patient, COPD severity was graded using both COPD-X and GOLD guidelines, and results were collectively analysed. If significant discrepancies were observed, comparisons of other health domains were carried out. After grading severity using COPD-X and GOLD guidelines, significant discrepancies were noted. Of nine subjects with no disease (normal) based on COPD-X, seven were judged to be 'mild' according to GOLD. Similarly, 11 of 12 patients with mild disease (COPD-X) had 'moderate' disease judged by GOLD, and 9 of 23 with moderate severity (COPD-X) had 'severe' COPD using GOLD. Finally, 6 of 17 patients with COPD-X-rated severe disease had 'very severe' disease using the GOLD criteria. Among patients with COPD-X severe disease, those with GOLD discordant (very severe) severity had a poorer quality of life compared with those with GOLD concordant (severe) severity (P = 0.006). Similarly, there was also a trend towards lower six-minute walk test distance and greater subjective dyspnoea in GOLD very severe patients compared with GOLD severe patients. Significant discrepancies in grading of severity exist between Australian and international COPD guidelines. Current Australian guidelines for severity grading may not fully reflect the effect COPD has on other key domains of health.

Vaccination for asthma exacerbations.

Most asthma exacerbations are caused by common cold virus infections, predominantly rhinovirus infections. Full protection against repeat infections with the same rhinovirus serotype is given by serum neutralizing antibody, but cross-reactive antibody developed against other serotypes could yield partial protection and result in attenuated cold and airway symptoms. It is proposed that vaccine-mediated induction of cross-reactive antibody might not prevent rhinovirus infections but might reduce severe asthma symptoms and exacerbations.

Reduced activation of peripheral blood neutrophils after late-phase asthmatic responses but not in mild stable asthma.

BACKGROUND: Asthma is a process of chronic allergic inflammation that may be worsened by the activation of neutrophils during acute exacerbations. OBJECTIVE: We investigated our hypothesis that changes in cellular activation may be detectable in peripheral blood (PB) during late-phase asthma and during clinical exacerbations. METHODS: Twenty-one stable asthmatics (9 on treatment with beta2-agonists only, 12 using inhaled corticosteroids) and 10 nonasthmatic volunteers were first compared using flow cytometry to measure beta2-integrin (CD11b/CD18) expression. Production of reactive oxygen species (ROS) was evaluated employing chemiluminescence. Next, 8 mild asthmatics were assessed using similar methods before and after allergen-induced late asthmatic reactions (LARs). Finally, 4 asthmatic subjects were evaluated over 3 months, and symptoms, peak expiratory flow (PEF) and ROS production were measured. Episodes of respiratory morbidity (exacerbations) were identified and their association with ROS production was examined. RESULTS: No differences were detected in adhesion molecule expression and ROS production comparing the normal and asthmatic groups. However, after development of the LAR, significant reductions in CD11b neutrophil expression (mean fluorescence intensity; MFI) were observed [before: 994 +/- 102 MFI (mean +/- SEM) versus after: 424 +/- 81 MFI; p < 0.01]. Furthermore, strong associations were found between decreases in CD11b and the severity of the LAR (r = 0.9; p < 0.02). In the clinical study, ROS production was significantly lower during exacerbations (median 43%; p < 0.05). Again, this measurement was significantly associated with reductions in PEF (r = 0.5, p < 0.03). CONCLUSIONS: In patients with mild stable asthma, no differences in the activation of circulating neutrophils were detectable compared to nonasthmatic individuals. During episodes of asthmatic airway obstruction, in the laboratory and in clinical disease, neutrophil activation decreased in PB, conceivably because activated cells may be preferentially sequestered in the lung.

Therapeutic equivalence study of two formulations (innovator v. generic) of beclomethasone dipropionate in adult asthmatic patients.

