Kathleen Healey

Relapse rates and enhancing lesions in a phase II trial of natalizumab in multiple sclerosis.

Background: Natalizumab, a humanized monoclonal IgG4 antibody, is an a4-integrin antagonist, which inhibits the migration of inflammatory cells into the central nervous system, a key pathogenic mechanism in multiple sclerosis (MS). In a six month, phase II clinical trial of patients with relapsing MS, natalizumab significantly reduced the formation of new gadolinium-enhanced (Gd +) lesions and the number of clinical relapses. Objective: To investigate the relationship of historical relapse rate and new Gd+ lesion number with subsequent MS disease activity and natalizumab treatment in the phase II study. Methods: Patients who participated in the phase II study were stratified into subgroups according to: (i) the number of relapses in the two years prior to entry into the study: 2 relapses (n=108), 3 relapses (n=57), and-3 relapses (n=48); (ii) the number of new Gd+ lesions at baseline (Month 0): 0 (n=129), 1-2(n=50), and >2(n=33). Relapses and new Gd+ lesions during the treatment phase of the trial were determined and compared for each subgroup. Results: Both the prestudy relapse rate and number of new Gd+ lesions at baseline were related to the subsequent risk of a relapse; baseline number of Gd+ lesions was related to the likelihood of subsequent new Gd+ lesion formation. There was a lower proportion of subjects with an on-study relapse and fewer new Gd+ lesions in all natalizumab-treated subgroups when compared with their placebo counterpart; the difference was most apparent in the subgroups of patients with >3 relapses in the two years prior to study entry and >2 new Gd+ lesions at Month 0. Conclusions: There was a lower proportion of subjects with an on-study relapse in natalizumab-treated patients, particularly in those with a more active disease at study entry. Larger ongoing phase III studies will allow more definitive investigation of these preliminary subgroup findings.

A randomized open label study of pain medications (naproxen, acetaminophen and ibuprofen) for controlling side effects during initiation of IFN β-1a therapy and during its ongoing use for relapsing-remitting multiple sclerosis

Multiple sclerosis (MS) patients initiating IFN b-1a, Avonex, therapy (Group 1, n-30) or experiencing side effects after 6 months on therapy (Group 2, n-30) were randomized for 5 weeks open label adjunct therapy to naproxen (Aleve®), acetaminophen (Tylenol®)or ibuprofen (Advil®). Our hypothesis was that non-prescription pain medications are effective in decreasing or alleviating the side effects associated with IFN b-1a therapy. Contrary to the hypothesis, most patients in both groups continued to report side effects on all pain medications. After 5 weeks, headache, fever, chills and injection site pain were low in5-50% of patients. Moderate to significant fatigue, muscle or joint pain continued in most patients. As a quality of life measure, the Modified Fatigue Impact Scale (mFIS) improved for Group 1 on naproxen or ibuprofen with greatest improvement in physical subset (P-0.002 for naproxen and PB-0.01 for ibuprofen). Total mFIS for Group 1 on acetaminophen improved (P-0.04) due to improved cognitive subset rather than physical subset. Group 2, with side effects initially, reported less significant fatigue (severity 5-10) but more moderate fatigue (severity 2-4) at study end for all three medications. All medications improved cognitive subset (P=0.05). Physical mFIS subset did not improve for Group 2 on acetaminophen, but did with naproxen (P=0.05) or ibuprofen (P=0.03). Naproxen and ibuprofen were more effective than acetaminophen in minimizing physical side effects of IFN b-1a. None of the three pain medications tested were as effective as hypothesized for minimizing fatigue or muscle and joint pain.

Cervical spinal cord multiple sclerosis: evaluation with 2D multi-echo recombined gradient echo MR imaging

Abstract Objective: The two-dimensional multi-echo recombined gradient echo (MERGE) technique automatically acquires and sums multiple gradient echoes at various echo times in cervical spine magnetic resonance (MR) imaging. This technique increases the grey–white matter contrast within the spinal cord and should also improve the depiction of cervical cord lesions. The aim of this study was to qualitatively and quantitatively evaluate MERGE imaging compared with T2-weighted fast spin-echo (T2WFSE) imaging for depicting multiple sclerosis (MS) lesions in the cervical cord. Methods: Nineteen consecutive patients (10 males and 9 females; age range 22–62 years, mean age 43.6 years) with clinically diagnosed MS were examined with cervical spinal cord MR imaging at 3 T including both MERGE and T2WFSE imaging. Qualitative evaluation for MS lesion conspicuity was performed. The quantitative criterion utilized to compare MERGE imaging with T2WFSE imaging was the lesion-to-background contrast-to-noise ratio (CNR). Results: MERGE imaging showed 79 lesions and missed 1 that was depicted on T2WFSE imaging. T2WFSE imaging showed 46 lesions and missed 34 that were depicted on MERGE imaging. MERGE imaging was markedly superior to T2WFSE imaging in rendering greater lesion conspicuity. In the quantitative evaluation, the lesion-to-background CNR upon MERGE imaging was significantly higher than that upon T2WFSE imaging (P < 0.001, paired t-test). Conclusions: MERGE imaging in the cervical spinal cord increases detection and conspicuity of MS lesions. Strong consideration should be given to utilizing axial MERGE images in the diagnosis and follow-up study of cervical cord MS.

