Cerebrospinal fluid (CSF) flow maintains healthy brain homeostasis, facilitating solute transport and the exchange of brain waste products. CSF flow is thus important for brain health, but the mechanisms that control its large-scale movement through the ventricles are not well understood. While it is well established that CSF flow is modulated by respiratory and cardiovascular dynamics, recent work has also demonstrated that neural activity is coupled to large waves of CSF flow in the ventricles during sleep. To test whether the temporal coupling between neural activity and CSF flow is in part due to a causal relationship, we investigated whether CSF flow could be induced by driving neural activity with intense visual stimulation. We manipulated neural activity with a flickering checkerboard visual stimulus and found that we could drive macroscopic CSF flow in the human brain. The timing and amplitude of CSF flow was matched to the visually evoked hemodynamic responses, suggesting neural activity can modulate CSF flow via neurovascular coupling. These results demonstrate that neural activity can contribute to driving CSF flow in the human brain and that the temporal dynamics of neurovascular coupling can explain this effect. Cerebrospinal fluid flows around the brain to remove its waste products and maintain brain health. This study shows that driving neural activity via visual stimulation can rapidly induce large-scale fluid flow. Changes in brain hemodynamics can explain this pattern, providing a way to non-invasively manipulate brain fluid dynamics in humans. Cerebrospinal fluid (CSF) circulates through the central nervous system, transporting solutes and clearing potentially harmful metabolic waste from brain tissue ,2. ReducSystemic physiological dynamics such as respiration and the cardiac cycle have long been known to drive CSF flow, as CSF pulses with each heartbeat and breath –16. RecePrevious work from both humans and animal models supports the existence of a neurally driven compensatory CSF flow mechanism. Local decreases in CSF volume have been observed during cerebral vasodilation evoked by various stimuli –22. In aHere, we manipulated neural activity in 3 independent experiments, each using high-intensity visual stimulation to test whether sensory-evoked neural activity could drive macroscopic CSF flow in the awake human brain. We used fast functional magnetic resonance imaging (fMRI) to simultaneously measure blood-oxygenation-level-dependent (BOLD) signals as well as CSF inflow in the fourth ventricle. Accelerated fMRI paradigms contain flow-related enhancement signals  in which—but not flicker frequency—was positively correlated with CSF flow, consistent with the temporal dynamics of neurovascular coupling serving as a key driver of CSF patterns. Finally, in Experiment 3, we found that macroscopic CSF flow is also coupled to systemic physiology, in parallel to the neurally driven flow during this high-intensity task condition. Together, our results show that large-scale changes in neural activity can drive macroscopic CSF flow in the human brain and elucidate the key properties of sensory stimulation that maximize flow.First, in Experiment 1, we measured neural, hemodynamic, and CSF signals during visual stimulation using simultaneous electroencephalography (EEG)-fMRI at high temporal resolution. We established a clear temporal sequence of events during stimulation, in which neural activity recruited large-scale cortical BOLD changes, which alternated with macroscopic CSF flow. Next, in Experiments 2 and 3, we used independent fMRI datasets to replicate our findings from Experiment 1 and manipulated stimulus parameters to test whether this pattern was consistent with a mechanism based in neurovascular coupling. We found that stimulus durationWe manipulated neural activity to test whether sensory-evoked neural activity could induce CSF flow locked to a visual stimulus . Prior wp = 0.0312, Wilcoxon signed-rank test). This stimulus-locked flow signal was not driven by motion artifacts . We conducted a third additional experiment and again replicated the visually induced CSF flow in the ventricle, in Experiment 3 . The results therefore replicated the finding that sensory stimuli induce large-scale CSF flow, and this property was robustly observed with distinct acquisition paradigms across 3 independent experiments.We then extracted CSF inflow signals from the fourth ventricle, allowing us to measure upwards CSF flow simultaneously with the cortical BOLD signal . We invertifacts . We thenrtifacts . We inveTo investigate the timing of this evoked flow across all experiments, we used a sliding window analysis and found a significant increase in upwards CSF flow between t = 18.5 s and 34.5 s, peaking at 25 s , cortical hemodynamics (using BOLD), and CSF flow obtained in Experiment 1. A potential mechanism by which neural activity could drive CSF flow is through inducing changes in blood volume via neurovascular coupling, as large-scale changes in blood volume should be compensated for by CSF flow to maintain intracranial pressure . Furtherp < 0.001, Pearson correlation). The CSF inflow signal was also anticorrelated with the amplitude envelope of the evoked occipital EEG signal . Examining this pattern across lags, we found that the CSF inflow signal was maximally anticorrelated (R = −0.85) with the BOLD signal at a lag of 3.25 s. To test our model of neurally driven CSF flow mediated by neurovascular coupling, we convolved the average visually evoked neural signal  with a standard hemodynamic response function to estimate the predicted BOLD signal, and then took the negative derivative of the estimated BOLD signal as the prediction of CSF flow . The evoked CSF flow was also significantly higher than baseline flow for all stimulus durations  except for the 0.17 s duration, which was not significant (p = 0.45). We next tested how CSF flow changed across stimulus durations and observed significantly larger CSF inflow responses to longer stimuli  stimuli inducing far smaller BOLD responses than long (16 s) stimuli –37. We t). We found an analogous pattern in the ventricle: the CSF signal amplitude also did not differ across stimulus frequencies . In addition, since autonomic changes contribute to CSF flow [We next investigated whether systemic physiology, rather than neurovascular coupling, could have induced these sensory-evoked CSF effects. Systemic physiological factors, such as systemic vasoconstriction and cardiovascular pulsatility, can drive widespread BOLD changes –42, leadCSF flow , we alsoWe tested whether a neural mechanism contributes to CSF flow in the awake human brain, using fast imaging to investigate the temporal dynamics of neural, hemodynamic, and CSF signals. Across three experiments, we found that neural activity evoked by high-intensity visual stimulation drove macroscopic CSF flow in the fourth ventricle. We identified a sequence of events that led to CSF flow, in which neural activity recruited widespread cortical BOLD changes, which were followed by CSF inflow. Furthermore, we found that modulating visual stimulus parameters consistently caused CSF flow responses that matched hemodynamic responses. These findings supported our hypothesis that neurovascular coupling that induces sufficiently large changes in blood volume—and in turn changes in the global BOLD signal—can drive waves of CSF flow.Our results from the simultaneous EEG-fMRI measurements in Experiment 1 suggested that CSF flow could be driven by manipulations of neural activity with high-intensity visual stimuli. In Experiments 2 and 3, we modulated the hemodynamic response dynamics by modifying visual stimulus parameters. Altering the duration of the stimulus profoundly affected CSF responses, with patterns consistently mirroring the hemodynamic response for each stimulus condition. However, altering the stimulus frequency of the visual stimulus did not significantly alter the global cortical signal response , nor the magnitude of CSF inflow. This finding is consistent with our hypothesis that CSF flow is tightly coupled to cerebral blood volume changes driven by neural activity, when changes in neural activity are sufficiently large and coherent across the brain.In keeping with this idea, our results are consistent with neural activity being one of multiple drivers of CSF flow, as under this model, any large-scale modulator of cerebral blood volume will also be expected to induce CSF flow. The effects of the cardiac and respiratory rhythms on CSF flow are well established –15. FurtDisentangling these mechanisms in resting-state, spontaneous data can be challenging due to the frequent collinearity of neural activity with systemic physiological state changes, which precludes simple regression models. Our use of sensory-evoked neural activity allowed us to separately investigate the contributions of physiological drivers of flow and neural drivers of flow, establishing a proof-of-concept. Our work thus highlights that neurovascular coupling is indeed one of the causal contributors to macroscopic CSF flow movement and can exert large effects on CSF flow even during wakefulness if a high-intensity, slow task design is used.Future work could investigate whether alternate stimuli, such as multisensory stimuli that engage larger swaths of cortex, could be used to manipulate CSF flow. Research in mice has shown that 40-Hz gamma entrainment with audiovisual stimulation can reduce phosphorylated tau and amyloid in mice –47. GammA key next question is what the physiological consequences of this macroscopic CSF flow are for waste clearance, as these experiments did not include measures of endogenous metabolite clearance, and the solute transport mechanisms of the brain remain a topic of debate ,49–52. COur results raise the intriguing question of why neural activity would be coupled to fluid flow—is this coupling an epiphenomenon, or does it serve a functional purpose to link these electrical and fluid systems? One possibility is that this mechanism enables neurons to exert spatial control over solute transport and fluid flow, with coordinated local neuronal activity inducing higher flow rates. In this scenario, neurons that were most active could theoretically induce higher local solute clearance when they cease firing. However, CSF flow was most tightly predicted by global hemodynamics, which are not always directly coupled to neuronal metabolic rate, as many large changes in neuronal activity will not necessarily induce a large hemodynamic response. In this scenario, the systemic drivers of CSF flow could act as a parallel mechanism to ensure fluid flow in cases where neurovascular coupling-driven flow is altered or reduced, such as in natural aging or in disease. Future work will be needed to investigate the functional consequences of this coupling.Taken together, these results demonstrate that CSF flow can be driven by inducing high-intensity visually evoked neural activity during the awake state in humans. We conclude that in addition to the well-established effects of systemic physiological factors such as respiration and vasoconstriction on CSF flow, neural activity and neurovascular coupling is an additional contributing mechanism that can drive fast, large-scale changes in CSF flow. Furthermore, our noninvasive approach provides an avenue to now test the integrity of this mechanism in clinical populations, to ultimately understand its consequences for brain function.3 isotopic multi-echo MPRAGE [7, with TR = 0.367 s, 2.5 mm3 isotropic voxels, 40 slices, Multiband factor = 8, matrix = 92 × 92, blipped CAIPI shift = FOV/4, flip angle = 32° to 37°, and no in-plane