Joan Martí-Fàbregas

Risk of Ischemic Stroke Associated With Functional Thrombin-Activatable Fibrinolysis Inhibitor Plasma Levels

Background and Purpose— Recently, a novel procarboxypeptidase B–like proenzyme, called thrombin-activatable fibrinolysis inhibitor (TAFI), has been described. It plays an important role in the delicate balance between coagulation and fibrinolysis. TAFI leads to potent inhibition of tissue plasminogen activator–induced fibrinolysis. The relevance of TAFI in thromboembolic disease is unclear. We have investigated the risk of ischemic stroke (IS) in relation to plasma levels of functional TAFI. Methods— In a case-control study, we enrolled 264 individuals; 114 had IS, and 150 were recruited as controls who were age and sex matched and had no history of arterial disease. The individuals supplied information on their personal and family histories of cardiovascular diseases and conventional cardiovascular risk factors. Functional TAFI assays were performed by use of a method based on the activation of TAFI with thrombin-thrombomodulin and the measure of the TAFI activity generated. Other hemostatic parameters assayed were factor VIIIc, anti-phospholipid antibodies,fibrinogen, factor V Leiden, and the prothrombin gene G20210A mutations (PT20210A). Results— Functional TAFI levels were significantly higher in patients with IS (113.7±25%; range, 57% to 209%) than in controls (102.6±19%). The odds ratio for IS in patients with functional TAFI levels >120% was 5.7 (95% confidence interval, 2.3 to 14.1). Conclusions— We found that functional TAFI levels in plasma (>120%) increased the risk of IS ≈6-fold. Further studies should elucidate the physiological role of TAFI in arterial disease and possibly provide clues to therapeutic approaches.

Almost perfect concordance between simultaneous transcranial Doppler and transesophageal echocardiography in the quantification of right-to-left shunts.

Background and Purpose. Transesophageal echocardiography (TEE) and transcranial Doppler (TCD) are the methods of choice to study patent foramen ovale (PFO), but there are discrepancies between the 2 concerning PFO detection. No study has analyzed right‐to‐left shunt (RLS) quantification concordance. The 2 methods are carried out in different hemodynamic states, and the Valsalva maneuver (VM) required in each also differs. The authors compared PFO detection and concordance of RLS quantification classifications performing the 2 studies simultaneously. Methods. The authors prospectively included consecutive stroke patients undergoing TEE and applied the TCD protocol of the Consensus Conference. Echocardiographic PFO was diagnosed when at least 3 microbubbles (MBs) were detected in the left atrium within 3 heartbeats after opacification of the right atrium. RLS quantification was (1) TCD: minimum (1‐10 MBs), moderate (11‐25 MBs), and massive (>25 MBs) and (2) TEE: small (3‐10 MBs), moderate (11‐30 MBs), and large (>30 MBs). Statistics: contingency tables (χ2 and K test). Results. The authors studied 110 patients whose mean age was 56.7 ± 12.1 years, and 60.9% were men. PFO was detected at the first VM in 30% of patients with TCD and in 31.8% with TEE. At the second VM, both methods detected the same patients (32.7%). RLS was minimum (14), moderate (5), and massive (17) in TCD and small (13), moderate (3), and large (20) in TEE. There was an almost perfect concordance in RLS quantification (K = 0.928, P= .001), with only 4 discrepancies. Conclusions. Simultaneous study with TCD and TEE showed an almost perfect concordance in PFO detection and RLS quantification.

Homozygosity of the T Allele of the 46 C→T Polymorphism in the F12 Gene Is a Risk Factor for Ischemic Stroke in the Spanish Population

Background and Purpose— Ischemic stroke (IS) is a complex disease that involves genetic and environmental factors. In a family-based study (the Genetic Analysis of Idiopathic Thrombophilia [GAIT] Project) that included a genome-wide scan, we demonstrated that a common polymorphism (46 C→T) in the exon 1 of the F12 gene jointly influences variability of plasma Factor XII levels and susceptibility to thrombotic disease. We have investigated the risk of IS related to this polymorphism in a case–control study. Methods— We studied 436 individuals: 205 diagnosed with IS and 231 age–gender–ethnic control subjects. We measured Factor VIIIc, fibrinogen, and Factor XIIc levels, and we genotyped the 46 C→T polymorphism in the F12 gene. Results— There were 91 women and 114 men in the IS group and 109 women and 122 men in the control group. We confirmed our previous observation that individuals with different genotypes for the 46 C→T polymorphism showed significant differences in Factor XIIc levels. Most importantly, the mutated T allele in the homozygous state (genotype T/T) was associated with an increased risk of IS with an adjusted odds ratio of 4.1 (95% CI, 1.1 to 15.9). Conclusions— This study suggests that the 46 C→T polymorphism is a genetic risk factor for IS in the Spanish population. In addition, our results confirm that the use of genetic linkage studies along with a case–control association study is an extremely valuable approach for identifying DNA variants that affect complex diseases.

