Beverly McElroy

Placebo-Controlled Trial of Rituximab in IgM Anti-Myelin-Associated Glycoprotein Antibody Demyelinating Neuropathy

Report a double‐blind, placebo‐controlled study of rituximab in patients with anti–MAG demyelinating polyneuropathy (A‐MAG‐DP).

The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome

Objective: To evaluate the clinical spectrum of anti-GAD-positive patients with stiff-person syndrome (SPS) and provide reproducible means of assessing stiffness. Background: SPS can be difficult to diagnose. Delineation of the clinical spectrum in a well defined population will increase diagnostic sensitivity. Methods: In 20 anti-GAD-positive patients with SPS (six men, 14 women), screened among 38 referred patients, the authors assessed symptoms and signs, degree of disability, associated conditions, and immunogenetic markers. Degree of bending, distribution of stiff areas, timed activities, and magnitude of heightened sensitivity were examined monthly for 4 months in five patients. Results: Average age at symptom onset was 41.2 years. Time to diagnosis was delayed from 1 to 18 years (mean 6.2). Stiffness with superimposed episodic spasms and co-contractures of the abdominal and thoracic paraspinal muscles were characteristic. All had stiff gait and palpable stiffness in the paraspinal muscles. Stiffness was asymmetric or prominent in one leg in 15 patients (stiff-leg syndrome) and involved facial muscles in 13. In one patient spasms lasted for days (status spasticus). Twelve patients needed a cane and seven a walker due to truncal stiffness and frequent falls (average three to four per month). Distribution of stiffness and degree of heightened sensitivity were two reproducible indices of stiffness and spasms. Autoimmune diseases or autoantibodies were noted in 80% and an association of with DRβ1 0301 allele in 70%. Conclusions: SPS is 1) frequently misdiagnosed due to multifaceted presentations and asymmetric signs, 2) disabling if untreated, and 3) associated with other autoimmune conditions.–1535

Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis

Sporadic inclusion-body myositis (sIBM) is the most common disabling, adult-onset, inflammatory myopathy histologically characterized by intense inflammation and vacuolar degeneration. In spite of T cell-mediated cytotoxicity and persistent, clonally expanded and antigen-driven endomysial T cells, the disease is resistant to immunotherapies. Alemtuzumab is a humanized monoclonal antibody that causes an immediate depletion or severe reduction of peripheral blood lymphocytes, lasting at least 6 months. We designed a proof-of-principle study to examine if one series of Alemtuzumab infusions in sIBM patients depletes not only peripheral blood lymphocytes but also endomysial T cells and alters the natural course of the disease. Thirteen sIBM patients with established 12-month natural history data received 0.3 mg/kg/day Alemtuzumab for 4 days. The study was powered to capture ≥10% increase strength 6 months after treatment. The primary end-point was disease stabilization compared to natural history, assessed by bi-monthly Quantitative Muscle Strength Testing and Medical Research Council strength measurements. Lymphocytes and T cell subsets were monitored concurrently in the blood and the repeated muscle biopsies. Alterations in the mRNA expression of inflammatory, stressor and degeneration-associated molecules were examined in the repeated biopsies. During a 12-month observation period, the patients’ total strength had declined by a mean of 14.9% based on Quantitative Muscle Strength Testing. Six months after therapy, the overall decline was only 1.9% (P < 0.002), corresponding to a 13% differential gain. Among those patients, four improved by a mean of 10% and six reported improved performance of daily activities. The benefit was more evident by the Medical Research Council scales, which demonstrated a decline in the total scores by 13.8% during the observation period but an improvement by 11.4% (P < 0.001) after 6 months, reaching the level of strength recorded 12 months earlier. Depletion of peripheral blood lymphocytes, including the naive and memory CD8+ cells, was noted 2 weeks after treatment and persisted up to 6 months. The effector CD45RA+CD62L cells, however, started to increase 2 months after therapy and peaked by the 4th month. Repeated muscle biopsies showed reduction of CD3 lymphocytes by a mean of 50% (P < 0.008), most prominent in the improved patients, and reduced mRNA expression of stressor molecules Fas, Mip-1a and αB-crystallin; the mRNA of desmin, a regeneration-associated molecule, increased. This proof-of-principle study provides insights into the pathogenesis of inclusion-body myositis and concludes that in sIBM one series of Alemtuzumab infusions can slow down disease progression up to 6 months, improve the strength of some patients, and reduce endomysial inflammation and stressor molecules. These encouraging results, the first in sIBM, warrant a future study with repeated infusions (Clinical Trials. Gov NCT00079768).

Gender-related differences in the clinical presentation of malignant and benign pheochromocytoma

Signs and symptoms associated with pheochromocytomas are predominantly caused by catecholamine excess, but tend to be highly variable and non-specific. In this study, we evaluated 23 male and 35 female pheochromocytoma patients for symptoms and signs of pheochromocytoma with special regard to gender-related differences in presentation. Total symptom score comparison between genders showed significant differences (12.0 vs. 7.8, P-value 0.0001). Female patients reported significantly more headache (80% vs. 52%), dizziness (83% vs. 39%), anxiety (85% vs. 50%), tremor (64% vs. 33%), weight change (88% vs. 43%), numbness (57% vs. 24%), and changes in energy level (89% vs. 64%). Females and males displayed comparable biochemical phenotypes (60% and 65% noradrenergic phenotype, respectively). Use of α- and/or β-blockade between males and females did not differ significantly. Subgroup analyses and multiple regression analysis revealed gender differences to be irrespective of benign or malignant disease, use of adrenoceptor-blockade, age and biochemical phenotype. We conclude female patients have significantly more self-reported pheochromocytoma signs and symptoms than male patients irrespective of biochemical phenotype and tumor presentation which may be related to distinct catecholamine receptor sensitivity. Clinicians should be aware of these complaints in female pheochromocytoma patients and offer adequate treatment if indicated.

