BACKGROUND: Migraine is a prevalent and disabling disorder. Patent foramen ovale (PFO) has been associated with migraine, but its role in the disorder remains poorly understood.
OBJECTIVES: This study examined the efficacy of percutaneous PFO closure as a therapy for migraine with or without aura.
METHODS: The PREMIUM (Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management) was a double-blind study investigating migraine characteristics over 1 year in subjects randomized to medical therapy with a sham procedure (right heart catheterization) versus medical therapy and PFO closure with the Amplatzer PFO Occluder device (St. Jude Medical, St. Paul, Minnesota). Subjects had 6 to 14 days of migraine per month, had failed at least 3 migraine preventive medications, and had significant right-to-left shunt defined by transcranial Doppler. Primary endpoints were responder rate defined as 50% reduction in migraine attacks and adverse events. Secondary endpoints included reduction in migraine days and efficacy in patients with versus without aura.
RESULTS: Of 1,653 subjects consented, 230 were enrolled. There was no difference in responder rate in the PFO closure (45 of 117) versus control (33 of 103) groups. One serious adverse event (transient atrial fibrillation) occurred in 205 subjects who underwent PFO closure. Subjects in the PFO closure group had a significantly greater reduction in headache days (-3.4 vs. -2.0 days/month, p = 0.025). Complete migraine remission for 1 year occurred in 10 patients (8.5%) in the treatment group versus 1 (1%) in the control group (p = 0.01).
CONCLUSIONS: PFO closure did not meet the primary endpoint of reduction in responder rate in patients with frequent migraine. (Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management [PREMIUM]; NCT00355056).
AIMS: Migraine with aura and patent foramen ovale (PFO) are associated. The Percutaneous Closure of PFO in Migraine with Aura (PRIMA) trial is a multicentre, randomized trial to investigate the effect of percutaneous PFO closure in patients refractory to medical treatment.
METHODS: Migraine with aura patients and PFO who were unresponsive to preventive medications were randomized to PFO closure or medical treatment. Both groups were given acetylsalicylic acid 75-100 mg/day for 6 months and clopidogrel 75 mg/day for 3 months. The primary endpoint was reduction in monthly migraine days during months 9-12 after randomization compared with a 3-month baseline phase before randomization. The committee reviewing the headache diaries were blinded to treatment assignment.
RESULTS: One hundred and seven patients were randomly allocated to treatment with an Amplatzer PFO Occluder (N = 53) or control with medical management (N = 54). The trial was terminated prematurely because of slow enrolment. Eighty-three patients (40 occluder, 43 control) completed 12-month follow-up. Mean migraine days at baseline were 8 (+/-4.7 SD) in the closure group and 8.3 (+/-2.4) in controls. The primary endpoint was negative with -2.9 days after PFO closure vs. -1.7 days in control group (P = 0.17). Patent foramen ovale closure caused five adverse events without permanent sequelae.
CONCLUSION: In patients with refractory migraine with aura and PFO, PFO closure did not reduce overall monthly migraine days.
BACKGROUND: Arthroscopic partial meniscectomy is one of the most common orthopedic procedures, yet rigorous evidence of its efficacy is lacking.
METHODS: We conducted a multicenter, randomized, double-blind, sham-controlled trial in 146 patients 35 to 65 years of age who had knee symptoms consistent with a degenerative medial meniscus tear and no knee osteoarthritis. Patients were randomly assigned to arthroscopic partial meniscectomy or sham surgery. The primary outcomes were changes in the Lysholm and Western Ontario Meniscal Evaluation Tool (WOMET) scores (each ranging from 0 to 100, with lower scores indicating more severe symptoms) and in knee pain after exercise (rated on a scale from 0 to 10, with 0 denoting no pain) at 12 months after the procedure.