acceleration. EEG was acquired using MR-compatible 256-channel nets  at a sampling rate of 1,000 Hz. EEG acquisition was synchronized to the scanner 10 MHz clock and the scanner cryopump was turned off during the scans to reduce the vibrational artifact. A reference layer made of vinyl and conductive satin was used to acquire reference signals for EEG noise removal [Six healthy adults  were included. All subjects gave written informed consent to procedures approved by Massachusetts General Hospital’s Institutional Review Board (IRB #2014P001038). All procedures were in accordance with the Declaration of Helsinki. Scans were performed on a 3T Siemens Prisma scanner with a 64-channel head and neck coil. Anatomical scans used a 1 mmo MPRAGE . FunctioWe presented a counterphase flickering radial checkerboard using Matlab and Psychtoolbox . Each ru3 isotropic multi-echo MPRAGE [3 isotropic resolution .We analyzed a previously published dataset  of 20 heo MPRAGE . FunctioThe same flickering checkerboard stimulus as in Experiment 1 was used. The ON block duration for the fixed duration condition was 16 s. The ON block durations for the variable duration condition were 0.167, 0.5, 1, 2, or 4 s. An 8 s duration condition was also present but was not collected for all subjects so it was excluded from the duration analysis.3 isotropic T1-weighted multi-echo MPRAGE [3 isotropic voxels, 40 slices, Multiband factor = 8, blipped CAIPI shift = FOV/4, flip angle = 35° to 37°, and no in-plane acceleration. Additional sensors were used to record systemic physiology: Respiration was measured simultaneously using an MRI-safe pneumatic respiration transducer belt around the abdomen and pulse was measured with a photoplethysmogram (PPG) transducer . Physiological signals were acquired at 2,000 Hz using Acqknowledge software and were aligned with MRI data using triggers sent by the MRI scanner.We obtained written informed consent from 17 healthy young adults, and 16 were included in our final analysis . One subject was excluded because they did not complete the full set of task runs. The protocol was approved by the Boston University Charles River Campus Institutional Review Board (IRB #5059E and #5023E). All procedures were in accordance with the Declaration of Helsinki. Participants were scanned on a 3T Siemens Prisma scanner with a 64-channel head and neck coil. Anatomical runs were acquired using a 1 mmo MPRAGE . FunctioWe presented a counterphase flickering checkerboard visual stimuli using Matlab and Psychtoolbox . The stiEEG preprocessing was performed as described in detail in Fultz and colleagues . Gradienα1 = 6, β1 = 1, and Γ represents the gamma function [A is the amplitude, which we set to equal 5. Finally, to produce a predicted CSF signal, we took the negative derivative of the estimated BOLD signal, approximating flow changes.In Experiment 1, we selected the occipital EEG channel closest to Oz with good signal quality for each subject, and bandpass filtered the signal at the stimulus frequency for each run. We then extracted the instantaneous amplitude envelope of the band-passed signal using the Hilbert transform. For the cross-correlation analysis, the envelope of the EEG data was first downsampled to match the resolution of the upsampled fMRI data (upsampled sampling frequency = 4 Hz). Next, to generate a prediction of the BOLD signal, the amplitude envelope was convolved with a gamma function using the following equation:function . A is thhttps://fsl.fmrib.ox.ac.uk/fsl/fslwiki) [https://afni.nimh.nih.gov/). Each motion-corrected run was then registered to the anatomical data using boundary-based registration (bbregister) [The cortical surface was reconstructed from the MPRAGE volume using recon-all from Freesurfer version 7 . All funfslwiki)  and motiegister) .p < 0.05.For the higher level FEAT analysis, functional runs were registered to 2 mm MNI common space and registrations were manually checked for accuracy. The linear functional to anatomical bbregister matrices were converted to FSL compatible matrices. The anatomical scan was then warped into 2 mm MNI space using nonlinear registration (FNIRT) that was initialized with linear transform matrices (FLIRT). Subject-level averages to the visual stimulus were extracted using a fixed effects model with the canonical double gamma hemodynamic response function and its temporal derivative. The group-level mean responses to the stimulus were extracted with a FLAME mixed effects model. Z-statistic images were thresholded using clusters determined by Z > 3.1 and a corrected significance threshold of We defined the left and right hemisphere cortical gray matter regions of interest (ROIs) using the automatically generated Freesurfer-derived segmentations of cortical gray matter . We alsoTo identify the CSF ROI, we manually traced the intersection of the fourth ventricle with the bottom slice of the imaging frame for each run for each subject. We extracted the mean signal in this region as the CSF inflow signal. All CSF inflow time series were converted to percent signal change by dividing by the value of the time series that represented the bottom 15th percentile value . All time series were upsampled to a new sampling frequency of 4 Hz using spline interpolation before stimulus-locked averages were calculated.p-value threshold = 0.0024  to correct for multiple comparisons across time windows.We calculated the stimulus-locked CSF flow response to visual stimuli by averaging the CSF time series locked to each stimulus onset. We used a Wilcoxon signed-rank test to test whether the CSF inflow signal evoked by the neural manipulation was significantly different from baseline CSF inflow, by comparing the median CSF value in the 4 to 16 s range after stimulus onset, to the median CSF flow in the 4 to 16 s range after stimulus offset. To identify the specific time windows during which CSF flow increased significantly , we combn = 596, higher trials n = 405). The global cortical and visual cortical time series for each trial were averaged across the 2 categories.To test whether evoked CSF was more strongly driven by differences in visual cortex versus global cortex, we split all 1,001 trials from Experiment 3 into 2 categories  using a threshold cutoff of 95% for high-flow trials. The threshold was set individually for each run as the 95% percentile of the time series. This threshold was chosen to give a roughly even split between the 2 categories  of subjects in Experiment 2 viewed stimuli of multiple durations with long ISIs ranging from 17 s to 21 s, and these subjects were used in the duration analysis. To normalize the CSF signal across individuals, the bottom 15th percentile of values of a run was taken as the baseline. Each run time series was divided by the baseline to convert to percent signal change. Delta functions lasting 0.25 s each were placed beginning at stimulus onset and deconvolved to extract a trial response for each stimulus duration. We used the following windows around each stimulus onset to extract trial responses for cortical gray matter and CSF flow: [A subgroup n =  of subjeSF flow: 141417To quantify differences in the magnitudes of CSF and BOLD trial response for each duration, we calculated the areas under the average response waveform separately for each duration. The area under the curve for CSF responses was calculated between t = 5 s and t = 141417t test. We defined “baseline” as t = 0 to t = 5 s for CSF traces, and t = 0 to t = 2 s for cortical BOLD traces. We averaged over the remaining time period to estimate the evoked response. For CSF, the response window was defined t = 2 s to t = [To test whether evoked CSF flow and BOLD responses were significant, we tested whether the average deconvolved response function during a defined baseline period was significantly different from the average value during the response window for each subject using a paired s to t = 141417We calculated the group mean waveform for each stimulus frequency and smoothed the resulting waveform using a sliding 5-s window. BOLD and CSF waveforms were baseline corrected separately. The baseline value was taken at t = 2 s for the BOLD waveform and at t = 5 s for the CSF waveform. We calculated the area between the evoked CSF and BOLD curves in a 24-s window  Tissue within the functional imaging volume (yellow) becomes saturated after experiencing multiple radiofrequency (RF) pulses. Fresh CSF (purple) that flows into the imaging volume has not experienced any RF pulses and can be detected as bright signals at the edge slices of the image volume, which is intentionally positioned in the fourth ventricle to capture fluid flow. The signal intensity changes from incoming fresh fluid are due to flow-related enhancement (FRE). (B) CSF (see arrow) is visible in the fourth ventricle as it flows upwards into the fourth ventricle. (C) Schematic of how CSF flow is reflected in fMRI FRE signals. Top—the true CSF velocity at the edge of the imaging volume consists of both positive (inflow) and negative (outflow) flow. Bottom—CSF measured via flow-related enhancement is only detected as it moves upwards into the imaging frame. Periods of outflow are not detected. Three example time points with no inflow (t1), slow inflow (t2), and fast inflow (t3) are indicated with dots. (D) Schematic of how flow signals appear in the edge slices of the imaging volume. Low-velocity flow (t2) is visible in only bottom slices as it travels slowly, experiencing an RF pulse and reaching steady state before the fluid reaches other slices. This results in bright flow signals in only the lowest slices of the volume. High-velocity flow (t3) travels across several slices before reaching steady state, as it flows farther before experiencing RF pulses. This results in bright CSF signals in several slices .(PDF)Click here for additional data file.S2 Fig(A) An example CSF trace across an entire run shows distinct inflow periods that do not overlap with periods of higher motion . (B) The distribution of correlation coefficients between CSF inflow traces and framewise displacement across all runs for all subjects show low correlations between flow and motion time series (mean correlation = 0.03).(PDF)Click here for additional data file.S3 Fign = 42), with no temporal smoothing. Shading indicates standard error across subjects. A sliding window analysis was used to test for significant flow changes in 1-s windows; green star indicates periods of CSF flow that differed significantly from baseline flow .Average CSF flow across all subjects ((PDF)Click here for additional data file.S4 Fig(A) Average CSF flow (purple) for high-flow trials (frames with flow above 95% percentile) and low-flow trials (dotted line). (B) Average global cortical BOLD responses sorted by high-flow and low-flow trials show a large difference in the cortical trace between trial types. (C) Average primary visual cortex BOLD responses sorted by CSF flow trial type show small differences between trial types. Error bars are standard error across trials.(PDF)Click here for additional data file.S5 FigTop: The bandpass-filtered EEG signal (blue) from an occipital channel in 1 example subject from the block design visual stimulus, flickering at 12 Hz. Overlayed on the filtered voltage trace is the amplitude envelope (orange) that shows the clear increases in the evoked EEG response during each stimulation period. Bottom: The CSF flow signal (purple) shows peaks following the decay of the cortical signal and is suppressed during on blocks when the cortical signal is high. The primary visual cortex (V1) signal (green) shows large responses to the visual stimulus as expected.(PDF)Click here for additional data file.