A double blind, placebo-controlled study of rituximab in patients with stiff person syndrome

In stiff person syndrome (SPS), an antibody‐mediated impaired γ‐aminobutyric acidergic (GABAergic) neurotransmission is believed to cause muscle stiffness and spasms. Most patients improve with GABA‐enhancing drugs and intravenous immunoglobulin, but some respond poorly and remain disabled. The need for more effective therapy prompted a trial with the anti‐CD20 monoclonal antibody rituximab.

Are Repeated Single-Limb Heel Raises and Manual Muscle Testing Associated With Peak Plantar-Flexor Force in People With Inclusion Body Myositis?

Background Repeated heel raises have been proposed as a method of ankle plantar-flexor strength testing that circumvents the limitations of manual muscle testing (MMT). Objective The study objective was to examine the relationships among ankle plantar-flexion isometric maximum voluntary contraction (MVC), repeated single-limb heel raises (SLHRs), and MMT in people with myositis. Design This was a cross-sectional study with a between-group design. The ability to complete 1 SLHR determined group assignment (SLHR group, n=24; no-SLHR group, n=19). Methods Forty-three participants with myositis (13 women; median age=64.9 years) participated. Outcome measures included MVC, predicted MVC, Kendall MMT, and Daniels-Worthingham MMT. Results The Kendall MMT was unable to detect significant ankle plantar-flexor weakness established by quantitative methods and was unable to discriminate between participants who could and those who could not perform the SLHR task. Ankle plantar-flexion MVC was not associated with the number of heel-raise repetitions in the SLHR group (pseudo R2=.13). No significant relationship was observed between MVC values and MMT grades in the SLHR and no-SLHR groups. However, a moderate relationship between MVC values and MMT grades was evident in a combined-group analysis (ρ=.50–.67). Limitations The lower half of both MMT grading scales was not represented in the study despite the profound weakness of the participants. Conclusions Both Kendall MMT and Daniels-Worthingham MMT had limited utility in the assessment of ankle plantar-flexor strength. Repeated SLHRs should not be used as a proxy measure of ankle plantar-flexion MVC in people with myositis.

Reliability of the adult myopathy assessment tool in individuals with myositis.

The Adult Myopathy Assessment Tool (AMAT) is a 13‐item performance‐based battery developed to assess functional status and muscle endurance. The purpose of this study was to determine the intrarater and interrater reliability of the AMAT in adults with myositis.

Validity of the single limb heel raise test to predict lower extremity disablement in patients with sporadic inclusion body myositis

Abstract Purpose: To determine the validity of the single limb heel raise (SLHR) test as a potential screening tool to detect lower extremity disability in patients with sporadic inclusion body myositis (sIBM). Methods: We compared gait speed and fall history between subjects with sIBM who either could complete one SLHR (SLHR group) or could not complete one SLHR. Discriminative validity was established by comparing between group differences in functional measures based on group assignment. Receiver operating characteristics curve analysis was used to determine the predictive validity of completing one repetition on the SLHR test. Spearman correlations were used to determine the association between gait kinematics and number of repetitions achieved on the SLHR test. Results: Forty-three subjects (13 females) were studied. The SLHR group (n = 21) showed significantly greater gait speed (p < 0.001) and decreased gait aid use (p < 0.05) compared to the no SLHR group (n = 22). SLHR cut scores of 1, 20, and 22 repetitions maximized positive likelihood ratios (+LR) for the ability to walk at 54.9 (+LR. 2.2), 63.2 (+LR. 9.5), and 73.1 m/min (+LR. 5.0), respectively. Conclusion: The SLHR test demonstrates adequate discriminative and predictive validity as a screening tool for lower extremity disablement in patients with sIBM. Implications for Rehabilitation The SLHR test has adequate reliability and validity to screen for the presence of lower extremity disablement in patients with sIBM. Results of this rapid field test may be used to guide the need for rehabilitation services to mitigate the effects of slow gait speeds in patients with sIBM.

Lower extremity peak force and gait kinematics in individuals with inclusion body myositis.

To determine the relationship between peak isometric muscle force and temporal characteristics of gait in individuals with sporadic inclusion body myositis (s‐IBM).

Reply: Comment on alemtuzumab and inclusion body myositis

Sir, Dr Greenberg misinterprets several important aspects of our study, including the scope and applied methodology. Below we have addressed the points raised in his correspondence. This was a proof-of principle molecular clinicopathological study designed to investigate the effect of alemtuzumab on endomysial T cells and disease progression; it was not primarily a trial of clinical efficacy. As stated, alemtuzumab did not significantly improve patients’ strength and function but only induced short-term stability based on the difference between two time periods. Contrary to Dr Greenbergs comments, outcome was not based on any predetermined percentages that were subsequently amended. The percentages mentioned by Dr Greenberg were used only to power the sample size. As our results show, these percentages do not relate to the outcome or conclusions of the study because, regardless of whether a 10%, 13% or 15% difference is used, there is no significant improvement in the patients’ strength (as he correctly points out, only 4 of 13 patients improved, by only 4%–19%, while the mean strength for all patients declined by 1.9%). Our data and the interpretation of results have now been ratified in an independent review by the National Institutes of Health. The main finding was a significant reduction of relevant molecules seen in repeated muscle biopsies, combined with short-term clinical stability; this is encouraging and, as we stressed, warrants a controlled study. One should not read more than that from these results. The study was arguably small and uncontrolled but taught us a lot about …