RESULTS: In the intention-to-treat analysis, there were no significant between-group differences in the change from baseline to 12 months in any primary outcome. The mean changes (improvements) in the primary outcome measures were as follows: Lysholm score, 21.7 points in the partial-meniscectomy group as compared with 23.3 points in the sham-surgery group (between-group difference, -1.6 points; 95% confidence interval [CI], -7.2 to 4.0); WOMET score, 24.6 and 27.1 points, respectively (between-group difference, -2.5 points; 95% CI, -9.2 to 4.1); and score for knee pain after exercise, 3.1 and 3.3 points, respectively (between-group difference, -0.1; 95% CI, -0.9 to 0.7). There were no significant differences between groups in the number of patients who required subsequent knee surgery (two in the partial-meniscectomy group and five in the sham-surgery group) or serious adverse events (one and zero, respectively).
CONCLUSIONS: In this trial involving patients without knee osteoarthritis but with symptoms of a degenerative medial meniscus tear, the outcomes after arthroscopic partial meniscectomy were no better than those after a sham surgical procedure. (Funded by the Sigrid Juselius Foundation and others; ClinicalTrials.gov number, NCT00549172.).
BACKGROUND: Perineural inhibitors of tumor necrosis factor have recently generated intense interest as an alternative to epidural steroid injections for lumbosacral radiculopathy.
OBJECTIVE: To evaluate whether epidural steroids, etanercept, or saline better improves pain and function in adults with lumbosacral radiculopathy.
DESIGN: A multicenter, 3-group, randomized, placebo-controlled trial conducted from 2008 to 2011. Randomization was computer-generated and stratified by site. Pharmacists prepared the syringes. Patients, treating physicians, and nurses assessing outcomes were blinded to treatment assignment. (ClinicalTrials.gov registration number: NCT00733096)
SETTING: Military and civilian treatment centers.
PATIENTS: 84 adults with lumbosacral radiculopathy of less than 6 months' duration.
INTERVENTION: 2 epidural injections of steroids, etanercept, or saline, mixed with bupivacaine and separated by 2 weeks.
MEASUREMENTS: The primary outcome measure was leg pain 1 month after the second injection. All patients had 1-month follow-up visits; patients whose condition improved remained blinded for the 6-month study period.
RESULTS: The group that received epidural steroids had greater reductions in the primary outcome measure than those who received saline (mean difference, -1.26 [95% CI, -2.79 to 0.27]; P = 0.11) or etanercept (mean difference, -1.01 [CI, -2.60 to 0.58]; P = 0.21). For back pain, smaller differences favoring steroids compared with saline (mean difference, -0.52 [CI, -1.85 to 0.81]; P = 0.44) and etanercept (mean difference, -0.92 [CI,-2.28 to 0.44]; P = 0.18) were observed. The largest differences were noted for functional capacity, in which etanercept fared worse than the other treatments: steroids vs. etanercept (mean difference, -16.16 [CI, -26.05 to -6.27]; P = 0.002), steroids vs. saline (mean difference, -5.87 [CI, -15.59 to 3.85]; P = 0.23), and etanercept vs. saline (mean difference, 10.29 [CI, 0.55 to 20.04]; P = 0.04). More patients treated with epidural steroids (75%) reported 50% or greater leg pain relief and a positive global perceived effect at 1 month than those who received saline (50%) or etanercept (42%) (P = 0.09).
LIMITATION: Short-term follow-up, small sample size, and a possibly subtherapeutic dose of etanercept.
CONCLUSION: Epidural steroid injections may provide modest short-term pain relief for some adults with lumbosacral radiculopathy, but larger studies with longer follow-up are needed to confirm their benefits.
PRIMARY FUNDING SOURCE: The John P. Murtha Neuroscience and Pain Institute, International Spinal Intervention Society, and Center for Rehabilitation Sciences Research.
OBJECTIVE: We sought to assess the long-term faith of migraine in patients with high risk anatomic and functional characteristics predisposing to paradoxical embolism submitted to patent foramen ovale (PFO) transcatheter closure.