OBJECTIVE: To study the therapeutic equivalence of two formulations (innovator v. generic) of beclomethasone dipropionate (BDP) 400 micrograms twice daily administered per metered dose inhaler (MDI), in adults with moderate to severe asthma. METHODS: A double-blind randomised parallel-group trial was performed with a 2-week run-in and an 8-week treatment period. Thirty-six symptomatic adult asthmatics on a mean daily dose of 750 micrograms inhaled corticosteroids during run-in, a mean forced expiratory volume in 1 second (FEV1) of 70% predicted normal and a mean histamine concentration provoking a 20% reduction in FEV1 (histamine PC20) of 0.11 mg/l were randomised to one of the two treatment groups. Primary variables were morning peak expiratory flow (mPEF), FEV1 and histamine PC20. Secondary variables were beta 2-agonist use, symptom score and nocturnal awakening. The Schuirmann two one-sided tests procedure was used for the statistical analysis. Ninety-five per cent confidence intervals (CIs) were calculated for the differences in means. RESULTS: The mean differences end of treatment to baseline for the two formulations (Becotide and Beclate) respectively were: mPEF 5.6 l/min (CI - 16.4-27.6) and -22.3 l/min (CI -35.6(-)-9); FEV1 -2.9% (CI -11-5.2) and 0.2% (CI -4.8-5.2); Histamine PC20 -0.04 mg/ml (CI -0.15-0.06) and 0.02 mg/ml (CI -0.37-0.4). Changes in clinical variables were not conclusive. The mean differences with CIs for primary variables were contained within the limits set for equivalence. The sample size was sufficient to differentiate the groups for mPEF, but this was not of clinical significance. CONCLUSION: After 8 weeks of treatment the two formulations of BDP, delivered by MDI through a large-volume spacer, were therapeutically equivalent in moderate-to-severe asthmatic adults.

Guideline for the management of chronic asthma in adults--2000 update. South African Pulmonology Society Adult Asthma Working Group.

OBJECTIVE: To make recommendations for the cost-effective management of asthma incorporating recent advances in the understanding and treatment of asthma since the last guideline statement in 1992. The guideline is applicable to adults and children over 12 years of age. OPTIONS: Asthma should be graded according to standard severity criteria. The principle of 'hit early, hit hard' with corticosteroids to achieve rapid control is encouraged; thereafter treatment should be tailed down to the lowest dose of corticosteroids that maintains the aims of asthma treatment. OUTCOMES: The aims of asthma management should be achieved; these include: (i) avoidance of causative and trigger factors; (ii) abolition of symptoms and ability to lead a normal lifestyle; (iii) restoration of normal (or best possible) lung function; (iv) reduction of the risk of severe attacks; and (v) optimisation of treatment with minimal side-effects. EVIDENCE: Based on a selective review of randomised, controlled studies to support an evidence-based approach to treatment. BENEFITS, HARMS AND COSTS: Appropriate management of asthma should lead to a reduction in morbidity and mortality of asthma and a consequent reduction in cost of asthma care. Side-effects of corticosteroids are placed in perspective together with a strategy to minimise these effects. RECOMMENDATIONS: Asthma should be managed with inhaled corticosteroids as the most important anti-inflammatory treatment, except in the case of mild intermittent asthma which may be treated with beta 2 agonists on a pro re nata (prn) basis. It is preferable to add long-acting beta 2 agonists to low-dose inhaled corticosteroids before increasing corticosteroids. Leukotriene receptor antagonists are currently recommended for use in combination with inhaled corticosteroids pending further data on their long-term benefits. Differentiation of asthma from chronic obstructive pulmonary disease (COPD) is important. Early referral to a pulmonologist in difficult cases is encouraged. VALIDATION: Endorsed by the South African Pulmonology Society, the Allergy Society of South Africa and the South African Medical Association. The guideline is compatible with those of other international societies.

Rhinoviruses infect the lower airways.

