Fluoxetine for motor recovery after acute intracerebral hemorrhage, the FMRICH trial.

OBJECTIVES: Acute intracerebral hemorrhage (ICH) is a very common cause of disability. Previous evidence suggests that fluoxetine and other selective serotonin reuptake inhibitors improve, the recovery of motor function in patients with cerebral infarct. The purpose of this study was to investigate whether fluoxetine also improves motor recovery in patients with ICH. PATIENTS AND METHODS: This is a double blind, placebo controlled, multicenter randomized trial, patients recruited from three centers were assigned to receive 20 mg/day of fluoxetine or matching placebo for three months from within ten days after onset of symptoms. Primary outcome was change in Fugl-Meyer Motor Scale from baseline to day 90. RESULTS: Thirty patients (50 % women) were recruited to the fluoxetine (n = 14) or placebo (n = 16) groups. Median age was 55 years, the cause of the ICH was hypertension in 93.3 %, median volume of the hematomas was 22mm3. Basal ganglia hematoma was present in 67 % and, lobar location in 20 % of the patients. Improvement in FMMS at day 90 was significatively higher in the treatment group (median score 23) than in the placebo group, (median score 48), p = 0.001. No serious adverse events occurred. CONCLUSION: In addition to standard treatment, early prescription of fluoxetine was safe and helped to increase motor recovery 90 days after ICH. This finding adds to the evidence regarding its beneficial effect upon stroke related disability. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01737541.

Outcome, Recurrence and Mortality after Non-Valvular Atrial Fibrillation Stroke: Long-Term Follow-Up Study.

OBJECTIVE: Non-valvular atrial fibrillation (NVAF) is a major risk factor for ischemic stroke (IS) and a powerful predictor of mortality. This study investigates early and long-term outcome among patients with IS secondary to NVAF and identify the main factors associated with poor outcome, recurrence, and death. METHODS: We analyzed the data from our consecutive NVAF acute IS database, over a period of 23 years. The endpoints were bad outcome (Modified Rankin Score ≥3), recurrence, and mortality at discharge, after 6 months, 12 months, and final follow-up. Multivariate Cox and Kaplan-Meier analysis were used to estimate the probability of death. RESULTS: 129 consecutive acute IS patients were included (77 [59.7%] females, mean age 70.2 ± 10.1 years). Discharge, 6 and 12 months bad outcome was 62%, 63%, and 61%, respectively. After a median follow-up of 17 months (IQR 6-54.5), 35.6% patients had bad outcome, 21.7% had recurrence and 36.4% died. The recurrence and death annual rates were 19.1% and 6.32%. The absence of oral anticoagulation (OAC) and NIHSS score > 12 were the strongest predictors of mortality. CONCLUSIONS: IS secondary to NVAF has a high rate of stroke recurrence and mortality in our population, with the absence of OAC and major stroke as the main risk factors.

Large field-of-view movement-compensated intrinsic optical signal imaging for the characterization of the haemodynamic response to spreading depolarizations in large gyrencephalic brains.

Haemodynamic responses to spreading depolarizations (SDs) have an important role during the development of secondary brain damage. Characterization of the haemodynamic responses in larger brains, however, is difficult due to movement artefacts. Intrinsic optical signal (IOS) imaging, laser speckle flowmetry (LSF) and electrocorticography were performed in different configurations in three groups of in total 18 swine. SDs were elicited by topical application of KCl or occurred spontaneously after middle cerebral artery occlusion. Movement artefacts in IOS were compensated by an elastic registration algorithm during post-processing. Using movement-compensated IOS, we were able to differentiate between four components of optical changes, corresponding closely with haemodynamic variations measured by LSF. Compared with ECoG and LSF, our setup provides higher spatial and temporal resolution, as well as a better signal-to-noise ratio. Using IOS alone, we could identify the different zones of infarction in a large gyrencephalic middle cerebral artery occlusion pig model. We strongly suggest movement-compensated IOS for the investigation of the role of haemodynamic responses to SDs during the development of secondary brain damage and in particular to examine the effect of potential therapeutic interventions in gyrencephalic brains.

Ketamine modulation of the haemodynamic response to spreading depolarization in the gyrencephalic swine brain.

Spreading depolarization (SD) generates significant alterations in cerebral haemodynamics, which can have detrimental consequences on brain function and integrity. Ketamine has shown an important capacity to modulate SD; however, its impact on SD haemodynamic response is incompletely understood. We investigated the effect of two therapeutic ketamine dosages, a low-dose of 2 mg/kg/h and a high-dose of 4 mg/kg/h, on the haemodynamic response to SD in the gyrencephalic swine brain. Cerebral blood volume, pial arterial diameter and cerebral blood flow were assessed through intrinsic optical signal imaging and laser-Doppler flowmetry. Our findings indicate that frequent SDs caused a persistent increase in the baseline pial arterial diameter, which can lead to a diminished capacity to further dilate. Ketamine infused at a low-dose reduced the hyperemic/vasodilative response to SD; however, it did not alter the subsequent oligemic/vasoconstrictive response. This low-dose did not prevent the baseline diameter increase and the diminished dilative capacity. Only infusion of ketamine at a high-dose suppressed SD and the coupled haemodynamic response. Therefore, the haemodynamic response to SD can be modulated by continuous infusion of ketamine. However, its use in pathological models needs to be explored to corroborate its possible clinical benefit.

Incidence, hemodynamic, and electrical characteristics of spreading depolarization in a swine model are affected by local but not by intravenous application of magnesium.

