Apixaban versus Aspirin for Embolic Stroke of Undetermined Source.

BACKGROUND: Rivaroxaban and dabigatran were not superior to aspirin in trials of patients with embolic stroke of undetermined source (ESUS). It is unknown whether apixaban is superior to aspirin in patients with ESUS and known risk factors for cardioembolism. METHODS: We conducted a multicenter, randomized, open-label, blinded-outcome trial of apixaban (5 mg twice daily) compared with aspirin (100 mg once daily) initiated within 28 days after ESUS in patients with at least one predictive factor for atrial fibrillation or a patent foramen ovale. Cardiac monitoring was mandatory, and aspirin treatment was switched to apixaban in case of atrial fibrillation detection. The primary outcome was any new ischemic lesion on brain magnetic resonance imaging (MRI) during 12-month follow-up. Secondary outcomes included major and clinically relevant nonmajor bleeding. RESULTS: A total of 352 patients were randomly assigned to receive apixaban (178 patients) or aspirin (174 patients) at a median of 8 days after ESUS. At 12-month follow-up, MRI follow-up was available in 325 participants (92.3%). New ischemic lesions occurred in 23 of 169 (13.6%) participants in the apixaban group and in 25 of 156 (16.0%) participants in the aspirin group (adjusted odds ratio, 0.79; 95% confidence interval, 0.42 to 1.48; P=0.57). Major and clinically relevant nonmajor bleeding occurred in five and seven participants, respectively (1-year cumulative incidences, 2.9 and 4.2; hazard ratio, 0.68; 95% confidence interval, 0.22 to 2.16). Serious adverse event rates were 43.9 per 100 person-years in those given apixaban and 45.7 per 100 person-years in those given aspirin. The Apixaban for the Treatment of Embolic Stroke of Undetermined Source trial was terminated after a prespecified interim analysis as a result of futility. CONCLUSIONS: Apixaban treatment was not superior to cardiac monitoring-guided aspirin in preventing new ischemic lesions in an enriched ESUS population. (Funded by Bristol-Myers Squibb and Medtronic Europe; ClinicalTrials.gov number, NCT02427126.)

[Resuscitation room diagnostics]. / Schockraumdiagnostik.

CLINICAL PROBLEM: The indication for resuscitation room care is an acute (potentially) life-threatening patient condition. Typical causes for this are polytrauma, acute neurological symptoms, acute chest and abdominal pain or the cause remains unclear at first. The care is always provided in a suitably composed interdisciplinary team. This requires cause-specific standards tailored to the care facility and requires a mutual understanding of the partners involved with regard to specialist interests and care processes. STANDARD RADIOLOGICAL METHODS: Whole-body CT is established for polytrauma imaging and usually each institution has already defined an institutional standard. For the other causes, first imaging with CT is just as common, but the protocols and procedures to be used are often not as clear as in the case of polytrauma. METHODICAL INNOVATION AND EVALUATION: For polytrauma service, ATLS and procedures according to ABCDE already serve as a largely standardized framework in the resuscitation room. For every other group of causes, comparable concepts should be developed and institutionally strive for objectification of continuous improvement. This refers not only to the resuscitation room stay but also to the interfaces before and after resuscitation room service. PRACTICAL RECOMMENDATIONS: After the patient has arrived, it has to be determined whether the assessment of a vital risk is retained. If so, institutionally defined care standards must be followed for the various causes. This concerns the interface logistics, the definition of a team leader including associated tasks, the supply processes including the CT examination protocols as well as the close communication.

Apixaban for treatment of embolic stroke of undetermined source (ATTICUS randomized trial): Rationale and study design.