Rhinoviruses are the major cause of the common cold and a trigger of acute asthma exacerbations. Whether these exacerbations result from direct infection of the lower airway or from indirect mechanisms consequent on infection of the upper airway alone is currently unknown. Lower respiratory infection was investigated in vitro by exposing primary human bronchial epithelial cells to rhinoviruses and in vivo after experimental upper respiratory infection of human volunteers. Bronchial infection was confirmed by both approaches. Furthermore, rhinoviruses induced production of interleukin-6, -8, and -16 and RANTES and were cytotoxic to cultured respiratory epithelium. This evidence strongly supports a direct lower respiratory epithelial reaction as the initial event in the induction of rhinovirus-mediated asthma exacerbations. The frequency of infection and the nature of the inflammatory response observed are similar to those of the upper respiratory tract, suggesting that rhinovirus infections may be one of the most important causes of lower in addition to upper respiratory disease.

Peak expiratory flow changes during experimental rhinovirus infection.

Rhinovirus (RV) colds are associated with asthma exacerbations and experimental infections are commonly used to investigate the mechanisms involved. However, a temporal association between experimental RV infections and falls in peak expiratory flow (PEF) have not been demonstrated. PEF was measured in 22 volunteers (11 normal, five atopic, six atopic asthmatic) who developed RV serotype 16 colds after inoculation. PEF was measured twice daily for 2 weeks prior and 6 weeks after RV infection and episodes of respiratory morbidity based on changes in PEF were defined using validated criteria. Six significant reductions in PEF were temporally related to the RV infections (in two (18%) normal, one (20%) atopic, three (50%) atopic asthmatic subjects, p=0.1) and occurred 4-9 days (median 6) after inoculation. Mean+/-SEM PEF at day 6 was 87.8+/-1.8% of the predicted value in the six subjects with reductions versus 99.4+/-1.4% pred in those without (p=0.01). Symptom scores were significantly different at day 6 in the two groups (10.6+/-1.9 versus 6.8+/-1.0, p=0.03), but no differences were noted in the viral culture scores and changes in nasal albumin. In subjects with significant PEF reduction, the decrease in the provocative concentration causing a 20% fall in the forced expiratory volume in one second (FEV1) (PC20) was 1.7+/-1.3 mg x mL(-1) versus 1.2+/-1.1 mg x mL(-1) in the negative group (p=0.06). The degree of seroconversion to RV was significantly higher in the group with reduced PEF (median change dilutions 8 versus 4, p=0.02). The results of the present study suggest that rhinovirus-associated, respiratory morbidity occurs during experimental infection in some but not all normal and asthmatic subjects and also that experimental colds are a valid model for the study of rhinovirus-associated airway symptoms and asthma exacerbations.

Alpha-dihydroergocryptine in Parkinson's disease: a multicentre randomized double blind parallel group study.

INTRODUCTION: A multicentre randomized double-blind parallel group study was carried out on 68 patients suffering from idiopathic Parkinson's disease (PD) treated with L-dopa for at least 1 year with inadequate therapeutic responsiveness. The aim of the study was to compare the efficacy of alpha-dihydroergocryptine (alpha-DHEC) vs lisuride as an adjunct therapy to L-dopa on dyskinesias and clinical fluctuations (Unified Parkinson's Disease Rating Scale [UPDRS] part IV), on the symptoms pattern (Columbia University Rating Scale [CURS]), on disability (Northwestern University Disability Scale [NUDS]), and to evaluate the incidence of adverse events. PATIENTS AND METHODS: Thirty-two patients (18 males, 14 females with a mean age of 64.5+/-1.5 SEM) were randomized to alpha-dihydroergocryptine and 36 (16 males, 20 females with a mean age of 61.8+/-1.4) to lisuride. The treatment lasted 3 months and the dosage was increased until it reached 60 mg/day of alpha-dihydroergocryptine and 1.2 mg/day of lisuride, while the L-dopa dosage was kept constant in both groups. Per protocol and intention to treat analyses were performed on response variables. RESULTS: The adjunctive treatment with the two dopamine agonists determined a significant improvement of PD symptoms in both groups. Alpha-dihydroergocryptine showed a superior efficacy in reducing the clinical complications (P < 0.01 by ANOVA). The number of patients complaining of adverse events was 8 out of 32 (25%) for alpha-dihydroergocryptine and 24/36 (67%) for lisuride (P < 0.05). CONCLUSION: Alpha-dihydroergocryptine effect seems to be superior to that of lisuride both in terms of reduction of L-dopa therapy long term motor complications (UPDRS part IV) as well as in terms of the incidence and severity of adverse events.

