Early Magnesium Treatment After Aneurysmal Subarachnoid Hemorrhage: Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Trials of magnesium treatment starting <4 days after symptom onset found no effect on poor outcome or DCI in SAH. Earlier installment of treatment might be more effective, but individual trials had not enough power for such a subanalysis. We performed an individual patient data meta-analysis to study whether magnesium is effective when given within different time frames within 24 hours after the SAH. METHODS: Patients were divided into categories according to the delay between symptom onset and start of the study medication: <6, 6 to 12, 12 to 24, and >24 hours. We calculated adjusted risk ratios with corresponding 95% confidence intervals for magnesium versus placebo treatment for poor outcome and DCI. RESULTS: We included 5 trials totaling 1981 patients; 83 patients started treatment<6 hours. For poor outcome, the adjusted risk ratios of magnesium treatment for start <6 hours were 1.44 (95% confidence interval, 0.83-2.51); for 6 to 12 hours 1.03 (0.65-1.63), for 12 to 24 hours 0.84 (0.65-1.09), and for >24 hours 1.06 (0.87-1.31), and for DCI, <6 hours 1.76 (0.68-4.58), for 6 to 12 hours 2.09 (0.99-4.39), for 12 to 24 hours 0.80 (0.56-1.16), and for >24 hours 1.08 (0.88-1.32). CONCLUSIONS: This meta-analysis suggests no beneficial effect of magnesium treatment on poor outcome or DCI when started early after SAH onset. Although the number of patients was small and a beneficial effect cannot be definitively excluded, we found no justification for a new trial with early magnesium treatment after SAH.

Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial.

BACKGROUND: Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown. We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke. METHODS: In this randomised open-label trial, eligible patients lived in North America, Latin America, and Spain and had recent, MRI-defined symptomatic lacunar infarctions. Patients were recruited between March, 2003, and April, 2011, and randomly assigned, according to a two-by-two multifactorial design, to a systolic-blood-pressure target of 130-149 mm Hg or less than 130 mm Hg. The primary endpoint was reduction in all stroke (including ischaemic strokes and intracranial haemorrhages). Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00059306. FINDINGS: 3020 enrolled patients, 1519 in the higher-target group and 1501 in the lower-target group, were followed up for a mean of 3·7 (SD 2·0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137-139) in the higher-target group and 127 mm Hg (95% CI 126-128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0·81, 95% CI 0·64-1·03, p=0·08), disabling or fatal stroke (0·81, 0·53-1·23, p=0·32), and the composite outcome of myocardial infarction or vascular death (0·84, 0·68-1·04, p=0·32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0·37, 0·15-0·95, p=0·03). Treatment-related serious adverse events were infrequent. INTERPRETATION: Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial. FUNDING: National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS).

The CombiRx trial of combined therapy with interferon and glatiramer cetate in relapsing remitting MS: Design and baseline characteristics.

BACKGROUND: Interferon-ß1a (IFNB) and glatiramer acetate (GA) are distinct therapies which are both partially effective for relapsing MS. It is not known if combining the two treatments would be more effective. OBJECTIVE: To review the rationale, design, and baseline characteristics of the CombiRx study of combined treatment with IFNB and GA. METHODS: The key inclusion criteria included a diagnosis of relapsing MS, at least 2 episodes of MS activity in the previous 3 years, expanded disability status scale of 0 to 5.5, and no prior treatment with either IFNB or GA. Subjects were randomized to IFNB+GA, IFNB monotherapy, or GA monotherapy in a 2:1:1 ratio. RESULTS: From 2005 to 2009, we enrolled 1008 subjects. The participants were 72.4% female and 87.6% Caucasian with a mean age of 37.7 years. The median duration of symptoms was 2 years at entry into the study, and the mean EDSS was 2.1. On the baseline MRI, the mean total lesion load was 12.2 ml, and 40% of the participants had enhancing lesions. CONCLUSION: We have recruited a population of patients with clinical and MRI characteristics typical for early MS. The study results will aid in deciding on the optimum early treatment. This trial should serve as a model for future studies of combination therapy.