METHODS: In a prospective single-center non randomized registry from January 2004 to January 2010 we enrolled 80 patients (58 female, mean age 42±2.7 years, 63 patients with aura) submitted to transcatheter PFO closure in our center. All patients fulfilled the following criteria: basal shunt and shower/curtain shunt pattern on transcranial Doppler and echocardiography, presence of interatrial septal aneurysm (ISA) and Eustachian valve, 3-4 class MIDAS score, coagulation abnormalities, medication-refractory migraine with or without aura. Migraine Disability Assessment Score (MIDAS) was used to assess the incidence and severity of migraine before and after mechanical closure. High risk features for paradoxical embolism included all of the following.
RESULTS: Percutaneous closure was successful in all cases (occlusion rate 91.2%), using a specifically anatomically-driven tailored strategy, with no peri-procedural or in-hospital complications; 70/80 of patients (87.5%) reported improved migraine symptomatology (mean MIDAS score decreased 33.4±6.7 to 10.6±9.8, p<0.03) whereas 12.5% reported no amelioration: none of the patients reported worsening of the previous migraine symptoms. Auras were definitively cured in 61/63 patients with migraine with aura (96.8%).
CONCLUSIONS: Transcatheter PFO closure in a selected population of patients with severe migraine at high risk of paradoxical embolism resulted in a significant reduction in migraine over a long-term follow-up.
BACKGROUND: There are conflicting data on the role of a patent foramen ovale (PFO) in the pathogenesis of cryptogenic stroke. The aim of this study was to evaluate the incidence of cerebrovascular events associated with PFO in a large population of patients during mid-term follow-up.
METHODS AND RESULTS: We prospectively investigated 446 consecutive patients (58% female, age 50 ± 14 years) in whom PFO was detected by contrast echocardiography following cryptogenic stroke (30.5%), transient ischemic attack (TIA, 23.7%), migraine(10.5%) or evaluation for other cardiac diseases(35%). Prevalence of other clinical conditions potentially associated with cerebral embolism, such as mitral valve disease, atrial fibrillation and aortic atherosclerosis were 31%, 12.5%, 11.2%, respectively; 99 out of 446 patients (22%, group 1) underwent PFO closure, shortly after diagnosis, while 347 (78%, group 2) received only medical therapy (antiplatelet drugs and vitamin K antagonists). During 54 months (range 12-96) of average follow-up few events had been observed: one fatal stroke (1%) in group 1 and 3 nonfatal strokes (0.86%) in group 2 (not significant); there were more TIAs in group 1 than in group 2 (5, 5% versus 3, 0.86%, p=0.02): 8/12 new cerebrovascular events occurred in patients with previous cerebral ischemia and in 7/12 there were other cardioembolic sources. Kaplan-Meier survival free from cerebrovascular events showed a slightly better prognosis in unclosed PFO patients compared to closed PFO ones, statistically significant (p=0.004).
CONCLUSIONS: New cerebrovascular events are rare in unselected subjects with PFO, even in those with previous cerebral ischemia and those who have not undergone PFO closure, with an event rate similar to that observed in the general population.
OBJECTIVES: The aim of this study was to assess the prevalence of right-to-left (R to L) shunt in patients with visual aura and evaluate the effect of shunt closure on resolution of aura.
BACKGROUND: Right-to-left shunting is associated with migraine headache (MH) with aura. Some patients present with visual aura without headaches. It is unclear whether visual aura without headache is a form of migraine or a transient neurologic dysfunction.
METHODS: Of patients referred to the University of California, Los Angeles for suspected patent foramen ovale (PFO), 225 had visual aura with or without MH. Patients were assessed for a shunt and evaluated for MH and/or visual aura. They were divided into 3 groups: 1) visual aura associated with MH; 2) visual aura unrelated in time to MH; and 3) visual aura without MH. The frequency of R to L shunt was compared with a control group of 200 patients. Eighty patients underwent PFO closure. Residual shunts, MH, and visual aura were reassessed after 3 and 12 months.
RESULTS: The prevalence of R to L shunt in Groups A, B, and C was 96%, 72%, and 67%, respectively, versus 18% in the control group (p < 0.0001). The frequency of shunting was similar in Group B versus Group C, but much higher in all 3 groups compared with control subjects. Twelve months after PFO closure, symptoms of aura were resolved in 52%, 75%, and 80% of patients in Groups A, B, and C, respectively (p = NS).