Discordant functional and inflammatory parameters in multiple sclerosis patients after autologous haematopoietic stem cell transplantation

This article describes outcomes in four patients with advanced multiple sclerosis up to two years after autologous haematopoietic stem cell transplantation using a total-body irradiation-based preparative regimen. MRI and C SF analyses demonstrated clear suppression of the inflammatory processes. The results demonstrate however, a dissociation of inflammation parameters and functional disability findings raising questions about optimal future stem cell transplantatio n strategies for this disease.

High-dose cyclophosphamide in multiple sclerosis patients undergoing autologous stem cell transplantation

High-dose cyclophosphamide (CTX) is commonly used in preparation for autologous and allogeneic stem cell transplantation. CTX is a pro-drug, which undergoes complex oxidative metabolism with the metabolites being eliminated both renally and hepatically. In the following study, we evaluated the pharmacokinetic characteristics of high-dose CTX in three patients undergoing autologous stem cell transplantation for multiple sclerosis. The plasma concentration-time profiles for CTX and its hydroxy-metabolite were similar in multiple sclerosis patients to those reported in cancer patients undergoing stem cell transplantation. There was an increase in drug clearance after the second CTX dose indicating that the drug induced its own metabolism consistent with reports in other populations receiving high-dose CTX. One of the three patients cleared the drug slowly but this was not associated with greater toxicity. The patient with the slow clearance value and therefore highest drug exposure had stable disability scores at 2 years posttransplant compared with baseline values taken prior to transplantation. In conclusion, in this small case series, there was no indication that CTX metabolism was different than that in other populations undergoing transplantation.

Neurorehabilitation Strategies Focusing on Ankle Control Improve Mobility and Posture in Persons With Multiple Sclerosis.

Background and Purpose: The neuromuscular impairments seen in the ankle plantarflexors have been identified as a primary factor that limits the mobility and standing postural balance of individuals with multiple sclerosis (MS). However, few efforts have been made to find effective treatment strategies that will improve the ankle plantarflexor control. Our objective was to determine whether an intensive 14-week neurorehabilitation protocol has the potential to improve the ankle plantarflexor control of individuals with MS. The secondary objectives were to determine whether the protocol would also improve postural control, plantarflexion strength, and mobility. Methods: Fifteen individuals with MS participated in a 14-week neurorehabilitation protocol, and 20 healthy adults served as a comparison group. The primary measure was the amount of variability in the submaximal steady-state isometric torque, which assessed plantarflexor control. Secondary measures were the Sensory Organization Test composite score, maximum plantarflexion torque, and the spatiotemporal gait kinematics. Results: There was less variability in the plantarflexion torques after the neurorehabilitation protocol (preintervention, 4.15% ± 0.5%; postintervention, 2.27% ± 0.3%). In addition, there were less postural sway (preintervention, 51.87 ± 0.2 points; postintervention, 67.8 ± 0.5 points), greater plantarflexion strength (preintervention, 0.46 ± 0.04 Nm/kg; postintervention, 0.57 ± 0.05 Nm/kg), and faster walking speeds (preferred preintervention, 0.71 ± 0.05 m/s; preferred postintervention, 0.81 ± 0.05 m/s; fast-as-possible preintervention, 0.95 ± 0.06 m/s; postintervention, 1.11 ± 0.07 m/s). All of the outcome variables matched or trended toward those seen in the controls. Discussion and Conclusions: The outcomes of this exploratory study suggest that the neurorehabilitation protocol employed in this investigation has the potential to promote clinically relevant improvements in the ankle plantarflexor control, standing postural balance, ankle plantarflexion strength, and the mobility of individuals with MS. Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A110).

Program Evaluation Results of a Structured Group Exercise Program in Individuals with Multiple Sclerosis

Although research-based and anecdotal evidence support the beneficial role of physical activity in symptom management among individuals with multiple sclerosis (MS), the integration of physical activity into the lifestyles of people with disabilities remains a challenge. The purposes of this study were to evaluate the feasibility and perceived effectiveness of a group Jazzercise program that was modified to fit the needs of individuals with MS. The study population included patients diagnosed with definite MS who were receiving care at the University of Nebraska Medical Center. Eleven of 14 initial participants remained in the program after 16 weeks and were mailed a short anonymous questionnaire designed to assess self-reported improvement in balance, confidence, coordination, energy, flexibility, mood, and strength, and to determine satisfaction and motivation to continue the course. Nine of the 11 participants (82%) at week 16 returned the survey. Of the nine respondents, all (100%) reported improvemen...