Association Between Time to Reperfusion and Outcome Is Primarily Driven by the Time From Imaging to Reperfusion

Background and Purpose— A progressive decline in the odds of favorable outcome as time to reperfusion increases is well known. However, the impact of specific workflow intervals is not clear. Methods— We studied the mechanical thrombectomy group (n=103) of the prospective, randomized REVASCAT (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset) trial. We defined 3 workflow metrics: time from symptom onset to reperfusion (OTR), time from symptom onset to computed tomography, and time from computed tomography (CT) to reperfusion. Clinical characteristics, core laboratory-evaluated Alberta Stroke Program Early CT Scores (ASPECTS) and 90-day outcome data were analyzed. The effect of time on favorable outcome (modified Rankin scale, 0–2) was described via adjusted odds ratios (ORs) for every 30-minute delay. Results— Median admission National Institutes of Health Stroke Scale was 17.0 (14.0–20.0), reperfusion rate was 66%, and rate of favorable outcome was 43.7%. Mean (SD) workflow times were as follows: OTR: 342 (107) minute, onset to CT: 204 (93) minute, and CT to reperfusion: 138 (56) minute. Longer OTR time was associated with a reduced likelihood of good outcome (OR for 30-minute delay, 0.74; 95% confidence interval [CI], 0.59–0.93). The onset to CT time did not show a significant association with clinical outcome (OR, 0.87; 95% CI, 0.67–1.12), whereas the CT to reperfusion interval showed a negative association with favorable outcome (OR, 0.72; 95% CI, 0.54–0.95). A similar subgroup analysis according to admission ASPECTS showed this relationship for OTR time in ASPECTS<8 patients (OR, 0.56; 95% CI, 0.35–0.9) but not in ASPECTS≥8 (OR, 0.99; 95% CI, 0.68–1.44). Conclusions— Time to reperfusion is negatively associated with favorable outcome, being CT to reperfusion, as opposed to onset to CT, the main determinant of this association. In addition, OTR was strongly associated to outcome in patients with low ASPECTS scores but not in patients with high ASPECTS scores. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01692379.

Vitamin B12 deficiency, hyperhomocysteinemia and thrombosis: a case and control study

This study aimed at assessing the relationship between thrombosis, hyperhomocysteinemia and vitamin B12 deficiency using a case–control study carried out in 326 patients with thrombosis (case group) and 351 patients from the same hospital (control group). Apart from the classic risk factors, a number of hematological variables were evaluated, including serum vitamin B12 (B12), red cell folate (RCF), and serum homocysteine (Hcy). An evaluation of serum methylmalonic acid (MMA) and a clinical study were carried out to investigate B12 pathology. Results of univariate analysis demonstrated decreased B12 levels in thrombosis (Student’s t test, p < 0.0001). Vitamin B12 below 200 pmol/l (LB200) or below 150 pmol/l (LB150), and red cell folate below 600 nmol/l were found in 17.2, 8.6, and 2.2% of cases with thromboembolism, respectively. An increase in Hcy was detected in 86 cases with thrombosis (26.3%). An abnormality in vitamin B12 and/or renal function was found in 80% of cases with hyperHcy and thrombosis. The MMA increase demonstrated that vitamin B12 deficiency was present in these patients with low levels of vitamin B12 in serum, and the MMA levels were in concordance with Hcy levels. The clinical study revealed B12 malabsorption in most cases with LB200. Multivariate analysis showed that serum vitamin B12 (RR 0.998, CI 0.997–0.999) was moderately related to thromboembolism. The results indicated that vitamin B12 deficiency was common among patients with hyperhomocysteinemia and thrombosis. Moreover, HyperHcy was caused by vitamin B12 deficiency and/or chronic renal failure in most patients with thrombosis. As the main cause of vitamin B12 deficiency was vitamin malabsorption, parenteral vitamin B12 with or without folic acid should be administered for the treatment of this condition. However, it remains to be demonstrated whether this treatment approach prevents recurrent thromboses in patients with vitamin B12 deficiency and thrombosis, as suggested by some case reports.