The CombiRx trial of combined therapy with interferon and glatiramer acetate in relapsing remitting MS: Design and baseline characteristics.

BACKGROUND: Interferon-ß1a (IFNB) and glatiramer acetate (GA) are distinct therapies which are both partially effective for relapsing MS. It is not known if combining the two treatments would be more effective. OBJECTIVE: To review the rationale, design, and baseline characteristics of the CombiRx study of combined treatment with IFNB and GA. METHODS: The key inclusion criteria included a diagnosis of relapsing MS, at least 2 episodes of MS activity in the previous 3 years, expanded disability status scale of 0-5.5, and no prior treatment with either IFNB or GA. Subjects were randomized to IFNB+GA, IFNB monotherapy, or GA monotherapy in a 2:1:1 ratio. RESULTS: From 2005 to 2009, we enrolled 1008 subjects. The participants were 72.4% female and 87.6% Caucasian with a mean age of 37.7 years. The median duration of symptoms was 2 years at entry into the study, and the mean EDSS was 2.1. On the baseline MRI, the mean total lesion load was 12.2ml, and 40% of the participants had enhancing lesions. CONCLUSION: We have recruited a population of patients with clinical and MRI characteristics typical for early MS. The study results will aid in deciding on the optimum early treatment. This trial should serve as a model for future studies of combination therapy.

Boosting enrolment in clinical trials: validation of a regional network model.

BACKGROUND: Clinical trials of stroke therapy have been hampered by slow rates of enrolment. PURPOSE: Our purpose is to validate a previously developed model for accelerating enrolment in clinical trials by replicating it at new locations. The model employs coordinators who travel from a host institution to enrol participants from a network of participating hospitals. Active surveillance assures identification of all eligible patients. METHODS: Among 70 U.S. investigators participating in National Institutes of Health-funded trial of stroke prevention, five investigators were invited to develop local identification and outreach networks (LIONs). Each LION comprised a LION coordinating centre servicing multiple hospitals. Hospitals provided names of patients with stroke or transient ischaemic attack to researchers at the LION coordinating centre who initiated contact; patients were offered home visits for consent and randomization. Outcomes were feasibility, enrolment, data quality, and cost. RESULTS: Five LIONs varied in size from two to eight hospitals. All 24 hospitals we approached agreed to participate. The average monthly rate of enrolment at the research sites increased from 1.4 participants to 3.5 after expanding from a single institution model to the LION format (mean change = 2.1, range 0.9-3.7). Monthly performance improved over time. Data quality was similar for LIONs and non-LION sites, except for drug adherence which was lower at LIONs. The average cost to randomize and follow one participant during the study interval was 2.4 times the cost under the per-patient, cost-reimbursement strategy at non-LION sites. The cost ratio declined from 3.4 in year one to 1.8 in year two. LIMITATIONS: The LION strategy requires unprecedented collaboration and trust among institutions. Applicability beyond stroke requires confirmation. CONCLUSION: LIONs are a practical, reproducible method to increase enrolment in trial research. Twelve months were required for the average site to reach its potential. The per-participant cost at LIONs was higher than conventional sites but declined over time.

Electromyographic patterns suggest changes in motor unit physiology associated with early osteoarthritis of the knee.

