Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke.

BACKGROUND: Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy. METHODS: In a multicenter, randomized, open-label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3. RESULTS: A total of 663 patients underwent randomization and were followed for a mean (±SD) of 5.3±2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone. CONCLUSIONS: Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289 .).

Biallelic MYORG mutation carriers exhibit primary brain calcification with a distinct phenotype.

Primary familial brain calcification (PFBC) is a rare neurogenetic disorder with diverse neuropsychiatric expression. Mutations in four genes cause autosomal dominant PFBC: SLC20A2, XPR1, PDGFB and PDGFRB. Recently, biallelic mutations in the MYORG gene have been reported to cause PFBC with an autosomal recessive pattern of inheritance. We screened MYORG in 29 unrelated probands negatively screened for the autosomal dominant PFBC genes and identified 11 families with a biallelic rare or novel predicted damaging variant. We studied the clinical and radiological features of 16 patients of these 11 families and compared them to that of 102 autosomal dominant PFBC patients carrying a mutation in one of the four known autosomal dominant PFBC genes. We found that MYORG patients exhibited a high clinical penetrance with a median age of onset of 52 years (range: 21-62) with motor impairment at the forefront. In particular, dysarthria was the presenting sign in 11/16 patients. In contrast to patients with autosomal dominant PFBC, 12/15 (80%) symptomatic patients eventually presented at least four of the following five symptoms: dysarthria, cerebellar syndrome, gait disorder of any origin, akinetic-hypertonic syndrome and pyramidal signs. In addition to the most severe clinical pattern, MYORG patients exhibited the most severe pattern of calcifications as compared to the patients from the four autosomal dominant PFBC gene categories. Strikingly, 12/15 presented with brainstem calcifications in addition to extensive calcifications in other brain areas (lenticular nuclei, thalamus, cerebellar hemispheres, vermis, ±cortex). Among them, eight patients exhibited pontine calcifications, which were observed in none of the autosomal dominant PFBC patients and hence appeared to be highly specific. Finally, all patients exhibited cerebellar atrophy with diverse degrees of severity on CT scans. We confirmed the existence of cerebellar atrophy by performing MRI voxel-based morphometry analyses of MYORG patients with autosomal dominant PFBC mutation carriers as a comparison group. Of note, in three families, the father carried small pallido-dentate calcifications while carrying the mutation at the heterozygous state, suggesting a putative phenotypic expression in some heterozygous carriers. In conclusion, we confirm that MYORG is a novel major PFBC causative gene and that the phenotype associated with such mutations may be recognized based on pedigree, clinical and radiological features.

Long-term follow-up study of endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis trial.

BACKGROUND AND PURPOSE: We aimed at comparing the long-term benefit-risk balance of carotid stenting versus endarterectomy for symptomatic carotid stenosis. METHODS: Long-term follow-up study of patients included in Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis (EVA-3S), a randomized, controlled trial of carotid stenting versus endarterectomy in 527 patients with recently symptomatic severe carotid stenosis, conducted in 30 centers in France. The main end point was a composite of any ipsilateral stroke after randomization or any procedural stroke or death. RESULTS: During a median follow-up of 7.1 years (interquartile range, 5.1-8.8 years; maximum 12.4 years), the primary end point occurred in 30 patients in the stenting group compared with 18 patients in the endarterectomy group. Cumulative probabilities of this outcome were 11.0% (95% confidence interval, 7.9-15.2) versus 6.3% (4.0-9.8) in the endarterectomy group at the 5-year follow-up (hazard ratio, 1.85; 1.00-3.40; P=0.04) and 11.5% (8.2-15.9) versus 7.6% (4.9-11.8; hazard ratio, 1.70; 0.95-3.06; P=0.07) at the 10-year follow-up. No difference was observed between treatment groups in the rates of ipsilateral stroke beyond the procedural period, severe carotid restenosis (≥70%) or occlusion, death, myocardial infarction, and revascularization procedures. CONCLUSIONS: The long-term benefit-risk balance of carotid stenting versus endarterectomy for symptomatic carotid stenosis favored endarterectomy, a difference driven by a lower risk of procedural stroke after endarterectomy. Both techniques were associated with low and similar long-term risks of recurrent ipsilateral stroke beyond the procedural period. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00190398.