Rationale Optimal secondary prevention of embolic stroke of undetermined source is not established. The current standard in these patients is acetylsalicylic acid, despite high prevalence of yet undetected paroxysmal atrial fibrillation. Aim The ATTICUS randomized trial is designed to determine whether the factor Xa inhibitor apixaban administered within 7 days after embolic stroke of undetermined source, is superior to acetylsalicylic acid for prevention of new ischemic lesions documented by brain magnetic resonance imaging within 12 months after index stroke. Design Prospective, randomized, blinded, parallel-group, open-label, German multicenter phase III trial in approximately 500 patients with embolic stroke of undetermined source. A key inclusion criterion is the presence or the planned implantation of an insertable cardiac monitor. Patients are 1:1 randomized to apixaban or acetylsalicylic acid and treated for a 12-month period. It is an event-driven trial aiming for core-lab adjudicated primary outcome events. Study outcomes The primary outcome is the occurrence of at least one new ischemic lesion identified by axial T2-weighted FLAIR magnetic resonance imaging and/or axial DWI magnetic resonance imaging at 12 months when compared with the baseline magnetic resonance imaging. Key secondary outcomes are the combination of recurrent ischemic strokes, hemorrhagic strokes, systemic embolism; combination of MACE including recurrent stroke, myocardial infarction, and cardiovascular death and combination of major and clinically relevant non-major bleeding defined according to ISTH, and change of cognitive function and quality of life (EQ-5D, Stroke Impact Scale). Discussion Embolic stroke of undetermined source is caused by embolic disease and associated with a high risk of recurrent ischemic strokes and clinically silent cerebral ischemic lesions. ATTICUS will investigate the impact of atrial fibrillation detected by insertable cardiac monitor and the effects of early anticoagulation with apixaban compared with antiplatelet therapy with acetylsalicylic acid on the incidence of new ischemic lesion after embolic stroke of undetermined source.

Hypertrophic Olivary Degeneration: A Neurosurgical Point of View.

Hypertrophic olivary degeneration (HOD) is a rare form of transsynaptic degeneration characterized by hypertrophy of the inferior olivary nucleus situated in the olivary body, part of the medulla oblongata, representing a major source of input to the cerebellum. HOD typically results from focal lesions interrupting connections from the inferior olive within the dentato-rubro-olivary pathway, a region also known as the triangle of Guillain-Mollaret (TGM) (red nucleus, inferior olivary nucleus, and contralateral dentate nucleus). Clinically, HOD presents classically as palatal tremor and can include dentatorubral tremor and/or ocular myoclonus. The pathologic changes associated with HOD feature radiologic changes with the inferior olivary nucleus appearing larger and increasing its T2-weighted signal intensity on magnetic resonance images. HOD is commonly managed with pharmacotherapy but may require surgical intervention in extreme cases. HOD has been found to develop as a consequence of any injury that disrupts the TGM pathways (e.g., pontine cavernoma).These findings highlight the critical importance of a thorough knowledge of TGM anatomy to avoid secondary HOD. We present a patient who developed HOD secondary to resection of a tectal plate cavernous malformation and review the literature with an emphasis on the current knowledge of this disorder.

Deprivation and Recovery of Sleep in Succession Enhances Reflexive Motor Behavior.

Sleep deprivation impairs inhibitory control over reflexive behavior, and this impairment is commonly assumed to dissipate after recovery sleep. Contrary to this belief, here we show that fast reflexive behaviors, when practiced during sleep deprivation, is consolidated across recovery sleep and, thereby, becomes preserved. As a model for the study of sleep effects on prefrontal cortex-mediated inhibitory control in humans, we examined reflexive saccadic eye movements (express saccades), as well as speeded 2-choice finger motor responses. Different groups of subjects were trained on a standard prosaccade gap paradigm before periods of nocturnal sleep and sleep deprivation. Saccade performance was retested in the next morning and again 24 h later. The rate of express saccades was not affected by sleep after training, but slightly increased after sleep deprivation. Surprisingly, this increase augmented even further after recovery sleep and was still present 4 weeks later. Additional experiments revealed that the short testing after sleep deprivation was sufficient to increase express saccades across recovery sleep. An increase in speeded responses across recovery sleep was likewise found for finger motor responses. Our findings indicate that recovery sleep can consolidate motor disinhibition for behaviors practiced during prior sleep deprivation, thereby persistently enhancing response automatization.