Previous studies have shown that patients with a history of atrial fibrillation (AF) have a higher risk of developing coronary slow flow (CSF). However, whether AF episode status affects the incidence of CSF has not been confirmed. This study investigated the correlation between AF episode status and the incidence of CSF.We enrolled patients with AF who underwent coronary angiography for symptoms of myocardial ischemia between January 1, 2017, and April 30, 2022, at our institution and classified them according to whether they had an episode of AF in the perioperative period. The outcomes were defined the occurrence of CSF overall and in each of the three coronary arteries. The analysis was repeated after adjusting the baseline information by the propensity score matching method in a 1:1 ratio.P = 0.010, OR = 2.327, 95% CI: 1.226–4.416) than in the non-episode group.214 patients who met the inclusion and exclusion criteria were included in the study . Before matching, age, left atrial size, ejection fraction, heart rate, CSF incidence, and mean corrected thrombolysis in myocardial infarction frame counts were higher in patients with intraoperative AF episodes than in patients without episodes. To prevent the dependent variable (CSF incidence) from being confounded by confounding factors, we matched the two groups for age, left atrial size, and ejection fraction. In the logistic regression analysis, the incidence of CSF was significantly higher in the intraoperative AF episode group (In patients with AF, AF episode status is significantly correlated with an increased overall incidence of CSF. AccoCoronary slow flow (CSF) is a specific phenomenon of coronary microcirculatory dysfunction which is characteristic of delayed distal perfusion of the vessel in the absence of significant epicardial coronary stenosis . It may 2.2.1.In this retrospective cohort study, we included patients with AF who underwent coronary angiography for symptoms of myocardial ischemia   from Jan2.2.The following information was collected from the electronic medical record system of patients who met the inclusion criteria: general clinical data , personal history , cardiac ultrasound indices , and laboratory indices . We observed the coronary angiography videos of all the patients and analyzed them with the procedure and nursing records to determine whether the patients had AF episodes. Moreover, we collected the intraoperative mean heart rate, systolic blood pressure, diastolic blood pressure, and overall CSF occurrence, in each patient as well as each coronary artery's diameter, myocardial bridge, and CSF occurrence.2.3.This study defined CSF according to the TIMI test and the CTFC method. All angiograms were performed using the standard Judkins technique  and evalAccording to Gibson et al. a mean CTFC of more than 27 frames in three coronary arteries was defined as CSF. The CTFC cut-off values for each coronary artery were 21.3 ± 1.5 frames for the LAD, 22.2 ± 4.1 frames for the left circumflex coronary artery (LCX), and 20.4 ± 3 frames for the right coronary artery (RCA). When the CTFC was more than 2 standard deviations of these means then CSF was said to occur in those coronary arteries .2.4.The diameter of each coronary artery in the coronary angiography video was measured by two trained independent observers using the MicroDicom DICOM viewer 3.4.7 under clinical data confidentiality. The widest dimension of the proximal coronary artery was measured in diastole according to the methodology of Lip et al. . The dia2.5.t test or nonparametric tests. Categorical data was expressed using percentages, and differences between the two groups were compared using the chi-square test. Before and after PSM, factors associated with intraoperative AF episode status were analyzed using logistic regression analyses. After matching was completed, standardized mean differences (SMD) evaluated the balance of covariates. All tests were two-tailed, and a P value of less than 0.05 was considered to be statistically significant.The data was analyzed using IBM SPSS Statistics for Windows, version 26.0  and R software version 4.2.1. We grouped patients according to whether they were in an AF episode state during the perioperative period. Patients in different groups were matched in a 1:1 ratio using propensity score matching (PSM) to reduce baseline differences according to the methodology of the study by Teoh AYB et al. , 20. We 3.3.1.P = 0.002) and had a larger left atrial size  and ejection fraction . Other general clinical data , personal history , and laboratory parameters  were not statistically significant in both groups . 172 patients were included in this study's experimental and control groups in a 1:1 ratio. 42 patients were excluded because they were not successfully matched. Baseline information was not statistically significant in either group after PSM .3.2.P < 0.05). We, therefore, included these factors in a multifactorial logistic regression analysis and found that their statistical significance remained highly significant  was higher in the AF episode group compared with the control group. To exclude confounding factors for the dependent variable , we matched age, left atrial size, and ejection fraction in both groups. The final baseline information obtained for both groups was balanced  than in the non-episode group (The primary outcome indicators for this study were overall CSF occurrence and mean CTFC, while secondary outcome indicators were CSF occurrence and mean CTFC of each coronary artery. Before PSM, age, left atrial size, ejection fraction, mean intraoperative heart rate, and overall CSF incidence in the intraoperative AF group was statistically significant between the two groups (nificant . The ovebalanced . Becausebalanced –23. The de group . Howeverde group . Therefo4.Previous studies have shown that patients with a history of AF have a higher incidence of CSF . This fiBased on the presentation and duration of AF, AF is commonly classified into four subtypes: paroxysmal, persistent, long-term persistent, and permanent . In expeIn this study, AF events were defined as those being in a continuous state of AF during the perioperative period rather than as acute occurrences. During the compensatory phase of a sustained AF episode, atrial remodeling decreases the energy expenditure and oxygen demand of the atria. Electrical remodeling, especially the reduction of calcium currents, strongly reduces the contractility of the atria . Range eFurthermore, it has been suggested that the decrease in coronary blood flow may be related more to the change in RR interval. Kochiadakis et al.  found a This study has several limitations. First, coronary angiography cannot quantitatively assess the degree of vessel tortuosity and calcification. Subjective judgments are biased; hence, we did not use data in this regard. Second, our center only assesses the flow reserve fraction in patients with stenosis greater than 50% and lacks data on intraoperative coronary flow reserve. Third, our sample size could not be further expanded, and this study should be considered a pilot report.5.Our study shows that in patients with AF, AF episode status is significantly correlated with an increased overall incidence of CSF. The mechanism may be related to loss of normal atrial systolic function, dysregulation of ventricular rhythm.