Should decompressive surgery be performed in malignant cerebral venous thrombosis?: a series of 12 patients.

BACKGROUND AND PURPOSE: In malignant cerebral venous thrombosis (CVT) patients, emergency decompressive surgery has been suggested as a life-saving procedure. We report 12 patients with malignant CVT, among whom 8 underwent operation. METHODS: Retrospective study of 12 patients from 3 stroke units who had a malignant CVT as defined: (1) supratentorial cortical lesions attributable to superficial venous system thrombosis with or without sinus involvement; (2) with clinical (decreased consciousness and dilated pupils) or radiological signs of transtentorial herniation; (3) either at onset or after worsening despite heparin therapy. Surgery or abstention was decided individually by neurosurgeons on call. RESULTS: There were 9 women and 3 men with a mean age of 45+/-15 years. The delay between heparin therapy and signs of malignancy ranged from 2 to 30 hours. At malignant worsening all but 1 patient had hemorrhagic lesions; the median deviation of septum pellucidum was 12 mm (interquartile range, 6.7-13); 5 patients (including 3 who underwent operation) had a unilateral dilated pupil; and 4 (2 who underwent operation) had bilateral dilated pupils. Eight patients underwent surgical decompression, external decompression in 4, both external and internal decompression in 3, and internal decompression in 1. The 4 patients who did not undergo operation died within 1 to 5 days after diagnosis. One patient who underwent operation died of a pulmonary embolism. The 7 others survived, with, at last follow-up (median, 23.1 months; interquartile range, 19.7-45.6), an excellent recovery of mRS 0 or 1 in 6 and mRS 3 in 1. CONCLUSION: Decompressive surgery may save lives and may even allow a good functional outcome in malignant CVT, even in patients with bilateral dilated pupils.

Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis.

BACKGROUND: Carotid stenting is less invasive than endarterectomy, but it is unclear whether it is as safe in patients with symptomatic carotid-artery stenosis. METHODS: We conducted a multicenter, randomized, noninferiority trial to compare stenting with endarterectomy in patients with a symptomatic carotid stenosis of at least 60%. The primary end point was the incidence of any stroke or death within 30 days after treatment. RESULTS: The trial was stopped prematurely after the inclusion of 527 patients for reasons of both safety and futility. The 30-day incidence of any stroke or death was 3.9% after endarterectomy (95% confidence interval [CI], 2.0 to 7.2) and 9.6% after stenting (95% CI, 6.4 to 14.0); the relative risk of any stroke or death after stenting as compared with endarterectomy was 2.5 (95% CI, 1.2 to 5.1). The 30-day incidence of disabling stroke or death was 1.5% after endarterectomy (95% CI, 0.5 to 4.2) and 3.4% after stenting (95% CI, 1.7 to 6.7); the relative risk was 2.2 (95% CI, 0.7 to 7.2). At 6 months, the incidence of any stroke or death was 6.1% after endarterectomy and 11.7% after stenting (P=0.02). There were more major local complications after stenting and more systemic complications (mainly pulmonary) after endarterectomy, but the differences were not significant. Cranial-nerve injury was more common after endarterectomy than after stenting. CONCLUSIONS: In this study of patients with symptomatic carotid stenosis of 60% or more, the rates of death and stroke at 1 and 6 months were lower with endarterectomy than with stenting. (ClinicalTrials.gov number, NCT00190398 [ClinicalTrials.gov].).

Brain calcifications and PCDH12 variants.