CONCLUSIONS: The similar distribution of R to L shunting in all 3 patient groups and the correlation between PFO closure and improvement of aura suggests a similar pathophysiology between the presence of PFO and the visual aura phenomenon, whether or not headache is present in the symptom complex.
OBJECTIVE: To assess the efficacy of caudal epidural steroid or saline injection in chronic lumbar radiculopathy in the short (6 weeks), intermediate (12 weeks), and long term (52 weeks).
DESIGN: Multicentre, blinded, randomised controlled trial.
SETTING: Outpatient multidisciplinary back clinics of five Norwegian hospitals.
PARTICIPANTS: Between October 2005 and February 2009, 461 patients assessed for inclusion (presenting with lumbar radiculopathy >12 weeks). 328 patients excluded for cauda equina syndrome, severe paresis, severe pain, previous spinal injection or surgery, deformity, pregnancy, ongoing breast feeding, warfarin therapy, ongoing treatment with non-steroidal anti-inflammatory drugs, body mass index >30, poorly controlled psychiatric conditions with possible secondary gain, and severe comorbidity.
INTERVENTIONS: Subcutaneous sham injections of 2 mL 0.9% saline, caudal epidural injections of 30 mL 0.9% saline, and caudal epidural injections of 40 mg triamcinolone acetonide in 29 mL 0.9% saline. Participants received two injections with a two week interval.
MAIN OUTCOME MEASURES: Primary: Oswestry disability index scores. Secondary: European quality of life measure, visual analogue scale scores for low back pain and for leg pain.
RESULTS: Power calculations required the inclusion of 41 patients per group. We did not allocate 17 of 133 eligible patients because their symptoms improved before randomisation. All groups improved after the interventions, but we found no statistical or clinical differences between the groups over time. For the sham group (n = 40), estimated change in the Oswestry disability index from the adjusted baseline value was -4.7 (95% confidence intervals -0.6 to -8.8) at 6 weeks, -11.4 (-6.3 to -14.5) at 12 weeks, and -14.3 (-10.0 to -18.7) at 52 weeks. For the epidural saline intervention group (n = 39) compared with the sham group, differences in primary outcome were -0.5 (-6.3 to 5.4) at 6 weeks, 1.4 (-4.5 to 7.2) at 12 weeks, and -1.9 (-8.0 to 4.3) at 52 weeks; for the epidural steroid group (n=37), corresponding differences were -2.9 (-8.7 to 3.0), 4.0 (-1.9 to 9.9), and 1.9 (-4.2 to 8.0). Analysis adjusted for duration of leg pain, back pain, and sick leave did not change this trend.
CONCLUSIONS: Caudal epidural steroid or saline injections are not recommended for chronic lumbar radiculopathy. Trial registration Current Controlled Trials ISRCTN No 12574253.
BACKGROUND: A patent foramen ovale (PFO) is a risk factor for cerebral events such as cryptogenic stroke, transient ischemic attacks, and migraine headaches. Far less commonly, PFO is associated with non-cerebral, paradoxical systemic embolic events such as myocardial infarction (MI), renal infarct, and limb ischemia. This report details the incidence of systemic paradoxical emboli at our institution.
METHODS: 416 patients were referred for evaluation of PFO related conditions from 2001 to 2009. Clinical history and medical records of the patients were reviewed for incidence of cryptogenic stroke, transient ischemic attack (TIA), migraine headache, arterial desaturation, and noncerebral systemic embolism.
RESULTS: As the primary presenting symptom, 219 patients had a diagnosis of cryptogenic stroke, 38 patients had migraine headaches, and 80 patients had transient neurologic deficits consistent with a TIA or complex headache. Twelve patients (2.9% of the total population) presented with a presumptive diagnosis of systemic embolism. Eight of these patients had acute MI diagnosed by elevated cardiac biomarkers, electrocardiogram changes, and/or imaging evidence of a left ventricular wall motion abnormality, without evidence of obstructive coronary disease on angiography. Four patients had evidence of peripheral embolism to a systemic artery, including the popliteal artery, ophthalmic artery, and brachial artery. PFO closure was performed in 197 patients (47.4% of the total population), including eight patients in the systemic embolism group. All closure procedures were successful.
