Intravenous immunoglobulin in autoimmune neuromuscular diseases

Context  Intravenous immunoglobulin (IVIG) enhances immune homeostasis by modulating expression and function of Fc receptors, interfering with activation of complement and production of cytokines, providing anti-idiotypic antibodies, and affecting the activation and effector functions of T and B cells. These mechanisms may explain the effectiveness of IVIG in autoimmune neuromuscular disorders. Objective  To systematically review the current status of the treatment of autoimmune neuromuscular diseases with IVIG, with emphasis on controlled trials. Data Sources  Peer-reviewed publications identified through MEDLINE (1966-2003), EMBASE (1974-2003), and references from bibliographies of pertinent articles. Each autoimmune neuromuscular disease term was searched in combination with the term intravenous immunoglobulin. Study Selection and Data Extraction  Criteria for selection of studies included controlled study design, English language, and clinical pertinence. Data quality was based on venue of publication and relevance to clinical care. Data Synthesis  Outcomes of controlled trials indicate that IVIG at a total dose of 2 g/kg is effective as first-line therapy in Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy and as second-line therapy in stiff-person syndrome, dermatomyositis, myasthenia gravis, and Lambert-Eaton myasthenic syndrome. In other controlled studies, IVIG produced a modest, variable, and transient but not statistically significant benefit in patients with inclusion body myositis and paraproteinemic anti–myelin-associated glycoprotein antibody demyelinating polyneuropathy. Intravenous immunoglobulin is not effective in patients with multiple sclerosis who have established weakness or optic neuritis. In myasthenia gravis, it should be reserved for difficult cases or before thymectomy in lieu of plasma exchange. Conclusion  Intravenous immunoglobulin is effective in many autoimmune neurologic diseases, but its spectrum of efficacy, especially as first-line therapy, and the appropriate dose for long-term maintenance therapy are not fully established. Further controlled studies of IVIG, combined with a dose-finding effect, pharmacoeconomics, and quality-of-life assessments, are warranted to improve the evidence base for clinical practice.      

Influence of short-term dietary weight loss on cortisol secretion and metabolism in obese men

OBJECTIVES: Obesity is associated with increased inactivation of cortisol by hepatic A-ring 5alpha- and 5beta-reductases, impaired hepatic regeneration of cortisol from cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1), but increased subcutaneous adipose 11HSD1 activity enhancing local cortisol levels in fat. Cause and effect between obesity and abnormal cortisol metabolism is untested. DESIGN: Acute weight loss was induced by very low calorie diet (VLCD) or starvation in obese men. METHODS: Otherwise healthy males (aged 20-55 years; body mass index (BMI) 30-40 kg/m2) were studied after 6 days on a weight maintenance diet; then after either 6 days of starvation (n=6) or 3 weeks of VLCD (2.55 MJ; n=6); then after 1 week of weight maintenance; and finally after 2 weeks of being allowed to feed ad libitum. Plasma samples were obtained from indwelling cannulae at 0930 h and 1815 h and a 24 h urine collection was completed for analysis of cortisol metabolites by gas chromatography/mass spectrometry. RESULTS: Data are mean+/-S.E.M. BMI fell (kg/m3) from 34.8+/-0.8 at baseline to 31.8+/-1.4 on VLCD and 32.7+/-1.1 on starvation. Starvation caused a rise in plasma cortisol (at 0930 h from 143+/-17 to 216+/-11 nM, P<0.001) but no change in total urinary cortisol metabolites. VLCD did not alter plasma cortisol and markedly reduced cortisol metabolite excretion (from 15.8+/-1.1 mg/day at baseline to 7.0+/-1.1 mg/day, P<0.001). Relative excretion of 5alpha-reduced cortisol metabolites fell on both diets, but there were no changes in cortisol/cortisone metabolite ratios reflecting 11HSD activities. CONCLUSIONS: Weight loss with VLCD in obesity reverses up-regulation of hepatic A-ring reductases and normalises cortisol production rate; in contrast, starvation produces acute stress and further activation of cortisol secretion. We suggest that activation of cortisol secretion is not an irreversible intrinsic abnormality in obese patients, and speculate that dietary content has an important influence on the neuroendocrine response to weight loss.     