The control group (n = 18) received a sham treatment of TECAR therapy  in combination with real FM. The primary outcome was muscle tone of the lower limb muscles assessed with the Modified Ashworth Scale (MAS). The secondary outcomes were goniometric degrees of the MAS (goniometer), neuromuscular properties of the gastrocnemius/quadriceps (myotonometer), and passive range of motion (inclinometer). All measurements were performed at baseline (T0), immediately after treatment (T1), and at 30 min post-treatment (T2) by a blinded assessor. Results: The MAS score ankle dorsiflexion significantly decreased at T0–T1 (p = 0.046), and the change was maintained at T0–T2 (p = 0.019) in the experimental group. Significant improvements were noted in the passive range of motion for knee flexion (p = 0.012) and ankle dorsiflexion (p = 0.034) at T2. In addition, knee flexion improved at T1 (p = 0.019). Conclusion: A single session of Tecar therapy at the same time with FM on the gastrocnemius and rectus femoris immediately reduces muscle tone and increases the passive range of motion of both ankle and knee in chronic stroke survivors. There were no significant changes in the neuromuscular properties measured with myotonometer.Background: The aim of this study was to assess changes in muscle properties after a single session of capacitive and resistive energetic transfer (TECAR) therapy on spastic gastrocnemius and quadriceps muscles in chronic post-stroke. Methods: A total of 36 chronic stroke survivors with lower limb hypertonia were enrolled in a double-blind randomized controlled trial. The experimental group ( Spasticity is the most common sequel of stroke. It has a severe impact on motor and functional recovery . There iAccording to Kuo. et al. , the bioCommon lower limb muscle involvement of spasticity includes ankle plantar flexors and knee extensors, amongst other muscle groups . SpasticTecar therapy (TT) is another technique that reduces muscle stiffness  and imprIt is important to highlight that secondary musculoskeletal problems can hopefully be prevented, and more effective rehabilitation treatment will optimize recovery . There iTherefore, the aim of this study is to assess changes in muscle tone, passive range of motion, and mechanical properties that occur with a single TT session, in spastic gastrocnemius and quadriceps muscles of chronic stroke survivors, as an adjunct to FM.www.clinicaltrials.gov (accessed on 23 March 2023) under number NCT04824768. CONSORT 2010 and TIDieR guidelines were followed.A randomized double-blind controlled clinical trial was carried out in the laboratory of the Universitat Internacional de Catalunya. This study was approved by the local ethics committee of the university—Research Ethics Committee (FIS-2021-06)—according to the Declaration of Helsinki , and registered at The sample size was calculated based on the article by Lee et al.  for MAS Chronic stroke volunteers were recruited from different neurorehabilitation clinics and associations in the Catalunya (Spain) area from May 2021 to May 2022.Inclusion criteria were the following: (1) chronic stroke survivors (6 months post-stroke); (2) age >18 years; (3) score of 1–3 points on the Modified Ashworth Scale (MAS) ,27 on hiThe randomization was performed with OxMar computer software by a researcher who was not involved in data collection. The allocation concealment of the sequence was performed with opaque and numbered envelopes. Participants were randomly assigned to two groups. Both groups received FM with the mobile resistive/capacitive electrodes, and at the same time, the experimental group received TT, and the control group received the sham TT. The TT treatment, in combination with FM, was applied to the quadriceps, gastrocnemius, and Achilles tendon of the affected leg with the T-plus device .The experimental group received the procedure and dosage detailed below. The participant was in a prone position. A fixed electrode was set under the participant’s abdomen. The protocol started with massage and TT in the resistive mode  in the lumbar area, followed by massage and TT in the resistive mode  in the hamstrings of the affected leg. We continued in the gastrocnemius area with FM and TT in the same resistive mode , followed by FM and TT in the capacitive mode in the same region .The patient was moved to a supine position with the electrode fixed on the lumbar area. FM and TT in the resistive mode  were performed on the quadriceps, ending the session with FM and TT in the capacitive mode in the same region . The session lasted approximately 30 min. A “Thermocomed” digital thermometer (precision ±0.3° Celsius) was used to measure the surface temperature of the affected lower limb during the treatment.The same steps of the experimental group were followed for the control group but with sham TT (W/VA). To blind the participant to whether the electrode was generating a dose, we preheated it to provide a slight cutaneous thermal sensation (Beurer HK Comfort heat mat). A blinded assessor (RN) collected and recorded the measurements. All outcomes were measured at baseline (T0), immediately after the intervention (T1), and 30 min at the end-intervention (T2). The entire procedure lasted approximately 90 min. Although TT can significantly increase skin temperature , the dosNominal and clinical data were recorded prior to the measurement of motor functions. The outcome assessment procedure was carried out in the following order.Muscle properties of gastrocnemius and quadriceps muscles were assessed by myotonometry with MyotonPro  . The MyoPassive range of motion (PROM) at the end-feel of the ankle and knee was measured using an inclinometer (Clinometer Smartphone Application TM 4.9.2). To determine the strength, a handheld dynamometer  was used. The participant rested in a supine position with the knee straight on the treatment table to measure the ankle PROM. The assessor applied the maximum force against the metatarsal base with the dynamometer to assess at T0 A, and thMuscle tone was assessed with MAS. It is the most universally accepted clinical tool used to measure increases in muscle tone . The MASDegrees of the MAS for hip flexion, knee flexion, and ankle dorsiflexion were assessed with a long arm universal goniometer . The participant was lying in lateral decubitus position, with hip and knee at 0°, and then the assessor slowly moved their leg to maximum passive hip flexion, knee flexion, and ankle dorsiflexion. The assessor performed the respective measurements with the goniometer.Statistical analysis was performed with IBM SPSS Statistic version 26.0  to assess group differences in the variables at each time interval. A descriptive analysis was conducted. The mean and standard deviation were calculated for the quantitative variables. Frequencies were calculated for demographic and anthropologic qualitative variables. The Shapiro–Wilk test was used to determine non-normal distribution of quantitative data.A repeated-measures analysis of variance (ANOVA) with time  and group  was conducted to determine changes in the outcomes of each dependent variable  at each time interval. If the assumption of the sphericity test was not satisfied, the Greenhouse–Geisser correction was used for interpretation. When a statistically significant effect was observed, a post hoc analysis was performed, and the Bonferroni correction was used to adjust for multiple comparisons. For the qualitative variable, MAS, McNeimar’s test was used for the within-group analysis, and Fisher’s exact statistic for the between-group analysis.p < 0.05.All individuals originally enrolled were included in the final analysis as planned. Effect sizes were calculated using eta squared (ŋ2), considering an effect size of >0.14 as large, around 0.06 as medium, and <0.01 as small. The level of significance was set at Of 44 volunteers  recruited, 2 females and 6 males did not meet the inclusion or exclusion criteria. Two participants scored >2, and one scored <1 on the Modified Ashworth Scale. One participant carried osteosynthetic material that was incompatible with Tecar therapy. The remaining three excluded participants were in the subacute phase of stroke. Thus, this study involved 36 participants . The mean age was 58.6 ± 11.3 years. There were no dropouts for the 90 min after measurements. There were no significant differences between the two groups for any demographic or baseline measures . The comp = 0.046) and between T0 and T2 (p = 0.019). No statistically significant changes were observed for MAS hip flexion or MAS knee flexion  (p = 0.004) (p = 0.016) and between T2 and T0 (p = 0.000) (p = 0.005) and between T0 and T2 (p = 0.002). (p = 0.022) (p = 0.003)  . In the = 0.004) . For MAS= 0.000) . In the  0.002). . The MAS= 0.022) . In the = 0.003) .p = 0.034). In the within-group analysis, significant improvement was observed in the experimental group between T1 and T0 (p = 0.028) and between T2 and T0 (p = 0.033) (p = 0.012) and between T2 and T0 (p = 0.019). In the within-group analysis, no statistically significant changes were observed in both groups  . In the h groups .p = 0.021). There were no significant improvements in the stiffness of gastrocnemius lateralis or quadriceps, neither in the between-group nor within-group analysis in both groups , assessed by myotonometry, except for gastrocnemius medialis stiffness in the experimental group at the end of the intervention.To the best of our knowledge, the effects of TT, in addition to FM, have not been assessed on the neuromuscular properties of post-stroke spastic muscles in previous studies. Therefore, it has not been possible to compare our results with other similar studies. Although the MAS is the most accepted clinical tool that measures resistance to passive movement due to excess muscle tone, it has shown several limitations since it is a subjective method based on the experience of the assessor ,32. HoweWe have included the MAS degree variable in this study. It has provided additional objective information regarding muscle tone. Both the MAS score and the MAS degrees of ankle dorsiflexion improved in the experimental group; however, although the MAS score of the knee and hip flexion did not change, the MAS degrees showed improvement in the experimental group. Vidmar et al.  showed tPre- and post-treatment findings revealed no differences for the control group for any of the variables in this study. Only the experimental group showed significant improvements in MAS score, MAS degrees, and PROM, so the combination of TT with FM could exert more changes in muscle properties than FM alone.Stretching appears to have no benefit for neurological disorders like stroke or spinal cord injury . It is nOur study revealed fascicle lengthening of the calf muscles associated with the increased ankle joint range of motion. Different results were obtained in the knee where only the MAS degrees, but not the MAS score, for hip and knee flexion improved in the experimental group. These results could be explained by the greater thickness and extension of the quadriceps compared to the calf muscles, the latter obtaining greater benefits with the same treatment time. Furthermore, less muscle mass and more intramuscular fat have been recently found in the paretic quadriceps of chronic stroke survivors ,44. TT tSpasticity, disuse, and lack of activity following stroke produce adaptive changes in the biomechanics, anatomy, and functionality of the musculoskeletal and nervous systems. According to Bavikatte et al. , early dIt is also important to highlight that TT generates a thermotherapeutic effect in deep muscle layers, joints, and tendons without excessively increasing skin temperature. In this respect, TT was highly tolerable for our patients. On the other hand, a prospective study by Wissel et al.  reportedThis study has limitations. Firstly, the sample is too small to draw general conclusions. Secondly, we only provided results of the immediate effects of a single session. The reason was to have more control over factors that could mask the technique. This was achieved by continuous monitoring of the subjects. We also wanted to know whether there were any adverse effects with this first study. However, more studies in usual clinical conditions are needed. Finally, as the effects of TT plus FM were analyzed in chronic stroke survivors, we could not collect information regarding the subacute phase.Further studies are needed, with a larger sample and a greater number of sessions, to be able to fully assess the effects of TT on the neuromuscular properties of chronic stroke survivors. In future studies, it would be interesting to consider the subacute stage of stroke, as well as to conduct the study in the upper limb, where the prevalence of post-stroke spasticity is higher.According to our results, a single session of TT in combination with FM can immediately increase ankle and knee passive range of motion and reduce muscle tone of gastrocnemius and rectus femoris muscles in chronic stroke survivors. No adverse events were observed in the application of TT plus FM, and the participants rated the treatment as satisfactory.