Visual motion, eye motion, and relative motion: A parametric fMRI study of functional specializations of smooth pursuit eye movement network areas.

The ability to pursue moving objects with the eyes is vital to humans. However, it remains unclear how the brain differentiates visual object motion, smooth pursuit eye movements (SPEM), and eye movement-induced relative motion on the retina and where visual-to-oculomotor transformation takes place. To characterize functional differences of SPEM-processing cortical areas, we simultaneously measured functional magnetic resonance imaging (fMRI) and smooth pursuit to visual, oculomotor, and visuo-oculomotor stimuli varying the quantity of background dots of the stimuli. Resulting activations involved the whole visuo-oculomotor network. They varied among regions depending on the functional tasks and parametric changes of the background. Activation in many SPEM regions increased from 1 to 16 background dots but decreased at 36 dots. This could be an effect of coherent-texture perception. Putative MST area was not influenced by the amount of moving or stationary background dots. It probably participates in visuo-oculomotor transformation. Parts of the posterior parietal cortex seem specifically activated with relative motion between eye and background, but not with motion per se. This could be important for the perception of spatial references.

Eye movements during REM sleep and imagination of visual scenes.

It has been hypothesized that rapid eye movements (REMs) during sleep reflect the process of looking around in dreams. We questioned whether REMs differ from eye movements in wakefulness while imagining previously seen visual stimuli (dots, static images, videos). After looking at these stimuli individuals were asked to remember and imagine them. Subsequently, their REMs were recorded at the sleep laboratory. Kinematic parameters of REMs were similar to saccadic eye movements to remembered stimuli with closed eyes, irrespective of the stimulus type. In contrast, peak velocity of eye movements with open eyes was similar to REMs when semantic, but not nonsemantic, contents were imagined. Thus, REMs may be related to exploratory saccadic behaviour in the awake to remember visual stimuli.

Visual search disorders in acute and chronic homonymous hemianopia: lesion effects and adaptive strategies.

Patients with homonymous hemianopia due to occipital brain lesions show disorders of visual search. In everyday life this leads to difficulties in reading and spatial orientation. It is a matter of debate whether these disorders are due to the brain lesion or rather reflect compensatory eye movement strategies developing over time. For the first time, eye movements of acute hemianopic patients (n= 9) were recorded during the first days following stroke while they performed an exploratory visual-search task. Compared to age-matched control subjects their search duration was prolonged due to increased fixations and refixations, that is, repeated scanning of previously searched locations. Saccadic amplitudes were smaller in patients. Right hemianopic patients were more impaired than left hemianopic patients. The number of fixations and refixations did not differ significantly between both hemifields in the patients. Follow-up of one patient revealed changes of visual search over 18 months. By using more structured scanpaths with fewer saccades his search duration decreased. Furthermore, he developed a more efficient eye-movement strategy by making larger but less frequent saccades toward his blind side. In summary, visual-search behavior of acute hemianopic patients differs from healthy control subjects and from chronic hemianopic patients. We conclude that abnormal visual search in acute hemianopic patients is related to the brain lesion. We provide some evidence for adaptive eye-movement strategies developed over time. These adaptive strategies make the visual search more efficient and may help to compensate for the persisting visual-field loss.

Visual search disorders beyond pure sensory failure in patients with acute homonymous visual field defects.