OBJECTIVE: To assess characteristics of active motor units (MUs) during volitional vastus medialis (VM) activation in adults with symptomatic knee osteoarthritis (OA) across the spectrum of radiographic severity and age-comparable healthy control volunteers. METHODS: We evaluated 39 participants (age 65+/-3 years) in whom weight-bearing knee X-rays were assigned a Kellgren & Lawrence (KL) grade (18 with KL grade=0; four each with KL grades=1, 2 and 4; nine with grade 3). Electromyography (EMG) signals were simultaneously acquired using surface [surface EMG (S-EMG)] and intramuscular needle electrodes, and analyzed by decomposition-enhanced spike-triggered averaging to obtain estimates of size [surface-represented MU action potentials (S-MUAP) area], number [MU recruitment index (MURI)] and firing rates [MU firing rates (mFR)] of active MUs at 10%, 20%, 30% and 50% effort relative to maximum voluntary force [maximal voluntary isometric contraction (MVIC)] during isometric knee extension. RESULTS: Knee extensor MVIC was lower in OA participants, especially at higher KL grades (P=0.05). Taking the observed force differences into account, OA was also associated with activation of larger MUs (S-MUAP area/MVICx%effort; P<0.0001). In contrast, the estimated number of active units (MURI/MVICx%effort) changed differently as effort increased from 10% to 50% and was higher with advanced OA (KL=3, 4) than controls (P=0.0002). CONCLUSION: VM activation changes at the level of the MU with symptomatic knee OA, and this change is influenced by radiographic severity. Poor muscle quality may explain the pattern observed with higher KL grades, but alternative factors (e.g., nerve or joint injury, physical inactivity or muscle composition changes) should be examined in early OA.

Neuroprotective agents for clinical trials in ALS: a systematic assessment.

BACKGROUND: Riluzole is currently the only Food and Drug Administration-approved treatment for ALS, but its effect on survival is modest. OBJECTIVE: To identify potential neuroprotective agents for testing in phase III clinical trials and to outline which data need to be collected for each drug. METHODS: The authors identified 113 compounds by inviting input from academic clinicians and researchers and via literature review to identify agents that have been tested in ALS animal models and in patients with ALS. The list was initially narrowed to 24 agents based on an evaluation of scientific rationale, toxicity, and efficacy in previous animal and human studies. These 24 drugs underwent more detailed pharmacologic evaluation. RESULTS: Twenty drugs were selected as suitable for further development as treatments for patients with ALS. Talampanel and tamoxifen have completed early phase II trials and have demonstrated preliminary efficacy. Other agents (ceftriaxone, minocycline, ONO-2506, and IGF-1 polypeptide) are already in phase III trials involving large numbers of patients with ALS. Remaining agents (AEOL 10150, arimoclomol, celastrol, coenzyme Q10, copaxone, IGF-1-viral delivery, memantine, NAALADase inhibitors, nimesulide, scriptaid, sodium phenylbutyrate, thalidomide, trehalose) require additional preclinical animal data, human toxicity and pharmacokinetic data including CNS penetration prior to proceeding to large scale phase III human testing. Further development of riluzole analogues should be considered. CONCLUSIONS: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in ALS.

Fatigue effects on motor unit activity during submaximal contractions.

OBJECTIVE: To examine motor unit changes during the development of fatigue in healthy subjects. DESIGN: Automated decomposition-enhanced spike-triggered averaging was used to characterize motor unit size and firing rate in the dominant vastus medialis during maintained contractions at 10% and 30% of maxima voluntary contraction (MVC). SETTING: Academic outpatient neuromuscular clinic. PARTICIPANTS: Healthy laboratory personnel. MAIN OUTCOME MEASURES: Surface electromyogram, surface-detected motor unit action potential amplitude (S-MUAP), mean firing rate, force (MVC), motor unit index. RESULTS: Surface electromyogram values and S-MUAP amplitudes increased during both 10% and 30% MVC fatiguing contractions, while mean firing rates decreased. A motor unit index, indicating the degree of motor unit pool activation, increased similarly to S-MUAP size, implying that new and larger units were recruited to maintain the contraction. Repeated contractions led to earlier motor unit changes and fatigue. CONCLUSION: During submaximal fatiguing contractions, additional motor units are activated to maintain strength. These changes begin early, within the first minute, particularly after a previous fatiguing effort.

The relationship of motor unit size, firing rate and force.