Using median values of CSF chloride (123.2 mmol/L) as a cut-off, patients with CSF chloride level ≥ 123.2 mmol/L had a 120% increased relapse risk compared with those with CSF chloride level < 123.2 mmol/L . Conclusions: Elevated CSF chloride levels might be a biologically unfavorable predictive factor for disease relapse in RRMS.Background: Blood-brain barrier dysfunction in active multiple sclerosis (MS) lesions leads to pathological changes in the cerebrospinal fluid (CSF). This study aimed to investigate the possible association between routine CSF findings, especially CSF chloride, at the time of the first lumbar puncture and the relapse risk and disability progression of relapsing–remitting MS (RRMS). Methods: This retrospective study included 77 patients with RRMS at the MS Center of our institution from January 2012 to December 2020. The Anderson and Gill (AG) model and Spearman correlation analysis were used to explore predictors of relapse and disability during follow-up. Results: In the multivariate AG model, patients with elevated CSF chloride level (hazard ratio [HR], 1.1; 95% confidence interval [CI]: 1.06–1.22;  Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS). It is the primary cause of non-traumatic neurological disability among young adults, with a higher prevalence observed in women. The prevalence of MS varies globally, with the highest prevalence reported in northern regions and lower prevalence observed in equatorial countries. Recent data suggest that the prevalence of MS has been on the rise over the last few decades .MS has three distinct clinical courses: relapsing–remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). In addition, clinically isolated syndrome (CIS) often progresses to MS, especially when symptoms are accompanied by CNS lesions. RRMS is the most common phenotype  and is cRelapses are associated with a considerable increase in economic costs as well as a deterioration in health-related quality of life and functional abilities, which are some of the biggest concerns associated with the disease . RRMS caCurrently, RRMS remains incurable due to the unclear pathogenesis. However, with the development of increasingly effective therapies for RRMS, disease-modifying therapies could modify the course of disease through suppression or modulation of immune function ,7. They The diagnosis of MS typically involves a comprehensive evaluation of the patient’s medical history and a neurological examination, which aims to determine if there is dissemination in time and space of certain clinical symptoms while excluding other conditions with similar symptoms. Supportive diagnostic evidence may be obtained through paraclinical tests including Magnetic Resonance Imaging (MRI), evoked potential studies, and analysis of cerebrospinal fluid (CSF). These tests can provide supportive diagnostic information that helps clinicians confirm or rule out a diagnosis of MS . RecentlCerebrospinal fluid (CSF) analysis is a diagnostic or evaluative tool for many conditions affecting the CNS ; it has CSF chloride is a measure of the concentration of chloride ions present in the cerebrospinal fluid that surrounds the brain and spinal cord. It is an important electrolyte in the CSF and plays a role in maintaining the proper balance of fluids and electrolytes in the central nervous system. Abnormal levels of CSF chloride may indicate underlying neurological conditions ,18 such Chloride ions are the primary permeant anions in mammals, and homeostasis of their flux across cell membranes is important for a range of neurophysiological processes ,20,21. TTherefore, this study aimed to investigate the possible association between routine CSF findings , especially CSF chloride, and the relapse risk and disability progression of MS.This retrospective study, which followed the STROBE guidelines , was appWe retrospectively reviewed the clinical data of 335 patients with MS who attended the Neurology Department of the Third Affiliated Hospital of Sun Yat-sen University from January 2012 to December 2020. We included patients of all ages who fulfilled all the following criteria: diagnosed with RRMS according to the 2017 modified McDonald criteria [We collected the demographic and clinical data of eligible patients, including age at disease onset, sex, disease course phenotype, maintenance therapy, subsequent relapse , expanded disability status scale (EDSS) score, and laboratory examination data. Baseline characteristics were collected when patients were admitted for treatment due to a first attack or relapse during the study period and all relapses were recorded and archived by patient medical records during the follow-up period. For an individual subject, regular follow-up is set at 3 months, 6 months, and 1 year after the first day of MS diagnosis. If symptoms are stable, maintain annual follow-up. At least one senior neurologist calculated the EDSS score throughout the disease duration period.CSF was evaluated for the number of white blood cells, protein (g/L), chlorine and glucose levels (mmol/L), and quotient of CSF and serum glucose, chlorine, and protein levels. For analysis, maintenance therapies were classified into two categories: disease-modifying therapies (DMTs) such as interferon beta, fingolimod, mitoxantrone, rituximab, and dimethyl fumarate, and non-DMTs, such as azathioprine, mycophenolate mofetil, methotrexate, tacrolimus, cyclophosphamide, corticosteroids, and intravenous immunoglobulin administration. The duration of MS was calculated from the time of the patient-reported first clinical manifestation of the disease.Attack/relapse was defined as a monophasic clinical episode with patient-reported symptoms, increase in EDSS, and objective findings reflecting a focal or multifocal inflammatory demyelinating event in the central nervous system, developing acutely or sub-acutely, with a duration of at least 24 h, with or without recovery, and in the absence of fever or infection . ‘First Disease progression was evaluated by calculating multiple sclerosis severity score (MSSS), which is an algorithm that relates EDSS scores to the distribution of disability in patients with comparable disease duration .Baseline characteristics, including patient demographics, baseline EDSS score, annualized relapse rate, laboratory values at the time of the first LP, time between the first attack and LP, and maintenance therapies, are presented as counts and percentages for discrete variables and median  for continuous data. The correlation between the MSSS and CSF findings for the entire study population was calculated using the Spearman correlation coefficient. Survival curves were generated by estimating the cumulative hazard to reach the first relapse for RRMS patients stratified by the median of CSF findings using the Kaplan–Meier method expressing 95% confidence intervals (CIs) with the Survminer package .To assess the risk of relapse over the entire disease course in patients, the Anderson and Gill model was used using the survival package ,31,32. Uhttp://www.r-project.org/ (accessed on 1 November 2020)), and p-values < 0.05 were considered significant.All statistical analyzes were performed using R version 4.0.3  who underwent LP at the first clinical episode, with a mean age of 28.8 ± 12.6 years. The mean follow-up period was 57.2 ± 19.7 months (range: 22.1–97.7 months).sr = 0.23; p = 0.040). No significant difference was noted in CSF findings between male and female patients. The demographics and CSF results at the time of the LP are summarized in At the time of the first LP in our cohort, the CSF chloride levels were in the range of 117.4–130.0 mmol/L. The range of the CSF leukocyte count was 0–28.0 cells/µL and correlated with CSF chloride level . Overall, 45 patients (58.4%) had at least one relapse, and From univariate analysis, the risk of relapse decreased with the age of onset. Patients not treated with DMT had a greater risk of relapse over the entire disease course than those treated with DMT . In addiIn the multivariate analysis, the model was adjusted by including age at onset, sex, and maintenance treatment. Elevated CSF chloride level, CSF glucose level, CSF white blood cell (WBC) count, serum protein level, and protein quotient level were associated with a high risk of relapse. However, the remaining serum and quotient indicators had no significant effect on the risk of relapse .p = 0.012). Patients with CSF WBC count ≥ 2 cells/µL had an 84% increased risk of relapse compared with those with CSF WBC count < 2 cells/µL . Patients with CSF glucose level ≥ 3.3 mmol/L had a 141% increased risk of relapse compared with those with CSF glucose level < 3.3 mmol/L . The cumulative hazard of the relapse events is shown in To distinguish the potential relapse risk of patients with MS, we used the median values of CSF findings as cut-off values. Patients with CSF chloride level ≥ 123.2 mmol/L had a 120% increased risk of relapse compared with those with CSF chloride level < 123.2 mmol/L  were likely to show a high risk of relapse, indicating the need for a more active immunosuppressive treatment.