Patients with homonymous visual field defects (HVFD) are often crucially disabled during self-guided visual exploration of their natural environment. Abnormal visual search may be related to the sensory deficit, deficient spatial orientation or compensatory eye movements. We tested the hypothesis that visual search in HVFD is purely determined by the visual-sensory deficit by comparing nine patients with HVFD due to occipital stroke in an acute stage to nine healthy subjects with technically simulated "virtual" homonymous visual field defects (vHVFD) and to nine controls with normal visual fields. The simulated gaze-contingent visual field defects in vHVFD subjects were individually matched to the patients' HVFD with respect to their size and side. Eye movements were recorded while subjects searched for targets among distractors and indicated target detection by clicks. All patients, in particular those with lesions involving the inferior occipito-temporal (fusiform) gyrus, but also those with small lesions restricted to the visual cortex, showed longer search durations than vHVFD subjects. This was tightly related to the higher number of fixations and particularly "re-fixations" (repeated scanning of fixated items). Working memory across saccades during the search was intact (no increased "re-clicks"). Scanpath strategies were similar in patients and vHVFD subjects. For both groups amplitude and frequency of saccades did not differ between the hemifields. In HVFD patients with acute occipital brain lesions, visual input failure does not fully account for abnormal visual search. It might either result from disconnections of the primary visual cortex to associated occipital and temporal brain areas or reflect an early stage of compensatory eye movements which differ from chronic HVFD patients.

Optic flow stimuli in and near the visual field centre: a group FMRI study of motion sensitive regions.

Motion stimuli in one visual hemifield activate human primary visual areas of the contralateral side, but suppress activity of the corresponding ipsilateral regions. While hemifield motion is rare in everyday life, motion in both hemifields occurs regularly whenever we move. Consequently, during motion primary visual regions should simultaneously receive excitatory and inhibitory inputs. A comparison of primary and higher visual cortex activations induced by bilateral and unilateral motion stimuli is missing up to now. Many motion studies focused on the MT+ complex in the parieto-occipito-temporal cortex. In single human subjects MT+ has been subdivided in area MT, which was activated by motion stimuli in the contralateral visual field, and area MST, which responded to motion in both the contra- and ipsilateral field. In this study we investigated the cortical activation when excitatory and inhibitory inputs interfere with each other in primary visual regions and we present for the first time group results of the MT+ subregions, allowing for comparisons with the group results of other motion processing studies. Using functional magnetic resonance imaging (fMRI), we investigated whole brain activations in a large group of healthy humans by applying optic flow stimuli in and near the visual field centre and performed a second level analysis. Primary visual areas were activated exclusively by motion in the contralateral field but to our surprise not by central flow fields. Inhibitory inputs to primary visual regions appear to cancel simultaneously occurring excitatory inputs during central flow field stimulation. Within MT+ we identified two subregions. Putative area MST (pMST) was activated by ipsi- and contralateral stimulation and located in the anterior part of MT+. The second subregion was located in the more posterior part of MT+ (putative area MT, pMT).

Sleep is required for improving reaction times after training on a procedural visuo-motor task.

Sleep has been found to enhance consolidation of many different forms of memory. However in most procedural tasks, a sleep-independent, fast learning component interacts with slow, sleep-dependent improvements. Here, we show that in humans a visuo-motor saccade learning task shows no improvements during training, but only during a delayed recall testing after a period of sleep. Subjects were trained in a prosaccade task (saccade to a visual target). Performance was tested in the prosaccade and the antisaccade task (saccade to opposite direction of the target) before training, after a night of sleep or sleep deprivation, after a night of recovery sleep, and finally in a follow-up test 4 weeks later. We found no immediate improvement in saccadic reaction time (SRT) during training, but a delayed reduction in SRT, indicating a slow-learning process. This reduction occurred only after a period of sleep, i.e. after the first night in the sleep group and after recovery sleep in the sleep deprivation group. This improvement was stable during the 4-week follow-up. Saccadic training can thus induce covert changes in the saccade generation pathway. During the following sleep period, these changes in turn bring about overt performance improvements, presuming a learning effect based on synaptic tagging.

Long-term eye movement recordings with a scleral search coil-eyelid protection device allows new applications.