Anti-glutamic acid decarboxylase antibodies in the serum and cerebrospinal fluid of patients with stiff-person syndrome: correlation with clinical severity

BACKGROUND: Stiff-person syndrome (SPS) is an immune-mediated central nervous system disorder characterized by fluctuating muscle stiffness, disabling spasms, and heightened sensitivity to external stimuli. Up to 80% of patients with SPS have anti-glutamic acid decarboxylase (GAD) antibodies in the serum or cerebral spinal fluid (CSF). Whether these antibodies are clinically relevant and correlate with disease severity is unknown. OBJECTIVE: To correlate anti-GAD antibody titers in the serum and CSF of patients with SPS with the degree of clinical severity. DESIGN: Patients studied the last 6 years. SETTING: The Clinical Center of the National Institutes of Health, Bethesda, MD. PATIENTS: Sixteen patients with typical SPS and elevated serum anti-GAD antibody titers. INTERVENTIONS: Antibody titers in serum and CSF were measured by radioimmunoassay, and the intrathecal anti-GAD-specific IgG production was calculated. MAIN OUTCOME MEASURES: Comparison of antibody titers with stiffness index and heightened sensitivity scores based on scales that reliably measure disease severity. RESULTS: The mean disease duration was 11 years (range, 5-30 years). The mean anti-GAD antibody titer in the serum was 51 500 U/mL (range, 24 000-200 000 U/mL); and in the CSF, 181 U/mL (range, 30-400 U/mL). A 10-fold increased intrathecal production of GAD-specific IgG antibodies was noted. No correlation was found between antibody titers in serum or CSF with disease severity. In 4 patients, the anti-GAD antibody titers measured serially during a 2-year period did not correlate with clinical fluctuations. CONCLUSIONS: In patients with SPS, the anti-GAD antibody titers in serum and CSF do not correlate with disease severity or duration. Anti-GAD antibodies are an excellent marker for SPS, but monitoring their titers during the course of the disease may not be of practical value.     

The development, validation and reliability of a nutrition screening tool based on the recommendations of the British Association for Parenteral and Enteral Nutrition (BAPEN)

BACKGROUND & AIMS: Nutrition screening tools (NST) identify individuals who are malnourished or at risk of becoming malnourished and who may benefit from nutritional support. The aims of this study were to design, pilot and evaluate a NST based on four nutritional parameters (weight, height, recent unintentional weight loss and appetite) recommended by the British Association for Parenteral and Enteral Nutrition as the minimum required to identify patients with nutritional problems. METHODS: A dietitian assessed the nutritional status of 100 patients admitted to the general medical wards. Results from the study were used to design a NST. The concurrent validity of the screening tool was then assessed, by comparing it with a nutritional assessment by an experienced dietitian in 100 patients admitted to acute medical and elderly care wards. The inter-rater reliability of the screening tool was also assessed using three nurses and 26 acute medical patients. RESULTS: All four nutritional parameters were required to identify all at-risk patients. There was good agreement between the screening tool and the dietitian's assessment (kappa = 0.717) and inter-rater reliability was reasonable (mean kappa = 0.66). CONCLUSION: The screening tool was valid and reliable in identifying medical patients at risk of malnutrition and was quick and simple to use.     

Corneal perforation after conductive keratoplasty with previous refractive surgery

A 56-year-old woman had conductive keratoplasty (CK) for residual hyperopia and astigmatism. Three years before the procedure, the patient had arcuate keratotomy, followed by laser in situ keratomileusis 2 years later for high astigmatism correction in both eyes. During CK, a corneal perforation occurred in the right eye; during the postoperative examination, an iris perforation and anterior subcapsule opacification were seen beneath the perforation site. The perforation was managed with a bandage contact lens and an antibiotic-steroid ointment; it had a negative Seidel sign by the third day. The surgery in the left eye was uneventful. Three months after the procedure, the uncorrected visual acuity was 20/32 and the best corrected visual acuity 20/20 in both eyes with a significant improvement in corneal topography. Care must be taken to prevent CK-treated spots from coinciding with areas in the corneal stroma that might have been altered by previous refractive procedures.     