Tuberculous meningitis (TBM) mortality averages at 27% but may reach 70% in HIV co-infection. High MRC severity grade, lower cerebrospinal fluid (CSF) white blood cell count (WBC) count, low weight, low CD4 and low plasma sodium were linked to mortality in Vietnam. Prognostic factors in African adults with HIV-associated TBM are unknown. We sought to determine the baseline factors predictive of death in HIV-positive Ugandan adults with TBM.We prospectively enrolled patients who received TBM treatment and were classified as definite, probable or possible TBM by the uniform case definition from January 2019 to March 2023 in two National Referral Hospitals in Uganda. Participants received standard quadruple TB and corticosteroid therapy. We assessed association between baseline clinical and CSF characteristics , antiretroviral therapy (ART) status and 14-day mortality.In 261 participants, median age was 36 years, 46% were women, median CD4 count was 74 cells/µl. 27% had definite, 39% probable, and 34% possible TBM. 142 (54%) had baseline CSF WBC < 5, 50 (19%) had 5-100, and 69 (27%) had >100 cells/µl.Overall, 14-day mortality was 25.9%. Mortality was 73.6% in participants with CSF WBC count < 5, 7.5% in 5-100, and 18.9% in >100 cells/µl, p=0.0012. Factors associated with 14-day mortality were MRC severity grade, CSF WBC, CSF opening pressure (OP), CSF protein and glucose, CD4 count. ART status did not influence survival. The hazard of 14-day mortality was 4 times as high for those with CSF WBC < 5 cells/µl as for those with >100 cells/ µl . However, on adjustment for Glasgow Coma Scale (GCS), CSF OP, glucose, and CD4 count the association was less significant .14-day mortality varied significantly by baseline CSF WBC group, being extremely high (73.6%) in those with a paucity of CSF inflammation (WBC < 5 cells/µl). Those with intermediate inflammation (CSF WBC 5-100 cells/µl) had lowest mortality in-line with the damage response framework parabola. The association with acellular CSF and mortality was ameliorated by adjustment for CD4 count. CSF inflammation is at predictor of mortality in HIV-associated TBM and CSF WBC-directed corticosteroid therapy needs further exploration.All Authors: No reported disclosures


We present a case of a 63-year-old woman who experienced significant psychoemotional stress and was seen in the emergency department for an evaluation of chest pain. She was sent home after reassurance. Subsequent troponin levels came back above the normal range. The patient was called back to the hospital for further assessment, including a potential workup for the exclusion of acute coronary syndrome, given the existing risk factors, symptoms, and elevated cardiac enzymes. The patient has risk factors for atherosclerosis, including hypercholesterolemia, hypertension, and age. She has recently gone through hard personal, emotional, and psychosocial stress. She presented with atypical chest pain, subjective sense of breathlessness, and anxiety. She was reassured, had blood tests ordered, and was discharged after relative improvement. Later that day, her blood test results, which were taken earlier, showed elevated troponin levels. Therefore, she was asked to come back for a cardiology assessment and underwent coronary angiography, which showed normal patent coronary arteries. This case report highlights a patient with a non-cardiac elevation of troponin, emphasizing the importance of considering non-cardiac causes when interpreting elevated troponin levels. The objective of this report is to raise awareness among healthcare professionals regarding the potential causes of false troponin elevation and promote a comprehensive diagnostic approach to minimize unnecessary interventions. Elevated troponin levels are commonly associated with myocardial injury, particularly in the context of acute coronary syndrome. However, troponin elevations can also occur due to non-cardiac conditions, leading to diagnostic challenges. In this case report, we present a rare occurrence of a false elevation of troponin levels in a patient experiencing significant psychoemotional stress. Troponin is a cardiac biomarker commonly used to diagnose myocardial infarction (MI) and evaluate cardiac function. Elevated troponin levels are typically associated with cardiac injury or myocardial damage. However, in certain cases, troponin levels may be falsely elevated due to non-cardiac causes, including stress-induced myocardial stunning. Stress-induced myocardial stunning is a phenomenon characterized by reversible myocardial dysfunction in response to intense emotional or physical stress. It is commonly referred to as "broken heart syndrome" or takotsubo cardiomyopathy. This condition is often triggered by stressors such as the loss of a loved one, a traumatic event, or significant emotional distress. While the mechanisms underlying stress-induced myocardial stunning are not fully understood, it is believed that excessive catecholamine release and sympathetic hyperactivity play a significant role. These factors can lead to transient left ventricular dysfunction, resembling an acute coronary syndrome clinically and biochemically.Here, we present a case of a patient who presented with elevated troponin levels in the absence of any significant cardiac pathology. Through a thorough evaluation and assessment of the patient's history, we identified significant psychoemotional stress as the likely cause of the false elevation of troponin levels. This case highlights the importance of considering non-cardiac causes for elevated troponin levels, particularly in patients with a history of significant psychological stress .A 63-year-old woman with cardiovascular risk factors, including hypertension and hyperlipidemia, presented to the emergency department (ED) with emotional stress associated with atypical chest pain. Part of her evaluation included troponins and EKG without ST changes. Serial troponins showed an initial value of 84, after which she was reassured and discharged.The subsequent value came back 145, and she was contacted over the phone and advised to return for further evaluation. She was admitted overnight to the hospitalist service. A second EKG showed no changes compared to the initial EKG. An echocardiogram showed no wall motion abnormalities. Physical examination was normal. Heart sounds were rhythmic without murmurs, rubs, or gallops. The lungs were clear. There was no lower extremity edema and no elevation in the jugular venous pressure. Labs and imaging were reviewed. The assessment indicated that the patient has cardiovascular risk factors and significant elevation in troponin levels (a high delta between the first and third blood draws). We could not explain her elevated troponin to demand ischemia or other secondary causes. She did have elevated blood pressure on presentation, and she also had some complaints of intermittent palpitations, but there is no documentation of paroxysmal atrial arrhythmias or ventricular tachycardia. Her echocardiogram ruled out stress cardiomyopathy. For that reason, we recommended a coronary angiogram to definitively exclude coronary artery disease (CAD), spontaneous coronary artery dissection, or other coronary pathology, which revealed no evidence of significantly occlusive CAD. The patient's coronary angiogram shows the patent coronary blood vessels  diagnosis and improve patient care. It is essential for clinicians to consider the clinical context and potential confounding factors when interpreting troponin results. The use of high-sensitivity troponin assays has improved the accuracy of AMI diagnosis, but challenges still remain. Future research should focus on improving assay specificity, refining clinical algorithms, and evaluating the impact of different strategies on patient outcomes. By addressing false positives, clinicians can enhance the accuracy of AMI diagnosis and improve patient care.


IntroductionThe aim of the present study was to describe our institution’s nine years of experience in the endoscopic endonasal management of cerebrospinal fluid (CSF) rhinorrhea and to discuss the causes, sites, and outcomes. MethodologyThe medical records of patients diagnosed with CSF rhinorrhea in King Abdulaziz Medical City-Jeddah (KAMC-J) between 2014 and 2023 were retrospectively reviewed, and all relevant information including body mass index, medical and surgical history, and postoperative outcomes were obtained.Results2, and 33 Kg/m2 for the traumatic leaks, no statistically significant difference was noted. The cribriform plate was the most common site of leakage (65%). A multilayer surgical technique using facia lata graft with nasoseptal flap was the most common choice for reconstruction with a first-attempt success rate approximating 90%. A recurrence was observed in two patients only. No major complications were reported. The average length of stay was nine days.A total of 20 cases were included in the present study, sixteen (80%) of which were females and four (20%) were males. The mean age of participants was 42.59±13.9 years. Nine cases (45%) were spontaneous CSF rhinorrhea and 11 (55%) were traumatic; within the traumatic group, six cases (54%) were iatrogenic either following previous neurosurgery or functional endoscopic sinus surgery, while the remaining five cases were related to motor vehicle accidents. The mean body mass index for the spontaneous CSF leak was 32 Kg/mConclusionThe endoscopic endonasal repair of CSF leak is a safe and reliable procedure and is associated with high success rates and low risk of complications. Therefore, it should be preferred as a first-line treatment for CSF rhinorrhea. Cerebrospinal fluid (CSF) is a physiological fluid that forms a protective layer for the brain against acute changes and maintains intracranial pressure . It is sThe typical clinical presentation of CSF leak is clear, unilateral rhinorrhea, which is sometimes mixed with blood in traumatic etiologies; it is classically exacerbated by bending over or performing a Valsalva maneuver . The preA thorough history-taking remains one of the first and very important steps in the diagnostic algorithm of CSF rhinorrhea as it may uncover a history of trauma, meningitis, or surgery . ConfirmIn most cases, traumatic causes of CSF rhinorrhea can be managed conservatively through bed rest with or without placement of a lumbar drain, anti-emetics, stool softeners, and head elevation . HoweverVery few papers have been published locally, and little is known about the management trends of CSF rhinorrhea in Saudi Arabia -19. In tStudy subjects and siteThe present study included all patients with clinically and biochemically confirmed CSF rhinorrhea who presented to the department of Otolaryngology-Head & Neck Surgery or Neurosurgery at King Abdulaziz Medical City, Jeddah, Saudi Arabia between 2014 and 2023. The patients’ files were retrospectively reviewed for background data, radiological findings, surgical repair notes, outcome, and postoperative care. Statistical analysis has been performed using Statistical Package for Social Sciences (SPSS) version 29 . The present study has been ethically approved by the Institutional Review Board in King Abdullah International Medical Research Center (KAIMRC) with the number NRJ21J/217/09.Preoperative careA thorough clinical evaluation through proper history taking and physical examination was done prior to any investigation. After that, a careful assessment of the nasal cavities was performed in-office utilizing a variety of rigid and flexible nasal scopes. The presence of CSF rhinorrhea was then suspected upon the visualization of clear fluid drainage through the skull base. In