Hepatic Myelopathy: A Rare Complication of Portacaval Shunt

Myelopathy is a rare complication of chronic liver disease associated with extensive portal-systemic shunt of blood. Its main clinical feature is a spastic paraparesis without sensory or sphincteric impairment. We describe 3 patients who presented hepatic myelopathy following the performance of a portacaval shunt.

Oculomotor abnormalities in motor neuron disease

To determine whether there are oculomotor abnormalities in motor neuron disease (MND), electrooculographic recordings were performed prospectively in 16 MND patients and the results compared with age-matched healthy controls. Parameters analysed included random and fixed saccades (latency, velocity and accuracy), smooth pursuit (gain, total harmonic distortion and number of saccadic intrusions) and optokinetic nystagmus (maximal and mean slow component velocity). Increased saccadic latencies and decreased smooth pursuit gain were the main alterations in the MND group. Correlation with clinical variables showed a positive relationship between smooth pursuit saccadic intrusions and the bulbar clinical score and the rate of progression and a lower optokinetic nystagmus maximal velocity in patients with pseudobulbar syndrome. Our results demonstrate the presence of subclinical supranuclear abnormalities in MND, and support the notion that MND is not merely a degeneration of the motor system.

Alien Hand Sign after a Right Parietal Infarction

Involuntary movements are unusual during or after acute stroke, and alien hand sign has not been reported after single parietal infarction. We report on a woman who presented with involuntary movements and a sense of alienness of her left upper limb following a right parietal infarction. This combination, that can meet the criteria for the ‘alien hand syndrome’, is rarely seen after acute lesions sparing the corpus callosum and the mesial frontal areas.

Absence of thallium-201 brain uptake in progressive multifocal leukoencephalopathy in AIDS patients.

Objective ‐ To evaluate the presence of thallium‐201 brain uptake determined by thallium‐201 brain SPECT (Tl‐201 SPECT) in patients with progressive multifocal leukoencephalopathy (PML) and AIDS. Material and methods ‐ Six AIDS patients with stereotactic biopsy diagnosis of PML were prospectively evaluated with Tl‐201 SPECT, Magnetic Resonance Imaging (MRI), and proton magnetic resonance spectroscopy (1 H‐MRS). Tl‐201 SPECT results were compared with 2 patients with AIDS and biopsy proven primary CNS lymphoma. Results ‐ In all patients with PML, Tl‐201 SPECT studies showed lack of uptake while MRI demonstrated subcortical white matter focal brain lesions and‘ H‐MRS disclosed metabolic abnormalities. Intense thallium uptake (uptake ratios of 3.2 and 5.6) was demonstrated in the 2 patients with primary CNS lymphoma. Conclusions ‐ The present study shows that PML lesions are not detectable on Tl‐201 SPECT while MRI and‘H‐MRS demonstrate abnormalities, and intense thallium‐201 uptake may be detected in primary CNS lymphoma. These results suggest that Tl‐201 SPECT is a method which, combined with other non‐invasive techniques such as MRI and 1 H‐MRS, may help in the diagnostic approach of PML and to differentiate PML from other high proliferative brain lesions characterized by positive thallium uptake.

Respiratory function deterioration is not time-linked with upper-limb onset in amyotrophic lateral sclerosis

Introduction– In amyotrophic lateral sclerosis (ALS), symptoms apparently spread following regional rules, and depending on the site of onset. We examined if respiratory function deterioration appears earlier or is more severe in patients with upper‐limb onset. Material & methods– We compared the results of various pulmonary function tests (PFT) obtained at diagnosis depending on the site of onset in 49 ALS patients. In a longitudinal study, we compared the deterioration of forced vital capacity (FVC) in relation to the site of onset, and analyzed the time elapsed to reach values below 80% of predicted according to site of onset, and we compared the survival depending on the site of onset. Results– No significant differences in PFT were found in the upper‐limb onset group in any of the analysis performed. No differences in survival were detected in any disease onset group. Conclusion– Pulmonary function deterioration does not appear to be time‐linked to arm onset in ALS.