OBJECTIVE: To assess the potential connection between PCDH12 and brain calcifications in a patient carrying a homozygous nonsense variant in PCDH12 and in adult patients with brain calcifications. METHODS: We performed a CT scan in 1 child with a homozygous PCDH12 nonsense variant. We screened DNA samples from 53 patients with primary familial brain calcification (PFBC) and 26 patients with brain calcification of unknown cause (BCUC). RESULTS: We identified brain calcifications in subcortical and perithalamic regions in the patient with a homozygous PCDH12 nonsense variant. The calcification pattern was different from what has been observed in PFBC and more similar to what is described in in utero infections. In patients with PFBC or BCUC, we found no protein-truncating variant and 3 rare (minor allele frequency <0.001) PCDH12 predicted damaging missense heterozygous variants in 3 unrelated patients, albeit with no segregation data available. CONCLUSIONS: Brain calcifications should be added to the phenotypic spectrum associated with PCDH12 biallelic loss of function, in the context of severe cerebral developmental abnormalities. A putative role for PCDH12 variants remains to be determined in PFBC.

Proportion of single-chain recombinant tissue plasminogen activator and outcome after stroke.

OBJECTIVE: To determine whether the ratio single chain (sc)/(sc + 2 chain [tc]) recombinant tissue plasminogen activator (rtPA) influences outcomes in patients with cerebral ischemia. METHODS: We prospectively included consecutive patients treated with IV rtPA for cerebral ischemia in 13 stroke centers and determined the sc/(sc + tc) ratio in the treatment administered to each patient. We evaluated the outcome with the modified Rankin Scale (mRS) at 3 months (prespecified analysis) and occurrence of epileptic seizures (post hoc analysis). We registered Outcome of Patients Treated by IV Rt-PA for Cerebral Ischaemia According to the Ratio Sc-tPA/Tc-tPA (OPHELIE) under ClinicalTrials.gov identifier no. NCT01614080. RESULTS: We recruited 1,004 patients (515 men, median age 75 years, median onset-to-needle time 170 minutes, median NIH Stroke Scale score 10). We found no statistical association between sc/(sc + tc) ratios and handicap (mRS > 1), dependency (mRS > 2), or death at 3 months. Patients with symptomatic intracerebral hemorrhages had lower ratios (median 69% vs 72%, adjusted p = 0.003). The sc/(sc + tc) rtPA ratio did not differ between patients with and without seizures, but patients with early seizures were more likely to have received a sc/(sc + tc) rtPA ratio >80.5% (odds ratio 3.61; 95% confidence interval 1.26-10.34). CONCLUSIONS: The sc/(sc + tc) rtPA ratio does not influence outcomes in patients with cerebral ischemia. The capacity of rtPA to modulate NMDA receptor signaling might be associated with early seizures, but we observed this effect only in patients with a ratio of sc/(sc + tc) rtPA >80.5% in a post hoc analysis.

Diffusion-weighted imaging of intravascular clots in cerebral venous thrombosis.

BACKGROUND AND PURPOSE: Hyperintensities on diffusion-weighted MRI at the site of venous occlusion have previously been reported in cerebral venous thrombosis (CVT). The frequency of these signal changes according to late venous recanalization was not determined yet. METHODS: In a series of 28 patients with recent CVT, the frequency of hyperintense signals as seen on diffusion-weighted MRI in vein(s) or sinus(es) (HSVdwi) was assessed at the time of diagnosis, as was rate of recanalization 2 to 3 months after anticoagulation. RESULTS: HSVdwi was detected in 20 occluded vein(s) or sinus(es) in 12 patients (41%) with recent CVT. The mean apparent diffusion coefficient measured in 5 patients within HSVdwi in the superior sagittal sinus was 4.88+/-1.49x10-4mm2/s. The delay since clinical onset was larger in the presence than in the absence of HSVdwi as detected at the time of diagnosis. No HSVdwi was visible at the second MRI although some vessels remained occluded. Complete recanalization of the vessel was less frequent when HSVdwi was observed on the first MRI (35% versus 88%, P=0.005). CONCLUSIONS: Results of this study suggest that the movements of water molecules are more or less restricted within the venous clot according to the stage of thrombus formation in CVT. The presence of HSVdwi in occluded veins at the time of diagnosis might be predictive of a low rate of vessel recanalization 2 or 3 months later.

