Sasa Zivkovic

A Randomized Study of Alglucosidase Alfa in Late-Onset Pompe's Disease

BACKGROUND Pompes disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompes disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompes disease. METHODS Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC). RESULTS At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients). CONCLUSIONS In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)

R(+) pramipexole as a mitochondrially focused neuroprotectant: Initial early phase studies in ALS

R(+) pramipexole (PPX) is a lipophilic cation that concentrates into brain and mitochondria and efficiently scavenges reactive oxygen and nitrogen species (RONS). Under the auspices of a Physician‐Sponsor IND, R(+)PPX was dosed to small numbers of ALS patients for tolerability and safety while efficacy measures were also collected. The purpose of this paper is to describe the outcomes of these initial clinical studies. In a futility design study, 30 patients with early SALS were evaluated monthly for ALSFRS‐R scores and FVC measurements for three months during lead‐in, followed by open‐label dosing at 30 mg/day of R(+)PPX for the next six months. In the dose escalation study, 10 subjects with early ALS received daily doses of R(+)PPX from 10 mg t.i.d. to 100 mg t.i.d. over seven weeks. In the open‐label extension analysis, subjects from the initial studies were treated with 30 mg/day for at least six months, then switched to 60 mg/day. R(+)PPX was tolerated well in all studies. In the futility study, slopes of decline in ALSFRS‐R scores and neurophysiological index (NI) values yielded non‐significant reductions during treatment. In the dose‐escalation study, all subjects increased daily R(+)PPX intake safely to 100 mg t.i.d. Markers of ALS did not change (ALSFRS‐R) or improved (FVC). Trough and peak plasma (PPX) increased linearly with dosing, and several subjects achieved plasma (PPX) >1 µM. In the open‐label extension protocol, changing from 30 to 60 mg/day caused a non‐significant 17% reduction in slope of decline of ALSFRS‐R. It was concluded that R(+)PPX was tolerated well in long‐term dosing at 30 and 60 mg/day. Encouraging but non‐significant effects of R(+)PPX on ALS decline were observed. High doses of R(+)PPX were tolerated well and yielded neuroprotective plasma levels. These findings support longer‐term testing of higher R(+)PPX doses as a potential disease‐altering therapy for SALS.

Severe sensory neuropathy associated with long-term linezolid use

Linezolid is an antibiotic used for treatment of drug-resistant gram-positive micro-organisms. It is recommended to treat patients with linezolid for up to 28 days,1 but sometimes it is used for a longer period of time in the treatment of bone infections. It is usually well tolerated, and few patients develop myelosuppression, diarrhea, or nausea.1 However, recent reports indicate a risk of a potentially irreversible neuropathy following prolonged use.2–5 We report an additional patient with severe sensory polyneuropathy following a 6-month course of linezolid. A 42-year-old, otherwise healthy woman sustained left ankle, tibia, femur, pelvic, and rib fractures in a motor vehicle accident in December 1999. Subsequently, she underwent multiple orthopedic surgeries, complicated by treatment-resistant staphylococcal osteomyelitis. In May 2001, she was treated with linezolid 600 mg bid orally. This …

Sensory and Motor Peripheral Nerve Function and Incident Mobility Disability

To assess the relationship between sensorimotor nerve function and incident mobility disability over 10 years.

Sensory and motor peripheral nerve function and longitudinal changes in quadriceps strength.

BACKGROUND Poor peripheral nerve function is common in older adults and may be a risk factor for strength decline, although this has not been assessed longitudinally. METHODS We assessed whether sensorimotor peripheral nerve function predicts strength longitudinally in 1,830 participants (age = 76.3 ± 2.8, body mass index = 27.2 ± 4.6kg/m(2), strength = 96.3 ± 34.7 Nm, 51.0% female, 34.8% black) from the Health ABC study. Isokinetic quadriceps strength was measured semiannually over 6 years. Peroneal motor nerve conduction amplitude and velocity were recorded. Sensory nerve function was assessed with 10-g and 1.4-g monofilaments and average vibration detection threshold at the toe. Lower-extremity neuropathy symptoms were self-reported. RESULTS Worse vibration detection threshold predicted 2.4% lower strength in men and worse motor amplitude and two symptoms predicted 2.5% and 8.1% lower strength, respectively, in women. Initial 10-g monofilament insensitivity predicted 14.2% lower strength and faster strength decline in women and 6.6% lower strength in men (all p < .05). CONCLUSION Poor nerve function predicted lower strength and faster strength decline. Future work should examine interventions aimed at preventing declines in strength in older adults with impaired nerve function.

Sensory neuropathy associated with metronidazole: report of four cases and review of the literature.

Objective To better characterize sensory neuropathy associated with metronidazole. Methods We report four patients who developed dysesthesias after metronidazole treatment. One received topical metronidazole only. All four underwent electrodiagnostic studies, including nerve conduction studies (NCS), quantitative sensory testing (QST), and quantitative sudomotor axon reflex testing (QSART). One underwent nerve biopsy. Results NCS were normal in all patients. QST showed impaired vibration thresholds in three patients. Three of four patients had abnormal tests of small fiber function. Cooling thresholds were abnormal in one; QSART was abnormal in one and borderline in another. The nerve biopsy specimen showed mild loss of small myelinated axons. Conclusions This study shows that paresthesias associated with metronidazole exposure may be the result of a relatively mild sensory neuropathy with predominant involvement of small fibers and milder, mostly subclinical involvement of large fibers.