some cases, a sample of the fluid was taken and B2 transferrin was then performed to confirm the nature of the fluid. Localization of the leak site was mainly performed by HRCT to visualize the defect site as well as other signs such as empty sella; however, there were some instances where MRI was utilized. All patients in the current study were managed by both Otolaryngology and Neurosurgery teams.Surgical techniqueAn endonasal endoscopic repair of CSF leak under general anaesthesia was attempted in all patients in the present study. Firstly, intra-venous antibiotics were given with the induction of anaesthesia, and then nasal mucosa was decongested by lidocaine or epinephrine-soaked tampons. Afterwards, an evaluation of the nasal cavity was done using both 0° and 30° rigid scope. In order to reach the defect site and achieve decent exposure, multiple methods of sinus dissection were employed. For defects in the medial aspects of the cribriform plate, a traditional anterior-posterior ethmoidectomy was performed, while defects in the fovea ethmoidalis or lateral side of cribriform plate require expansion of the ethmoidectomy and partial middle turbinectomy. For defects in the sphenoid sinus, there was no need to disrupt the ethmoidal sinus anatomy. Once the site of the defect is well exposed, preparation of the recipient bed involves careful debridement or cautery of surrounding mucosa and tissue to encourage successful graft integration, repair grafts were prepared and chosen based on the size of the defect. For small defects a two-layer approach was used, while larger defects employed a multilayered repair. A variety of graft materials have been used including fascia lata, pedicled nasoseptal flap, septal cartilage, and middle turbinate mucosa. Preservation of sinus drainage is of paramount importance to prevent postoperative complications such as infection or mucocele. Additionally, any encephaloceles encountered during the process are meticulously reduced and ablated using bipolar cautery, ensuring the safe and effective removal of these abnormal tissue growths. Finally, to achieve impermeable closure fibrin glue (Tisseel) was used between layers.Postoperative careAfter the procedure, all patients were instructed to avoid exertion and were confined to bed rest with head elevation for a minimum of 48 hours. Additionally, measures to prevent increased intracranial pressure were followed such as stool softeners, and instructions to avoid nose blowing, coughing, sneezing with mouth open, etc. Antibiotics were prescribed for all patients who underwent the surgery. The nasal packs were removed after three to five days. On one week follow-up any crustations were removed, and assessment of nasal cavity was reattempted. Frequent follow-ups were then offered for patients to assess for any recurrence through an endonasal endoscope.Demographic dataThe present chart review identified 20 patients who underwent endonasal endoscopic repair of CSF leak, of which 16 (80%) were females and four (20%) were males. Patients were classified according to etiology of CSF leak into traumatic and spontaneous groups. There were no significant differences in gender among the spontaneous and traumatic groups . The mean age of study participants was 42.59±13.9 years. The mean age of the traumatic group was 40.09±15.5 years while the mean age for the spontaneous group was 46.44±11.64 years. There was no statistically significant difference between the two groups regarding age . Demographic data and clinical characteristics are summarized in Table Presentation dataThe mean duration of CSF rhinorrhea in all patient groups was 515 days. The mean duration in the traumatic group was 716 days, while in the spontaneous group it was 270 days. There was no significant difference in the duration of CSF leak between the groups . A total of 10 (50%) patients had a past medical history of meningitis; four of which were in the spontaneous group and six in the traumatic group. In the traumatic group, four patients had a history of sinus surgery, and three patients had a history of previous neurosurgeries.EtiologyTraumatic causes of CSF rhinorrhea constituted 55% n=11) of the entire study population, of which six cases  in Table 1 of the Size and site of defectThe most common defect site was the cribriform plate 65%; n=13) followed by sphenoidal and fovea ethmoidalis each accounting for 15% (n=3), and the frontal bone was the least . Eighty-one percent of the anatomical defects in the traumatic group were localized to the cribriform plate, 9.1% in the frontal recess, and 9% in the sphenoidal bone. However, in the spontaneous group, four (44.4%) cases involved the cribriform plate, two cases 22.2%) in the sphenoidal bone, and three cases (33.3%) within the fovea ethmoidalis. There was no statistically significant difference in the distribution of leakage sites between the two groups . The mean defect size was 6.5mm±3.9 mm in all patient groups. In the traumatic group the mean defect size was estimated to be 7.5mm±5mm, with a maximum and minimum defect size approaching 20mm and 3mm, respectively. In the spontaneous group, the mean defect size was 5.3mm±1.22mm. There was no significant difference in the defect size between the groups . Distribution of defect sites and defect sites according to etiology of CSF leak are shown in Figure 3 followe2.2% in tBody mass indexThe mean body mass index (BMI) in the entire population was 33.16±7.2 Kg/m2. In the traumatic group the mean BMI was 33.86±8.6 Kg/m2, while in the spontaneous group it was approximately 32.3±5.3 Kg/m2. There was no significant difference between the two groups . The relationship between BMI and etiology of CSF leak is depicted in Figure Preoperative careNasal secretions were sent for B2 transferrin analysis in only nine (45%) cases. The diagnosis was achieved through CT scan in 18 (90%) cases, while MRI was needed only in two (10%) cases (cases 10 and 15) in Table Surgical managementThe overall success rate in our experience is approximately 90% with two cases of recurrent CSF leak recorded. Multiple different graft types were employed for the repair of the defect. In most cases a fascia lata graft with nasoseptal flap was used. In the other cases fascia lata was supported by middle turbinate graft, and in one case an inferior turbinate graft with TachoSil and NasoPore was used for closure of the defect. There were no major postoperative complications recorded except for one case where the patient developed meningitis after the surgery. The hospital stays postoperatively ranged from one day to 56 days with a mean of 9±11 days. The mean follow-up duration postoperatively was two years. There were no significant differences in the follow-up durations between the groups .The present study describes nine years of experience at a tertiary medical center with CSF rhinorrhea. The primary goal of this comprehensive review is to assess all potential causes of CSF rhinorrhea, the diagnostic methods used, the therapeutic strategy for patients at our center, and the prognosis of these patients as well as the recurrence rate. In this review, 20 patients were identified as CSF leak cases and underwent endonasal endoscopic repair. Our study observed that most of them were obese females (80%) which is consistent with the result reported in the literature [In our series, iatrogenic damage accounted for most cases with CSF leak. These findings are in accordance with findings reported by Al-Ghamdi et al. . Post-trTo prevent complications like meningitis and low-pressure headaches, it is crucial to correctly locate the CSF leak site and source and provide the required treatment . The cliSurgical treatment of CSF leak can be done by an intracranial or extracranial method. The extent and pathophysiology of the leak guided the decision. Management of CSF rhinorrhea by an intracranial approach has morbidity and failure rates ranging from 20 to 40% . EndoscoCSF rhinorrhea is a very rare condition caused by a variety of etiologies, most encountered in middle-aged obese female patients. Due to dangerous complications, the disease must be diagnosed and managed as soon as possible. In our department, iatrogenic trauma was the most prevalent cause of CSF rhinorrhea, and the cribriform plate was the most common defect site. In terms of management, the high overall rate of closure in this study demonstrates that the trans-nasal endoscopic method is a safe and effective surgical therapy for CSF rhinorrhea.


To elucidate the changes in coronal lumbar-pelvic-femoral alignment after conversion total hip arthroplasty (THA) in patients with unilateral ankylosed hip. A retrospective radiologic study of 48 patients (48 hips) with unilateral hip arthrodesis who underwent conversion THA was conducted. Cobb’s angle of lumbar scoliosis (LS), the pelvic obliquity (PO) angle, and the hip adduction angle (HAA) on standing anterior–posterior spine-pelvis-hip radiographs were measured before and after THA. The differences of LS, PO, and HAA before and after THA were defined as ΔLS, ΔPO, and ΔHAA, respectively. A paired samples t-test or the Wilcoxon signed-rank test were used to compare the absolute values of the LS, PO, and HAA between preoperative and postoperative groups. The Pearson’s correlation coefficient (r) or Spearman’s correlation coefficient (ρ) was calculated to assess the relationship between ΔLS, ΔPO, and ΔHAA and possible associated factors. Significant differences were found in the preoperative LS , PO , and HAA . ΔLS was correlated with the preoperative LS , PO , and HAA . ΔPO was correlated with the preoperative LS , PO , and HAA . ΔHAA was correlated with the preoperative LS , PO , and HAA . LS, PO, and HAA were significantly improved after conversion THA. Greater improvement in LS, PO, and HAA can be expected in patients with larger preoperative LS, PO, and HAA values. In contrast, an inadequate hip position frequently causes compensatory scoliosis  and/or pain in the adjacent joints  with time. These could be indications for conversion total hip arthroplasty (THA)12. In fact, conversion of hip arthrodesis to arthroplasty was found to result in pain relief in the adjacent joints in 66–100% of cases and patient satisfaction in 63–100% of cases12. Possible reasons for these improvements include the improvement of hip joint mobility and lumbosacral spine alignment and their associated reduction in load on the adjacent joints. However, the changes in coronal lumbar-pelvic-femoral alignment due to conversion of hip arthrodesis to movable arthroplasty remain unclear. This study therefore aimed to elucidate the changes in coronal lumbar-pelvic-femoral alignment after conversion THA in patients with unilateral ankylosed hip.An ankylosed hip is a painless joint due to complete immobilization with a patient satisfaction rate of 69–100%The Institutional Review Board of the University of Saga at Saga city approved this study and informed consent was obtained from all participants (Registration No.: 2015-12-13). This study also adhered to the principles of the Declaration of Helsinki. Written informed consent was obtained from all patients.This study employed a retrospective design. Of 1881 consecutive patients (2257 hips) who underwent THA with a posterior approach at our institution between February 2003 and January 2018, 48 patients (48 hips) with a history of unilateral spontaneous hip arthrodesis were considered eligible for this study. No patients had surgical hip arthrodesis. The patients’ characteristics are shown in Table We collected data concerning the gender, age at conversion THA, height, weight, body mass index, duration of arthrodesis, cause of hip