Immunotherapy in autoimmune neuromuscular disorders

Important progress has been made in our understanding of the cellular and molecular processes underlying autoimmune neuromuscular diseases that has led us to identify targets for rational therapeutic intervention. Although antigen-specific immunotherapy is not yet available, old and new immunomodulatory treatments, alone or in combination, provide effective immunotherapy for most autoimmune disorders. In parallel, the achievements of molecular medicine provide more specific yet largely experimental therapeutic tools that need to be tested in the human diseases. Here we review the principles and targets of immunotherapy for autoimmune neuromuscular disorders, address applications and practical guidelines, and give an outlook on future developments.     

Stiff-person syndrome

Opinion statement Stiff-person syndrome (SPS) is a progressive neurologic disorder characterized by 1) stiffness that is prominent in axial muscles, with co-contraction of agonist and antagonist muscles; 2) sudden episodic spasms; and 3) absence of another disease that causes similar symptoms. The diagnosis of SPS is based on clinical grounds and requires a high degree of suspicion. The diagnosis is, however, aided by electromyography, which demonstrates motor unit firing at rest simultaneously from the agonist and antagonist muscles, and by high serum titers of antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of gamma-aminobutyric acid (GABA), which is the brain’s main inhibitory neurotransmitter. The reduced GABA level in the brain and cerebrospinal fluid explains the patients’ stiffness and justifies the clinical improvement observed by drugs enhancing GABAergic transmission. The association of SPS with other autoimmune disorders or autoantibodies, the intrathecal GAD-specific immunoglobulin G antibody synthesis, and the suppression of GABA by the patient’s antibodies supports the autoimmune nature of SPS and justifies the use of immunotherapies. At present, GABA-enhancing agents, such as benzodiazepines, valproate, vigabatrin, tiagabine, gabapentin, and baclofen, provide symptomatic relief. Plasmapheresis, steroids, and periodic intravenous immunoglobulin infusions provide additional and lasting benefit. In this article, the treatment options for patients with SPS are discussed based on the authors’ experience and that of others. The beneficial effects from the first controlled study conducted in SPS using intravenous immunoglobulin are presented.     

Endoscopic Sleeve Gastroplasty (ESG) Is a Reproducible and Effective Endoscopic Bariatric Therapy Suitable for Widespread Clinical Adoption: a Large,International Multicenter Study

Objective

Endoscopic sleeve gastroplasty (ESG), an incisionless endoscopic bariatric procedure, has shown impressive results in case series. This study examines the reproducibility, efficacy, and safety in three centers across two countries, and identifies key determinants for procedural success.

Design

Patients who underwent ESG between February 2016 and May 2017 at one of three centers (Australia and USA) were retrospectively analyzed. All procedures were performed on an outpatient basis using the Apollo OverStitch device (Apollo Endosurgery, Austin, TX). Primary outcomes included absolute weight loss (ΔWeight, kg), change in body mass index (?BMI, in kg/m²), total body weight loss (TBWL, %), excess weight loss (EWL, in %), and immediate and delayed adverse events.

Results

In total, 112 consecutive patients (male 31%, age 45.1?±?11.7 years, baseline BMI 37.9?±?6.7 kg/m²) underwent ESG. At 1, 3, and 6 months, Δweight was 9.0?±?4.6 kg (TBWL 8.4?±?4.1%), 12.9?±?6.4 kg (TBWL 11.9?±?4.5%), and 16.4?±?10.7 kg (TBWL 14.9?±?6.1%), respectively. The proportion of patients who attained greater than 10% TBWL and 25% EWL was 62.2 and 78.0% at 3 months post-ESG and 81.0 and 86.5% at 6 months post-ESG. Weight loss was similar between the three centers. Multivariable analysis showed that male sex, greater baseline body weight, and lack of prior endoscopic bariatric therapy were predictors of greater Δweight at 6 months. Three (2.7%) severe adverse events were observed.

Conclusions

ESG is an effective, reproducible, and safe weight loss therapy that is suitable for widespread clinical adoption.