Effect of selective phosphodiesterase 3 inhibition on the early and late asthmatic responses to inhaled allergen.

AIMS: Phosphodiesterase isoenzymes may play an important role in the regulation of airway calibre and bronchial smooth muscle function. Immunomodulatory actions may also be important in allergic airway inflammation. We have examined the effect of a phosphodiesterase (PDE) 3 inhibitor (MKS492) on the early and late responses to inhaled allergen in 18 atopic asthmatic subjects. METHODS: On three separate occasions, 2-4 weeks apart, patients were administered either placebo, 20 mg or 40 mg of oral MKS492 as a single dose. After 90 min they inhaled a dose of allergen (grass pollen or D. pteronyssinus) that had been demonstrated to produce a 20% decrease in FEV1. Measurements of FEV1 were repeated at 30 min intervals over the subsequent 7.5 h. RESULTS: After placebo, allergen inhalation produced bronchoconstriction with a maximum mean minimum FEV1 of 75.9% (12.7) (mean [s.d.]) of post-saline baseline values and a late response developed in 13 subjects (decrease in FEV1 > or = 15%). MKS492 (40 mg) increased the mean minimum % post-saline FEV1 at 30 min from 81.6% (14.0) for placebo to 93.1% (13.8), difference 11.5, 95% CI (2.6, 20.4). The mean minimum % post-saline FEV1 in the early response (0-2 h) was also increased by the 40 mg dose to 86.5% (11.8) vs 77.9% (13.8) for placebo, but not by the 20 mg dose. Significant bronchodilatation was noted 90 min after dosing (pre-allergen) in the MKS492 40 mg group. Late phase responses as assessed by 4 h % post-saline FEV1 was significantly improved by MKS 492 40 mg to 90.0% (6.3) vs 83.0% (12.4) for placebo-difference 7.0, 95% CI (0.1, 13.9), but again not by the 20 mg dose. Analysis of the area under the FEV1 response-time course curves showed non-significant reduction in the late response after the 40 mg dose (placebo 159.0, 134.8) vs 128.1, [81.5] for 40 mg). CONCLUSIONS: A novel PDE 3 inhibitor significantly decreases the early bronchoconstrictor response in asthma and attenuates the late response; effects that may be more marked at higher doses.

MMP and TIMP expression pattern in pleural effusions of different origins.

The matrix metalloproteinases (MMP) are proteolytic enzymes that are essentially involved in the turnover of the extracellular matrix (ECM). Their activity is counterbalanced by specific antagonists, the tissue inhibitors of metalloproteinases (TIMP). In this study, we sought to analyze the expression of MMP and TIMP isoforms in pleural effusions from 88 patients. We compared MMP and TIMP isoform expression in transudates (n = 21) and exudates (n = 67), the latter divided into exudates of paraneoplastic (n = 46) or parainfectious (n = 21) origin. Zymographic and Western blot analyses revealed constant expression of interstitial collagenase (MMP-1), gelatinase-A (MMP-2), and TIMP-1 in all 88 samples. In contrast, analyses of gelatinase-B (MMP-9) demonstrated a specific expression pattern, with high expression in exudates and lack of expression in transudates. Neutrophil collagenase (MMP-8) was detected in trace amounts, and correlated with the number of neutrophils in the effusion. Low levels of TIMP-2 were detected only in exudates and not in transudates. Quantitative analysis of the expression ratio of gelatinase-B to gelatinase-A revealed statistically significant differences between effusions of different origin. The ratio was highest in exudates of paraneoplastic origin and lowest in transudates. Our data thus suggest that interstitial collagenase, gelatinase-A, and TIMP-1 play a role in homeostasis of the pleural space in vivo as constitutively expressed proteins, whereas gelatinase-B and TIMP-2 expression are induced in specific disease states. These observations contribute to the understanding of the pathophysiology of pleural effusions, and may help to characterize and possibly distinguish effusions of different origin.