The aim was to characterize the effects of magnesium sulfate, using i.v. bolus and local administration, using intrinsic signal imaging, and on electrocorticographic activity during the induction and propagation of spreading depolarizations in the gyrencephalic porcine brain. Local application of magnesium sulfate led to a complete inhibition of spreading depolarizations. One hour after washing out the topical magnesium sulfate, re-incidence of the spreading depolarizations was observed in 50% of the hemispheres. Those spreading depolarizations showed attenuation in hemodynamic characteristics and speed in intrinsic optical signal imaging. The electrical amplitude decreased through electrocorticographic activity. Intravenous magnesium therapy showed no significant effects on spreading depolarization incidence and characteristics.

Radial, spiral and reverberating waves of spreading depolarization occur in the gyrencephalic brain.

OBJECTIVES: The detection of the hemodynamic and propagation patterns of spreading depolarizations (SDs) in the gyrencephalic brain using intrinsic optical signal imaging (IOS). METHODS: The convexity of the brain surface was surgically exposed in fourteen male swine. Within the boundaries of this window, brains were immersed and preconditioned with an elevated K(+) concentration (7 mmol/l) in the standard Ringer lactate solution for 30-40 min. SDs were triggered using 3-5 µl of 1 mol/l KCl solution. Changes in tissue absorbency or reflection were registered with a CCD camera at a wavelength of 564 nm (14 nm FWHM), which was mounted 25 cm above the exposed cortex. Additional monitoring by electrocorticography and laser-Doppler was used in a subset of animals (n=7) to validate the detection of SD. RESULTS: Of 198 SDs quantified in all of the experiments, 187 SDs appeared as radial waves that developed semi-planar fronts. The morphology was affected by the surface of the gyri, the sulci and the pial vessels. Other SD patterns such as spirals and reverberating waves, which have not been described before in gyrencephalic brains, were also observed. Diffusion gradients created in the cortex surface (i.e., KCl concentrations), sulci, vessels and SD-SD interactions make the gyrencephalic brain prone to the appearance of irregular SD waves. CONCLUSION: The gyrencephalic brain is capable of irregular SD propagation patterns. The irregularities of the gyrencephalic brain cortex may promote the presence of re-entrance waves, such as spirals and reverberating waves.

Clinical spectrum of artery of Percheron infarct: clinical-radiological correlations.

BACKGROUND: The occlusion of the artery of Percheron results in bilateral thalamic and mesencephalic infarctions. In this series, we attempted to classify the subtypes of clinical presentations and long-term prognosis with regards to radiological patterns. METHODS: We sought the clinical and radiological findings of 15 (8 men and 7 women; mean age 48 years) consecutive patients with Percheron artery infarct over 10 years. We classified the clinical symptoms according to the presence of a mental status disturbance (MSD), behavioral amnesic impairment (BAI), aphasia/dysarthria, ocular movement disorders (OMDs), motor deficit, cerebellar signs, and others. The Percheron artery infarct images were classified as bilateral paramedian thalamic with rostral midbrain infarction (BPTRMI), bilateral paramedian thalamic without midbrain infarction (BPTWMI), bilateral paramedian and anterior thalamic with midbrain infarction (BPATMI), and bilateral paramedian and anterior thalamic without midbrain infarction. The outcome was evaluated using a modified Rankin Scale (mRS). RESULTS: OMD and MSD were the most common clinical manifestations in patients with BPTRMI (n = 8). BAI and MSD were the main clinical findings in patients with BPTWMI (n = 6). A patient with BPATMI had a combination of clinical manifestations. After a mean follow-up of 55 months, a good outcome (mRS score ≤ 2) was present in 25% of the patients with BPTRMI, 67% of the patients with BPTWMI, and in 1 patient with BPATMI. CONCLUSIONS: Our findings suggest that it is possible to identify clinical and radiological subgroups of Percheron artery infarct. The long-term follow-up outcome is generally good, except in cases with midbrain involvement.

Fluoxetine for motor recovery after acute intracerebral hemorrhage (FMRICH): study protocol for a randomized, double-blind, placebo-controlled, multicenter trial.

BACKGROUND: Spontaneous, nontraumatic intracerebral hemorrhage (ICH) is a subtype of stroke that causes a great amount of disability and economic and social burden. This is particularly true in developing countries where it accounts for between 20% and 50% of all strokes. Pharmacological and surgical interventions have been attempted to reduce the mortality and disability caused by ICH, with unsuccessful results. Recently, the use of fluoxetine in addition to physical rehabilitation has been proven useful to improve motor recovery following cerebral infarct. The purpose of this study is to test whether a 3-month treatment with fluoxetine enhances motor recovery in nondepressed patients with acute intracerebral hemorrhage. METHODS/DESIGN: Our study is a randomized, double-blind, placebo-controlled, multicenter clinical trial. We will recruit 86 patients with intracerebral hemorrhage of both sexes, aged >18 years, from four Mexican hospitals. The patients will receive either 20 mg of fluoxetine or a placebo once daily for 90 days. The primary outcome is the mean change in the Fugl-Meyer Motor Scale score between inclusion (day 0) and day 90. The secondary outcomes will be changes in the Barthel Index, the Modified Rankin scale and the National Institutes of Health stroke scale. The outcomes will be measured at day 42 ± 7 days and at day 90, for a total of four visits with each subject (at screening and at 0, 42 and 90 days). DISCUSSION: Current guidelines recommend early supported hospital discharge and home-based rehabilitation programs as the only cost-effective intervention to aid the recovery of patients with intracerebral hemorrhage. Nevertheless, such interventions are dependent on available resources and funding, which make them very difficult to implement in developing countries. We believe that the identification of a helpful pharmacological intervention to aid the motor recovery of these patients will constitute a breakthrough that will have a major impact in reducing the burden of disease caused by this subtype of stroke worldwide, especially in the developing world. TRIAL REGISTRATION: Current Controlled Trials NCT01737541.