The search coil technique is regarded as the gold standard in eye movement recordings. The manufacturers of scleral search coils (SSC) do not recommend using them longer than 30 min. The temporal limitations result from potential cornea damage and from irritations of the lid margins and palpebral conjunctiva which subjects perceive as unpleasant. Here we introduce a new coil-eyelid protection device (CEPD) which allows recording intervals up to 2 h with considerably reduced discomfort. Ophthalmic examinations and saccade recordings were used for comparison with the conventional SSC recording technique. In three experiments subjects were examined using SSCs with a commercially available cornea bandage lens on top of the search coil up to 120 min recording time. Ophthalmic testing revealed no apparent harmful effects on eyes or lid surface. Saccade parameters (main sequence) remained unchanged comparing SSC and CEPD recordings. Subjects rated less discomfort by using the CEPD. For the first time we show that SSC recordings can be extended over about 120 min without hazard to the eye, when using an eyelid protection lens. This advanced method allows new applications like eye movement recordings during sleep (rapid eye movements) or perceptional or motor learning tasks, e.g. saccade adaptation paradigms.

Coherent motion pops out during smooth pursuit.

Stimulus motion is a prominent feature that is used by the visual system to segment figure from ground and perceptually bind widely separated objects. Pursuit eye movements can be influenced by such perceptual grouping processes. We have examined the subjects' ability to detect small amounts of coherent motion in random dot kinematograms during pursuit. We compared performance on tests of coherent motion perception while subjects fixated a stationary spot or while they tracked a moving target. The results indicate that smooth pursuit can improve subjects' ability to detect the presence of coherent motion. We tentatively propose that an efference copy of the eye movement signal can enhance the ability of the visual system to detect correlations between sparsely placed targets among noisy distractors.

Event-related fMRI responses in the human frontal eye fields in a randomized pro- and antisaccade task.

We examined whether the frontal eye fields (FEF) are involved in the suppression of reflexive saccades. Simultaneous recording of horizontal eye movements and functional magnetic resonance imaging enabled us to perform a randomized pro- and antisaccade task and to sort blood oxygenation level dependent (BOLD) time series on the basis of task performance. Saccadic reaction time distributions were comparable across tasks indicating a similar effort in preprocessing of the saccades. Furthermore, we found similar BOLD activation in FEF during both correctly performed pro- and antisaccades. Frontal eye field activation started prior to target presentation and saccade generation. While we observed only few erroneous antisaccades, these were associated with a decrease in BOLD activity prior to target presentation, and increased BOLD activity after target presentation relative to correctly performed antisaccades. These findings are consistent with a role of the FEF in the suppression of reflexive saccades. The increase in activity after target presentation for antisaccade errors can only be indirectly linked to such a role but may also reflect activity related to the generation of a correction saccade. Frontal eye field BOLD activity may further represent general arousal, preparatory set, short-term memory, or salience-map related activity.

What is pathological with gaze shift fragmentation in Parkinson's disease?

Oculomotor dysfunction in Parkinson's disease (PD) is mainly characterized by a fragmentation of memory-guided gaze shifts (target is reached by several hypometric saccades). Since this phenomenon can also be observed in normal subjects, we scrutinized its pathophysiological significance in PD patients. We recorded horizontal eye movements in eleven mildly- or moderately-affected PD patients and eleven control subjects. A quantitative assessment of gaze shift fragmentation was made possible by increasing its incidence over a sequence of two visually- and two subsequent memory-guided gaze shifts. Basic saccade measures (latency, velocity, etc.) were similar in the two subject groups as well as in fragmented versus non-fragmented gaze shifts. Fragmentation probability is increased in the second memory-guided gaze shift, and this clearly more so in patients than in controls. The fragmentation shows a typical gain pattern (uniform increase of gain of saccadic amplitudes across correction saccades towards 1.0 with the last saccade of the gaze shift) independent of subject group, stimulus mode, and fragmentation degree. Gaze shift fragmentation represents a physiological phenomenon, which has thus far been overlooked. It reflects a robust correction mechanism, which assures that target is reached even if the pre-oculomotor drive through the basal ganglia to the superior colliculus becomes abnormally weak or under inadequately strong inhibition - as is postulated for PD. Thus, only the abnormally high incidence of fragmentation, and of the associated amplitude reduction of the primary saccades, rather than the phenomenon per se, can be used as a diagnostic criterion in early stages of PD.