OBJECTIVE: Using a clinical electromyographic (EMG) protocol, motor units were sampled from the quadriceps femoris during isometric contractions at fixed force levels to examine how average motor unit size and firing rate relate to force generation. METHODS: Mean firing rates (mFRs) and sizes (mean surface-detected motor unit action potential (mS-MUAP) area) of samples of active motor units were assessed at various force levels in 79 subjects. RESULTS: MS-MUAP size increased linearly with increased force generation, while mFR remained relatively constant up to 30% of a maximal force and increased appreciably only at higher force levels. A relationship was found between muscle force and mS-MUAP area (r2 = 0.67), mFR (r2 = 0.38), and the product of mS-MUAP area and mFR (mS-MUAP x mFR) (r2 = 0.70). CONCLUSIONS: The results support the hypothesis that motor units are recruited in an orderly manner during forceful contractions, and that in large muscles only at higher levels of contraction ( > 30% MVC) do mFRs increase appreciably. MS-MUAP and mFR can be assessed using clinical EMG techniques and they may provide a physiological basis for analyzing the role of motor units during muscle force generation.

Muscle quality and age: cross-sectional and longitudinal comparisons.

We addressed whether muscle quality (force per unit muscle mass) changes with age in cross-sectional and longitudinal analyses from three groups from the Baltimore Longitudinal Study of Aging: (1) Isometric arm strength studied cross-sectionally in 617 subjects with muscle mass estimated by cross-sectional area (CSA) from arm circumference and by 24-hour urinary creatinine excretion (CREAT); (2) longitudinal study for 10 to 25 years in 412 men using the same measures as the first group; and (3) isometric knee extensor strength studied cross-sectionally in 675 subjects; muscle mass estimated by CREAT, CSA from thigh circumference, and leg nonosseous fat free mass (FFM) from dual energy x-ray absorptiometry. Muscle quality declined in both arm and leg with age in cross-sectional analyses using CSA and FFM, but not CREAT. No age-associated arm muscle quality declines were observed longitudinally using CREAT or CSA. The relationship between muscle quality and age is dependent on how muscle mass is estimated and on whether subjects are studied cross-sectionally or longitudinally. In addition, CREAT may measure a muscle property not accounted for by CSA or FFM.

Firing rate analysis using decompostion-enhanced spike triggered averaging in the quadriceps femoris.

Electromyographic signals detected from the quadriceps femoris during various constant force contractions were decomposed to identify individual motor unit discharges and mean firing rates (FRs). Subject and group mean FRs were calculated for each force level. Mean FR values and FR variability increased with force. Individual, subject, and group mean FRs showed slight increases until 30% of maximum voluntary contraction and larger increases thereafter. Findings are discussed in relation to motor unit recruitment, frequency modulation, and fatigue.

Ulnar nerve injury associated with removal of Norplant implants.

Improperly placed Norplant implants pose a risk to neurovascular structures at the time of removal. Appropriate attention to insertion and removal should minimize the chance of injury. However, when injuries do occur, a logical and systematic approach to evaluation of the injury can help predict the outcome and establish a plan of care for the patient.

PIP: Due to the placement of the Norplant contraceptive implant system with respect to the neurovascular bundle of the arm, ulnar nerve injury is a possible complication of implant removal. Presented in this article is a case of ulnar nerve injury with subsequent neuropathy related to removal of improperly placed implants. The patient, a 23-year-old US woman, requested Norplant removal after 3.5 years of complication-free use. Before removal, the implants were noted to lie directly over the most anterior aspect of the triceps muscle, with the lower end of the implants lying about 5 cm from the medial condyle of the elbow. The patient returned to the facility 4 days after uneventful Norplant removal with persistent pain, definite weakness of the ulnar innervated muscles of the right hand, and numbness over the hypothenar eminence and fourth and fifth digits. Clinical neurologic evaluation was consistent with an ulnar nerve injury with diminished motor and sensory amplitude. Repeat studies at 6 weeks demonstrated improved motor response. Potential insertion-related injuries can best be prevented by choosing the appropriate placement site on the medial surface of the arm and by exaggerated tenting of the skin to help assure superficial subdermal placement and avoid deep structures. Before removal, identification of the path of the ulnar nerve and the relationship of the implants to the brachial groove is recommended, especially in thinner women. If pain, paresthesia, or anesthesia persists 4-6 weeks after an injury, repeat nerve conduction studies should be ordered to help outline a rehabilitation plan.