Frequency and predictors of post-traumatic stress disorder after stroke: a pilot study.

OBJECTIVE: Few data exist about post-stroke symptoms of post-traumatic stress disorder (sPTSD) and none on DSM-IV formally diagnosed PTSD (fdPTSD). We investigated the frequency and predictors of sPTSD and fdPTSD 1-6 months after a nondisabling ischemic stroke (IS) or transient ischemic attack (TIA). METHODS: Consecutive patients were assessed for sPTSD (Impact of Events Scale-Revised, IES-R, significant if >30) and fdPTSD (PTSD-Interview). We recorded sociodemographic factors, stroke features (including severity of the initial deficit, persistent disability, localization), associated mood changes, peritraumatic reactions during the stroke (Peritraumatic Distress Inventory (PDI) for fear and distress, Peritraumatic Dissociative Experience Questionnaire for cognitive appraisal), and psychiatric history. Patients with sPTSD and fdPTSD were compared to patients with IES-R<30. RESULTS: Among the 40 patients (65% male, mean age 52 years) studied post-IS (n=30; mean initial NIHSS 4) or TIA, 25% had sPTSD, including 10% with fdPTSD. sPTSD was more frequent in women (p=0.02), patients with intense peritraumatic reactions especially on PDI (p=0.001) or identified prior depression and anxiety (p=0.007). No other demographic factors or stroke characteristics were associated with sPTSD. Forty percent of sPTSD patients were depressed versus none of the controls (p<0.002). All fdPTSD patients had ≥ 3 prior psychiatric co-morbidities. CONCLUSIONS: After nondisabling IS or TIA, sPTSD is frequent, with fdPTSD for 10%. Patients with intense peritraumatic reactions, women, and those with prior psychiatric morbidity, require particular attention to detect sPTSD.

Very early neurologic improvement after intravenous thrombolysis.

OBJECTIVE: To evaluate whether very early neurologic improvement (VENI) after intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) perfusion in patients with acute ischemic stroke (AIS) predicts favorable outcome at 3 months. DESIGN: Retrospective analysis of prospective data. SETTING: Stroke registry at the Stroke Unit, Tenon University Hospital. PATIENTS: We analyzed consecutive patients with AIS treated with i.v. rt-PA between November 11, 2002, and December 24, 2007. MAIN OUTCOME MEASURES: VENI at 1 hour was defined as a National Institute of Health Stroke Scale score of 0 at the end of rt-PA perfusion or an improvement of 5 or more points compared with baseline. Favorable outcome was defined as a modified Rankin Scale score of 1 or less at 3 months. RESULTS: Of 120 patients with AIS treated with i.v. rt-PA, 22 (18.3%) had VENI after i.v. rt-PA perfusion. Favorable outcome was observed in 15 patients with VENI (68.2%) and in 29 patients without VENI (29.6%) (P < .001). No symptomatic intracerebral hemorrhage occurred in patients with VENI. Mortality rates were 0% in the patients with VENI and 17.3% in patients without VENI. Baseline scores for VENI (adjusted odds ratio, 6.23; 95% confidence interval, 2.03-19.13; P = .001) and the National Institute of Health Stroke Scale (0.83; 0.76-0.91; P < .001) were the only 2 factors associated with favorable outcome (modified Rankin Scale score of ≤1). CONCLUSIONS: VENI at the end of i.v. rt-PA perfusion in patients with AIS independently predicts favorable outcome at 3 months.

Thoracic spinal cord compression indicating Wegener's granulomatosis in a patient with a previous presumptive diagnosis of microscopic polyangiitis.

Neurological signs are observed in 20-50% of cases of Wegener's granulomatosis consisting of peripheral and cranial neuropathy, and central nervous system involvement during the disease and rarely as initial symptom. We report here a case of thoracic spinal cord compression due to dural masses in a patient with a previous presumptive diagnosis of microscopic polyangiitis indicating Wegener's granulomatosis on histological examination. No other site of involvement was found. Slight clinical improvement was observed under immunosuppressive treatment probably because of spinal cord vessels lesions.