CONCLUSION: Although most paradoxical emboli travel to the brain, noncerebral paradoxical embolism is also associated with PFO. In addition to embolism of thrombus, there may be paradoxical passage of vasoactive chemicals that induce intense coronary spasm and myocardial infarction. Diagnosis is often challenging, given the lack of definitive criteria and the need to exclude other potential etiologies.
BACKGROUND: Human retinal pigment epithelial (RPE) cells produce levodopa and their transplantation into the striatum might improve continuity of administration compared with that achieved with oral levodopa. We aimed to assess the safety, tolerability, and efficacy of transplantation of microcarrier-bound human RPE cells versus a sham surgery control in patients with advanced Parkinson's disease.
METHODS: In this randomised, double-blind study eligible patients were aged 36-70 years, had been symptomatic for at least 5 years, were in Hoehn and Yahr stage 3-4 and had unified Parkinson's disease rating scale (UPDRS) motor scores of 38-70 when off medication (off state), and had symptoms that responded to oral levodopa but were insufficiently controlled by optimised pharmacotherapy. Randomisation was done in a 1:1 ratio. Only the neurosurgical team was aware of treatment assignments. During stereotactic transplantation around 325,000 cells per side were injected into the postcommissural putamen; sham surgery patients received partial burr holes. The primary efficacy endpoint was change in UPDRS off-state motor score at 12 months. This study is registered with ClinicalTrials.gov, number NCT00206687.
FINDINGS: Of 71 enrolled patients, 35 underwent cell transplantation and 36 sham surgery. Change in mean motor scores did not differ significantly between groups (-10.5 [SD 10.26] for transplantation vs -10.1 [SD 12.26] for sham surgery, p=0.9). The overall rate of adverse events was similar in the two study groups, although the number attributable to surgery or RPE cells (mostly neurological or psychiatric) was higher in transplant recipients. Two and seven patients died in the sham surgery and transplantation group, respectively; one death in the latter group was possibly related to surgery or RPE cells.
INTERPRETATION: Transplantation of human RPE cells provided no antiparkinsonian benefits compared with sham surgery.
FUNDING: Bayer HealthCare AG.
Migraine is a prevalent and disabling disorder. Patent foramen ovale (PFO) has been associated with migraine, but its role in the disorder remains poorly understood.
OBJECTIVES:
This study examined the efficacy of percutaneous PFO closure as a therapy for migraine with or without aura.
METHODS:
The PREMIUM (Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management) was a double-blind study investigating migraine characteristics over 1 year in subjects randomized to medical therapy with a sham procedure (right heart catheterization) versus medical therapy and PFO closure with the Amplatzer PFO Occluder device (St. Jude Medical, St. Paul, Minnesota). Subjects had 6 to 14 days of migraine per month, had failed at least 3 migraine preventive medications, and had significant right-to-left shunt defined by transcranial Doppler. Primary endpoints were responder rate defined as 50% reduction in migraine attacks and adverse events. Secondary endpoints included reduction in migraine days and efficacy in patients with versus without aura.
RESULTS:
Of 1,653 subjects consented, 230 were enrolled. There was no difference in responder rate in the PFO closure (45 of 117) versus control (33 of 103) groups. One serious adverse event (transient atrial fibrillation) occurred in 205 subjects who underwent PFO closure. Subjects in the PFO closure group had a significantly greater reduction in headache days (-3.4 vs. -2.0 days/month, p = 0.025). Complete migraine remission for 1 year occurred in 10 patients (8.5%) in the treatment group versus 1 (1%) in the control group (p = 0.01).
CONCLUSIONS:
PFO closure did not meet the primary endpoint of reduction in responder rate in patients with frequent migraine. (Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management [PREMIUM]; NCT00355056).