Errors in the ankle plantarflexor force production are related to the gait deficits of individuals with multiple sclerosis

BACKGROUND Individuals with multiple sclerosis (MS) often have limited mobility that is thought to be due to the neuromuscular impairments of the ankle. Greater isometric motor control of the ankle has been associated with better standing postural balance but its relationship to mobility is less understood. The objectives of this investigation were to quantify the motor control of the ankle plantarflexors of individuals with MS during a dynamic isometric motor task, and explore the relationship between the ankle force control and gait alterations. METHODS Fifteen individuals with MS and 15 healthy adults participated in both a dynamic isometric ankle plantarflexion force matching task and a biomechanical gait analysis. FINDINGS Our results displayed that the subjects with MS had a greater amount of error in their dynamic isometric force production, were weaker, walked with altered spatiotemporal kinematics, and had reduced maximal ankle moment at toe-off than the control group. The greater amount of error in the dynamic force production was related to the decreases in strength, step length, walking velocity, and maximal ankle moment during walking. INTERPRETATION Altogether these results imply that errors in the ankle plantarflexion force production may be a limiting factor in the mobility of individuals with MS.

Two Different Types of High-Frequency Physical Therapy Promote Improvements in the Balance and Mobility of Persons With Multiple Sclerosis

OBJECTIVE To evaluate the mobility and postural balance improvements that could be achieved in a cohort of persons with multiple sclerosis (MS) who participated in a motor adaptation protocol and a cohort of persons with MS who participated in a therapeutic exercise protocol. DESIGN A cohort design, where subjects were evaluated before and after a 6-week intervention period. SETTING Clinical laboratory setting. PARTICIPANTS Individuals (N=42) with relapsing-remitting or secondary progressive MS (Expanded Disability Status Scale [EDSS] scores, 3.0-6.5) were initially screened for eligibility for participation in the study, from which those who fit the inclusion criteria (n=32) were enrolled in the study. Subjects were pseudorandomly assigned to a treatment group and matched based on EDSS scores. Fourteen individuals in the motor adaptation cohort (MAC) (mean age ± SD, 52.6±9y; mean EDSS score ± SD, 5.5±0.9) and 13 individuals in the therapeutic exercise cohort (TEC) (mean age ± SD, 54.0±9y; mean EDSS score ± SD, 5.3±0.9) completed the entire duration of their respective programs. INTERVENTIONS Both cohorts completed their therapy twice a day, 5 days each week, for 6 weeks. Each session of the MAC program consisted of balance and gait training that encouraged new ways to adapt to challenging task demands. The TEC program was similar to a traditional exercise program. MAIN OUTCOME MEASURES The Sensory Organization Test, 6-minute walk test, and gait spatiotemporal kinematics. RESULTS Collectively, both treatment groups had improvements in postural balance (P=.001), walking endurance (P=.002), walking speed (P=.004), and step length (P<.001) after therapy. However, there were no statistical differences between the 2 treatment groups for any of the outcome variables (P values >.01). CONCLUSIONS Our exploratory results suggest that a high frequency of physical therapy rather than a specific activity focus might be an important parameter for persons with MS.

A home-based comprehensive care model in patients with Multiple Sclerosis: A study pre-protocol.

Background Disability is prevalent in individuals with multiple sclerosis (MS), leading to difficulty in care access, significant caregiver burden, immense challenges in self-care and great societal burden. Without highly coordinated, competent and accessible care, individuals living with progressive MS experience psychological distress, poor quality of life, suffer from life-threatening complications, and have frequent but avoidable healthcare utilizations. Unfortunately, current healthcare delivery models present severe limitations in providing easily accessible, patient-centered, coordinated comprehensive care to those with progressive MS. We propose a home-based comprehensive care model (MAHA) to address the unmet needs, challenges, and avoidable complications in individuals with progressive MS with disabling disease. Objective The article aims to describe the study design and methods used to implement and evaluate the proposed intervention. Method The study will use a randomized controlled design to evaluate the feasibility of providing a 24-month, home-based, patient-centered comprehensive care program to improve quality of life, reduce complications and healthcare utilizations overtime (quarterly) for 24 months. A transdisciplinary team led by a MS-Comprehensivist will carry out this project. Fifty MS patients will be randomly assigned to the intervention and usual care program using block randomization procedures. We hypothesize that patients in the intervention group will have fewer complications, higher quality of life, greater satisfaction with care, and reduced healthcare utilization. The proposed project is also expected to be financially sustainable in fee-for-service models but best suited for and gain financial success in valued-based care systems. Discussion This is the first study to examine the feasibility and effectiveness of a home-based comprehensive care management program in MS patients living with progressive disability. If successful, it will have far-reaching implications in research, education and practice in terms of providing high quality but affordable care to population living with severe complex, disabling conditions.