arthrodesis, operative side, and hip joint on the non-operative side.14. This value was marked as positive in calculations when the convexity faced the fused hip side and negative when the convexity faced contra-laterally. The PO angle was measured as the angle between the horizontal line and the line passing through the inferior tip of the bilateral pelvic teardrops14. The angle was marked as positive in calculations when the downward direction was toward the fused hip side and negative when the downward direction was toward the opposite side. The HAA was defined as the angle between the perpendicular angle of the line passing through the inferior tip of the bilateral pelvic teardrops and the long axis of the femur on the affected side15. This value was calculated with abduction regarded as a positive angle and adduction regarded as a negative angle.All patients underwent standing anterior–posterior spine-pelvis-hip radiographs before and at least 12 months after THA. On the radiographs, Cobb’s angle of lumbar scoliosis (LS), the pelvic obliquity (PO) angle, and the hip adduction angle (HAA) were measured , unchanged (|ΔLS|≤ 5°), and progressed (|ΔLS|> 5° and postoperative LS moved away from 0°)13. Since the normal PO was reported to be 0°13, the PO was assessed as follows: improved (|ΔPO|> 3.5° and postoperative PO approached 0°), unchanged (|PO|≤ 3.5°), and progressed (|ΔPO|> 3.5° and postoperative PO moved away from 0°)13. Since the normal HAA was reported to be  − 8°16, the HAA was assessed as follows: improved (|ΔHAA|> 3.5° and postoperative HAA approached  − 8°), unchanged (|ΔHAA|≤ 3.5°), and progressed (|ΔHAA|> 3.5° and postoperative HAA moved away from  − 8°)13.The differences of preoperative and postoperative LS, PO, and HAA were defined as delta (Δ) LS, ΔPO, and ΔHAA, respectively. Since the normal LS was reported to be 0°Leg length discrepancy (LLD) was defined by the spinomalleolus distance on the healthy side from the spinomalleolus distance on the diseased side. The spinomalleolus distance was defined as the distance from the anterior superior iliac spine to the medial malleolus using a measuring tape. The differences of preoperative and postoperative LLD were defined as ΔLLD. When the spinomalleolus distance on the diseased side was longer than that on the healthy side, it was defined as positive. Otherwise, it was defined as negative.Passive hip range of motion (ROM) at operative side was assessed before THA. Hip flexion, abduction, adduction, internal rotation, and external rotation were measured in the supine position. Hip extension was measured in the prone position.17, which is a 100-point scale comprising the subcategories of pain (0–40 points), range of motion (0–20 points), ability to walk (0–20 points), and activities of daily living (0–20 points). The maximum total JOA score for a normal hip is 100 points, with higher scores indicating a better function. The JOA hip score was evaluated before and at least 12 months after THA. The difference in the preoperative and postoperative JOA hip score was defined as the ΔJOA hip score.The clinical outcome was evaluated using the Japanese Orthopaedic Association (JOA) hip score18.Radiographic parameters  were measured twice on separate days by two assessors (T.K. and T.Y.) and the intra-observer and inter-observer reliability were calculated. Values of < 0.40, 0.40–0.75, and > 0.75 are considered to indicate poor, good, and excellent reliability, respectivelyThe normality of distribution of quantitative data was determined using the Kolmogorov–Smirnov test. For normally distributed variables, the equality of variance between groups was tested using Levene’s test. A paired samples t-test was used to compare absolute values of LS and the JOA hip score between two related groups , as values that showed normal distribution with equal variance. The Wilcoxon signed-rank test was used for comparing absolute values of PO and HAA between two related groups , as values that did not show normal distribution. Student’s t-test was used to compare the absolute values of ΔPO and ΔHAA and ΔJOA hip score between two independent groups , as values that showed normal distribution with equal variance. The Mann–Whitney's U test was used to compare the absolute value of ΔLS between two independent groups , as values that did not show normal distribution.Descriptive analyses were performed to assess the distribution of improved, unchanged, and progressed LS, PO, and HAA.19.Pearson’s correlation coefficient (r) was calculated for variables with a normal distribution, and Spearman’s correlation coefficient (ρ) was calculated for variables without a normal distribution to assess the relationship between changes in alignment  and possible factors . Correlation coefficients of 0.00–0.10, 0.10–0.39, 0.40–0.69, 0.70–0.89, and 0.90–1.00 were defined as negligible, weak, moderate, strong, and very strong correlation, respectivelyP-values of < 0.05 were considered to indicate statistical significance. All analyses were performed using JMP® pro 14 .All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional review board of Saga University Hospital (Registration No.: 2015-12-13) and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.Informed consent was obtained from all subjects.The estimated mean intra-observer reliability for the measurement of preoperative LS, PO, and HAA was 0.95, 0.95, and 0.96, respectively. The mean inter-observer reliability for the measurement of preoperative LS, PO, and HAA was 0.88, 0.90, and 0.91, respectively. The intra-observer and inter-observer reliability were therefore judged to be excellent.The comparison of preoperative and postoperative coronal alignment is shown in Table Of 48 patients, 12 (25.0%), 33 (68.8%) and 3 (6.3%) had improved, unchanged, and progressed LS, respectively. Of 48 patients, 29 (60.4%), 19 (39.6%) and 0 (0%) had improved, unchanged, and progressed PO, respectively. Of 48 patients, 25 (52.0%), 14 (29.2%) and 9 (18.8%) had improved, unchanged, and progressed HAA, respectively   LS, PO, and HAA were significantly improved due to conversion of hip arthrodesis to arthroplasty; and (2) preoperative coronal lumbar-pelvic-femoral alignment was the main determinant of improvement in LS, PO, and HAA after conversion THA.22. A rigid spine can be detected on dynamic radiographs. This hypothesis should be investigated in future studies.Overall, we found a significant improvement in LS after conversion of hip arthrodesis to arthroplasty. To be more precise, 25% of patients showed improved LS. In addition, the larger improvement in LS was observed in patients with larger preoperative LS, PO, and HAA values. Contrarily, 6% of the patients showed progression in LS. The reported mechanisms of LS progression after conversion THA include de novo scoliosis with the rigid lumbosacral junction due to the long-term course or overcompensation at the lumbosacral junction and progression of L4 tilt23) in patients with unilateral ankylosed hip24. However, postoperative mechanical failure  and associated revision procedures are reported in 13–27% of patients12; thus further investigations regarding this issue is required.In this study, PO was significantly improved due to conversion of hip arthrodesis to arthroplasty. We found that 60% of patients showed improvement of PO and no patients showed progression of PO after conversion THA. Furthermore, a greater preoperative PO value was related to greater improvement in PO after conversion THA. It therefore seems likely that horizontalization of the pelvis is expected after conversion of hip arthrodesis to arthroplasty. These findings theoretically support the recommendation that acetabular inclination should be included in Lewinnek’s ‘safe zone’ . Therefore, separation of the hip adductor muscle in addition to conversion THA should be considered, with reference to preoperative coronal lumbar-pelvic-femoral alignment and the duration of hip arthrodesis.We found that the HAA was significantly changed due to conversion of hip arthrodesis to arthroplasty. Notably, 19% of patients showed progression of the HAA after conversion THA. As shown in Table 24. In addition, we did not assess the severity of hip osteoarthritis at the contralateral hip joint. Although we did not assess changes in hip ROM after conversion THA in this study, a movable hip joint after THA for abduction and adduction may have a great influence on high PO and HAA values in the standing position25.Unexpectedly, the main determinants of the postoperative change in PO and HAA were preoperative LS, PO, and HAA, and preoperative hip ROM for hip abduction and adduction, rather than preoperative LLD, ΔLLD, or the state of the contralateral hip joint. These findings may have been influenced by our study methods; spinomalleolus distance measurements were found to show low reliability in comparison to radiological methodsImportantly, we first reported the relationship between changes in the coronal spino-pelvic alignment and in the clinical outcomes after conversion THA. The JOA hip score was significantly improved due to conversion of hip arthrodesis to arthroplasty. Furthermore, improvement in PO and HAA after conversion THA was the main determinant of improvement in the JOA hip score. In contrast, improvement in LS after conversion THA was not a significant determinant of improvement in the JOA hip score, possibly due to the fact that the JOA hip score mainly includes questionnaire items regarding hip. A gait analysis may be useful for assessing these relationships in detail.2. When the rarity of hip arthrodesis was taken into consideration, the sample size could be accepted as a strength of this study. Second, sagittal lumbar-pelvic-femoral alignment and internal/external rotation of the spine, pelvis, and femurs was not assessed in this study, which may have affected our results. For instance, improvement in the pelvis rotation can lead to radiographic PO improvement, as the radiographic position of tear drops can change in the rotated pelvis. Although the inter- and intra-observer reliabilities were excellent, the accuracy of the measurement method would have been limited. Third, there was a lack of unity in the period of the assessment of radiographs after THA. It is reported that time may affect the radiographic assessment after THA26; measurements at intervals of a few months can demonstrate dynamic changes in LS, PO, and HAA for evaluating the presence of continuous improvement. Although at least a 12-month follow-up was done in all cases, this limitation may have influenced our results. Finally, and most importantly, full-length standing radiographs for the spine and lower limbs as well as lumbar bending radiographs were not evaluated in this study. These images are strongly needed to make a precise evaluation of the coronal deformity of the lumbo-pelvic complex both pre- and post-operation, especially for patients with LLD. Further investigations regarding these issues are required.The present study was associated with some limitations. First, the study population was limited to 48 patients. This is because the ideal candidates for hip arthrodesis are young adults of < 40 years of age with symptomatic non-inflammatory monoarticular end-stage osteoarthritis and hip arthrodesis is an uncommon procedure in modern times because of the increased popularity of THASignificant improvements of the LS, PO, and HAA were observed due to conversion of hip arthrodesis to arthroplasty. A larger improvement in LS, PO, and HAA can be expected in patients with larger preoperative LS, PO, and HAA values. However, there may be some exceptions, and further investigations are necessary.