The relationship of peripheral motor nerve conduction velocity to age-associated loss of grip strength.

Age-associated loss of muscle strength is attributed to decreasing muscle mass. Both strength and mass are dependent on peripheral innervation. However, the association between nerve function and age-associated strength loss has not been studied directly. The median nerve contribution to grip strength was estimated using nerve conduction velocity (NCV). Grip strength and NCV were measured in 197 male participants of the Baltimore Longitudinal Study of Aging (age 59.0 +/- 13.9 years). Multiple regression and path analyses were used separately to examine the association between median NCV and grip strength. Grip strength showed a negative quadratic relationship with increasing age (r2 = 0.32, p < 0.001) with a major change in slope occurring after 64.7 years of age. Median NCV (r2 = 0.14, p < 0.001) declined linearly with age. Median NCV significantly contributed to grip strength (p < 0.001) while controlling for forearm muscle mass (forearm circumference), self-reported 24-hour caloric expenditures, and age. The median nerve has an independent contribution to age-associated levels of muscle strength. The level of the effect was smaller than what could be attributed to forearm muscle mass or age.

Age-associated loss of power and strength in the upper extremities in women and men.

Cross-sectional and longitudinal age-associated reductions in power and isometric strength are described for the upper extremities. Over a 25-year period, repeated measures were taken approximately every 2 years from men and women in the Baltimore Longitudinal Study of Aging (BLSA). The longitudinal measures covered an average 9.6 years, range 1-25 years for men and an average 4.6 years, range 1-8 years for women. Strength and power declined beginning by age 40 in both women and men. Thereafter, power declined about 10% more than strength in men, while no significant differences were found in women. Age had a statistically independent influence on strength and power measures after adjusting for gender, height, weight, caloric expenditure, and muscle mass. Twenty-five-year longitudinal analyses in men confirmed the declines observed cross-sectionally, while no changes were observed in women over the 4-5 years of longitudinal data available. Further longitudinal studies are needed to understand the relationships between strength and power losses with age in women. The differences between power and strength changes with age in men argue for the importance of factors other than strength affecting power.

Decomposition-enhanced spike-triggered averaging: contraction level effects.

Decomposition-enhanced spike-triggered averaging (DE-STA) was applied to the vastus medialis muscle to examine size distributions of surface-detected motor-unit action potentials (S-MUAPs) at various force levels. Using DE-STA, 15-20 S-MUAPs were identified during 5%, 10%, 20%, and 30% of maximum voluntary contraction. Average S-MUAPs showed increase in peak to peak (and negative peak) amplitude with force (In microV): 5% = 37.9 +/- 6.1 (16.6 +/- 2.5), 10% = 44.0 +/- 4.0 (20.4 +/- 1.8), 20% = 80.7 +/- 9.3 (41.3 +/- 4.5), and 30% = 102.5 +/- 10.3 (53.6 +/- 5.0). Test-retest variability of peak to peak (and negative peak amplitude) between repeated trials was 0.10 (0.14), 0.14 (0.14), 0.17 (0.15), and 0.21 (0.20) at 5%, 10%, 20%, and 30% respectively. A relationship was found between the S-MUAP amplitude and force (r2 = 0.78, df = 90, F = 160, P < 0.001). Increase in average S-MUAP amplitude with force suggests that STA performed only at low levels of contraction may result in a biased sampling and small average S-MUAP amplitudes.

Methods for estimating the numbers of motor units in human muscles.

After the introduction by A. J. McComas of the original method for estimating the number of motor units based on manual incremental stimulation of a motor nerve, several new techniques have been developed, designed to correct for some of the errors inherent in the original technique. These methods incorporate algorithms to adjust for alternation and, to a greater or lesser extent, automate the methods, rendering the techniques less subject to operator bias and various physiological and technical errors. This review explores the advantages and drawbacks in the multiple-point stimulation (MPS), spike-triggered averaging (STA), and decomposition-enhanced STA techniques, illustrates some of the current applications of the techniques, and explores some tantalizing prospects for new studies of motor-unit physiology in the future.