Reproducibility of peroneal motor nerve conduction measurement in older adults

OBJECTIVE While neuropathy is common in the elderly, nerve conduction (NC) reproducibility in older adults is not well-established. We sought to evaluate intraobserver reproducibility of peroneal motor NC measures in a diverse sample of older adults. METHODS We measured peroneal motor NC amplitude and velocity in a subset of participants (mean age=82.9±2.7, n=62, 50% female, 51.6% black, 35.5% DM) in the Health, Aging, and Body Composition Study. Using coefficients of variation (CVs), intraclass correlation coefficients (ICCs), and Bland Altman Plots, we compared two sets of measurements taken by the same examiner hours apart on the same day. RESULTS Low CVs (2.15-4.24%) and moderate to high ICCs (0.75-0.99) were observed. No systematic variation was found across measures. Despite small numbers in some subgroups, we found no differences in reproducibility by diabetes, race or study site. CONCLUSION NC measures have moderate to high intraobsever reproducibility in older adults and are not affected by diabetes, race, or gender. SIGNIFICANCE These data provide evidence to support use of these measures in aging research.

Peripheral Nerve Function and Lower Extremity Muscle Power in Older Men

OBJECTIVE To assess whether sensorimotor peripheral nerve function is associated with muscle power in community-dwelling older men. DESIGN Longitudinal cohort study with 2.3±0.3 years of follow-up. SETTING One clinical site. PARTICIPANTS Participants (n=372; mean age ± SD, 77.2±5.1y; 99.5% white; body mass index, 27.9±3.7kg/m(2); power, 1.88±0.6W/kg) at 1 site of the Osteoporotic Fractures in Men Study (N=5994). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES A nerve function ancillary study was performed 4.6±0.4 years after baseline. Muscle power was measured using a power rig. Peroneal motor nerve conduction amplitude, distal motor latency, and mean f-wave latency were measured. Sensory nerve function was assessed using 10-g and 1.4-g monofilaments and sural sensory nerve conduction amplitude and distal latency. Peripheral neuropathy symptoms at the leg and feet were assessed by self-report. RESULTS After adjustments for age, height, and total body lean and fat mass, 1 SD lower motor (β=-.07, P<.05) and sensory amplitude (β=-.09, P<.05) and 1.4-g (β=-.11, P<.05) and 10-g monofilament insensitivity (β=-.17, P<.05) were associated with lower muscle power/kg. Compared with the effect of age on muscle power (β per year, -.05; P<.001), this was equivalent to aging 1.4 years for motor amplitude, 1.8 years for sensory amplitude, 2.2 years for 1.4-g monofilament detection, and 3.4 years for 10-g detection. Baseline 1.4-g monofilament detection predicted a greater decline in muscle power/kg. Short-term change in nerve function was not associated with concurrent short-term change in muscle power/kg. CONCLUSIONS Worse sensory and motor nerve function were associated with lower muscle power/kg and are likely important for impaired muscle function in older men. Monofilament sensitivity was associated with a greater decline in muscle power/kg, and screening may identify an early risk for muscle function decline in late life, which has implications for disability.

Chronic eosinophilic perimyositis with persistent myalgias

A 43‐year‐old man with an 8‐year history of hypereosinophilia was evaluated for persistent muscle pain. Methotrexate and corticosteroids were ineffective. Examination, limited by pain even with passive motion, showed only mild weakness. Electromyography and muscle enzymes were normal. A needle muscle biopsy specimen revealed eosinophilic perimyositis. This case illustrates that the diagnosis of eosinophilic perimyositis requires histopathological evaluation, which should be pursued in patients with eosinophilia and persistent myalgia despite normal electromyography and muscle enzymes.

Sensorimotor Peripheral Nerve Function and the Longitudinal Relationship With Endurance Walking in the Health, Aging and Body Composition Study

OBJECTIVES To determine whether lower extremity sensorimotor peripheral nerve deficits are associated with reduced walking endurance in older adults. DESIGN Prospective cohort study with 6 years of follow-up. SETTING Two university research clinics. PARTICIPANTS Community-dwelling older adults enrolled in the Health, Aging and Body Composition Study from the 2000-2001 annual clinical examination (N=2393; mean age ± SD, 76.5±2.9y; 48.2% men; 38.2% black) and a subset with longitudinal data (n=1178). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Participants underwent peripheral nerve function examination in 2000-2001, including peroneal motor nerve conduction amplitude and velocity, vibration perception threshold, and monofilament testing. Symptoms of lower extremity peripheral neuropathy included numbness or tingling and sudden stabbing, burning, pain, or aches in the feet or legs. The Long Distance Corridor Walk (LDCW) (400 m) was administered in 2000-2001 and every 2 years afterward for 6 years to assess endurance walking performance over time. RESULTS In separate, fully adjusted linear mixed models, poor vibration threshold (>130 μm), 10-g and 1.4-g monofilament insensitivity were each associated with a slower 400-m walk completion time (16.0 s, 14.4s, and 6.9 s slower, respectively; P<.05 for each). Poor motor amplitude (<1 mV), poor vibration perception threshold, and 10-g monofilament insensitivity were related to greater slowing per year (4.7, 4.2, and 3.8 additional seconds per year, respectively; P<.05), although poor motor amplitude was not associated with initial completion time. CONCLUSIONS Poorer sensorimotor peripheral nerve function is related to slower endurance walking and greater slowing longitudinally. Interventions to reduce the burden of sensorimotor peripheral nerve function impairments should be considered to help older adults maintain walking endurance-a critical component for remaining independent in the community.