Treatment of progressive pulmonary sarcoidosis with cyclosporin A. A randomized controlled trial.

Conventional treatment of sarcoidosis is often only partially effective. We examined the effect of cyclosporin A (CsA) combined with prednisone for the treatment of sarcoidosis. Thirty-seven patients with biopsy-proven sarcoidosis were treated with either prednisone 20 mg/d in a prospectively tapered regimen (P) or with combination therapy consisting of prednisone 20 mg/d in a prospectively tapered regimen and cyclosporin A, 5 to 7 mg/kg/d (P-CsA) for up to 18 mo in an open-label randomized controlled trial. Evaluation was done at baseline and at 3, 9, and 18 mo of the degree of dyspnea, pulmonary function, chest radiographs, bronchoalveolar lavage (BAL), and adverse events. Criteria for a good therapeutic response, improvement, treatment failure, and relapse were defined. Thirty-seven patients were treated for at least 9 mo and 18 mo. Six patients in remission were included in an intention-to-treat-analysis at 18 mo. The groups did not differ significantly with respect to therapeutic response from baseline. A significant (p < 0.05) improvement was observed in dyspnea until 9 mo (P) and 18 mo (P-CsA), and in lung function until 9 mo (P) and 3 mo (P-CsA). BAL results showed a significant decrease in lymphocyte counts at 9 mo for the P group only (p < 0.05). More side effects were observed in the P-CsA group than in the P group, including elevation of the mean serum creatinine concentration at 3 and 9 mo (p < 0.05), and a doubling of the number of infections in this group. Relapse after an initially good therapeutic response occurred in two of nine patients in the P group and five of seven patients in the P-CsA group (p < 0.07). Although CsA may have theoretical benefits in the treatment of sarcoidosis, our results do not support its use in this disease.

Sub-acute cerebellar degeneration with anti-Yo autoantibodies: immunohistochemical analysis of the immune reaction in the central nervous system.

We report the pathological findings of a woman with a sub-acute cerebellar syndrome who had undergone surgery 3 years before for endometrial carcinoma. Both serum and cerebrospinal fluid contained high titres of autoantibodies against the cytoplasm of Purkinje cells that recognized a band of 62 kDa on immunoblotting of neuronal extracted proteins (pattern anti-Yo). No tumour was found despite a full range of gynaecological investigations; the neoplastic marker CA125 was slightly elevated and oligoclonal bands were detected in the cerebrospinal fluid. The patient died from acute myocardial infarction 4 months after developing this syndrome. At autopsy, no macroscopic evidence of tumour was obtained and the brain showed no abnormalities. On microscopic examination of the central nervous system diffuse degeneration of Purkinje cells could be seen throughout the cerebellum. Immunohistochemical analysis showed a CD8 lymphocyte infiltration in the cerebellum and cerebral cortex and diffuse microglial activation throughout the brain. These cells expressed high levels of MHC-II antigens on their cell membranes. The serum autoantibodies reacted with the cytoplasm of the remaining Purkinje cells. The short interval between the onset of symptoms and death of the patient could explain the difference between our findings and those reported in the literature in which no inflammatory infiltrates were detected. The immunohistochemical findings as well as the inflammatory cerebrospinal fluid profile seen in our case seem to support the concept that in paraneoplastic cerebellar degeneration with anti-Yo antibodies, an immune mediated mechanism is responsible for the damage to the cerebellum.