Mixed nerve action potentials in acquired demyelinating polyneuropathy.

Uncertainty about motor and sensory contributions in abnormal nerves has limited the use of mixed nerve action potentials (MNAPs). We recorded MNAPs in 21 patients with an acquired demyelinating neuropathy, 18 age-matched control subjects, and 10 patients with an axonal polyneuropathy. Bipolar and unipolar recordings from median and ulnar nerves were made above the elbow after electrical stimulation of the nerves at the wrist. Antidromic digital sensory action potentials and motor conduction velocity were also recorded for both nerves. In 19 median and 12 ulnar nerves from demyelinating polyneuropathy patients, compared with control subjects, MNAP amplitudes were significantly reduced (mean, 6 microV vs. 31 microV), MNAP velocities were mildly reduced (mean, 50 m/s vs. 62 m/s), motor conduction velocities were significantly reduced (mean, 33 m/s vs. 57 m/s), and MNAPs were significantly dispersed, with markedly prolonged rise times (mean 2.0 ms vs. 1.0 ms). Compared with the axonal polyneuropathy group, MNAP amplitudes from the median nerve were similarly reduced (mean, 8 microV vs. 9 microV), MNAP velocities were only slightly slower (mean, 52 m/s vs. 58 m/s), but the rise times were significantly prolonged (mean, 2.0 ms vs 1.2 ms). We conclude that, in acquired demyelinating neuropathies, the onset and, in some cases, the whole MNAP is from afferent fibers, which can be abnormally dispersed, and that, over the same segment MNAP velocity is less affected than motor conduction velocity.

Sensorimotor neuropathy resembling CIDP in patients receiving FK506.

FK506 is an important immunosuppressant that has shown great promise in the treatment of autoimmune diseases. Approximately 5% of patients receiving FK506 develop major central nervous system toxicity, but the peripheral nerves are usually spared. During 1990-1991, some 1000 patients received liver transplants under FK506 immunosuppression. Of these, 3 patients developed severe multifocal demyelinating sensorimotor polyneuropathy 2-10 weeks after initiation of FK506 therapy. Improvement followed plasmapheresis or intravenous immunoglobulin (IVIG), suggesting an immune-mediated cause. Although autoimmune neuropathy has been previously reported in immune-deficient states such as Hodgkin's disease and AIDS, it is not an expected complication of immunosuppressive therapy. However, others have shown that this phenomenon can be produced in rats with cyclosporine A (CsA), whose effects on T-cell subsets are similar to those seen with FK506. These T-cell subset changes may have precipitated this dysimmune neuropathy in our patients.

Molecular genetic and genetic correlations in sodium channelopathies: lack of founder effect and evidence for a second gene.

We present a correlation of molecular genetic data (mutations) and genetic data (dinucleotide-repeat polymorphisms) for a cohort of seven hyperkalemic periodic paralysis (HyperPP) and two paramyotonia congenita (PC) families from diverse ethnic backgrounds. We found that each of three previously identified point mutations of the adult skeletal muscle sodium-channel gene occurred on two different dinucleotide-repeat haplotypes. These results indicate that dinucleotide-repeat haplotypes are not predictive of allelic heterogeneity in sodium channelopathies, contrary to previous suggestions. In addition, we identified a HyperPP pedigree in which the dominant disorder was not linked to the sodium-channel gene. Thus, a second locus can give rise to a similar clinical phenotype. Some individuals in this pedigree exhibited a base change causing the nonconservative substitution of an evolutionarily conserved amino acid. Because this change was not present in 240 normal chromosomes and was near another HyperPP mutation, is fulfilled the most commonly used criteria for being a mutation rather than a polymorphism. However, linkage studies using single-strand conformation polymorphism-derived and sequence-derived haplotypes excluded this base change as a causative mutation: these data serve as a cautionary example of potential pitfalls in the delineation of change-of-function point mutations.