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Introduction  The management of recurrent craniopharyngioma is complex with limited data to guide decision-making. Some reports suggest reoperation should be avoided due to an increased complication profile, while others have demonstrated that safe reoperation can be performed. For other types of skull base lesions, maximal safe resection followed by adjuvant therapy has replaced radical gross total resection due to the favorable morbidity profiles. Methods  Seventy-one patients underwent resection over a 9-year period for craniopharyngioma and were retrospectively reviewed. Patients were separated into primary resection and reoperation cohorts and stratified by surgical approach (endonasal vs. cranial) and survival analyses were performed based on cohort and surgical approach. Results  Fifty patients underwent primary resection, while 21 underwent reoperation for recurrence. Fifty endonasal transsphenoidal surgeries and 21 craniotomies were performed. Surgical approaches were similarly distributed across cohorts. Subtotal resection was achieved in 83% of all cases. There were no differences in extent of resection, visual outcomes, subsequent neuroendocrine function, and complications across cohorts and surgical approaches. The median time to recurrence was 87 months overall, and there were no differences by cohort and approach. The 5-year survival rate was 81.1% after reoperation versus 93.2% after primary resection. Conclusion  Compared with primary resection, reoperation for craniopharyngioma recurrence is associated with similar functional and survival outcomes in light of individualized surgical approaches. Maximal safe resection followed by adjuvant radiotherapy for residual tumor likely preserves vision and endocrine function without sacrificing overall patient survival.

While noninvasive brain stimulation is convenient and cost effective, its utility is limited by the substantial distance between scalp electrodes and their intended neural targets in the head. The tympanic membrane, or eardrum, is a thin flap of skin deep in an orifice of the head that may serve as a port for improved efficiency of noninvasive stimulation. Here we chose the cochlea as a target because it resides in the densest bone of the skull and is adjacent to many deep-brain-stimulation structures. We also tested the hypothesis that noninvasive electric stimulation of the cochlea may restore neural activities that are missing in acoustic stimulation. We placed an electrode in the ear canal or on the tympanic membrane in 25 human adults (10 females) and compared their stimulation efficiency by characterizing the electrically-evoked auditory sensation. Relative to ear canal stimulation, tympanic membrane stimulation was four times more likely to produce an auditory percept, required eight times lower electric current to reach the threshold and produced two-to-four times more linear suprathreshold responses. We further measured tinnitus suppression in 14 of the 25 subjects who had chronic tinnitus. Compared with ear canal stimulation, tympanic membrane stimulation doubled both the probability (22% vs. 55%) and the amount (-15% vs. -34%) of tinnitus suppression. These findings extended previous work comparing evoked perception and tinnitus suppression between electrodes placed in the ear canal and on the scalp. Together, the previous and present results suggest that the efficiency of conventional scalp-based noninvasive electric stimulation can be improved by at least one order of magnitude via tympanic membrane stimulation. This increased efficiency is most likely due to the shortened distance between the electrode placed on the tympanic membrane and the targeted cochlea. The present findings have implications for the management of tinnitus by offering a potential alternative to interventions using invasive electrical stimulation such as cochlear implantation, or other non-invasive transcranial electrical stimulation methods.

PurposeThe mechanisms of brain metastasis are incompletely understood. Circulating tumor cells travel to the right heart and through the pulmonary circulation, where they may become lung metastases, and can circulate further to the left heart and brain. In patients who develop brain metastases without lung involvement, we hypothesized that cancer cells may travel directly from the right atrium to left atrium via a patent foramen ovale (PFO), akin to paradoxical embolism. If the prevalence of PFO is greater in these individuals compared to the general population (20-30%), PFO may play a role in brain metastasis, and prophylactic closure may provide benefit. Accordingly, we investigated the prevalence of PFO in patients with brain metastases without prior lung involvement.MethodsWe prospectively identified patients with brain metastases from a non-lung primary cancer with no preceding or concurrent lung involvement. Nine eligible participants underwent a transcranial Doppler study with intravenous agitated saline to assess for PFO.ResultsAmong nine participants, primary cancers were breast (n = 6), upper gastrointestinal (n = 2), and thyroid (n = 1). A positive bubble study was identified in 2/9 (22.2%) participants: one female with breast cancer and one male with duodenal adenocarcinoma. No participants developed lung metastases on subsequent chest imaging.ConclusionIn this prospective pilot study, we found a similar prevalence of PFO in patients who developed brain metastases without preceding lung involvement compared to estimates for the general population. Through a larger study is needed, the development of brain metastases in these individuals may primarily reflect tumor-specific biological factors diecting metastasis organotropism.

Background The primary aim of this study was to characterize the middle cerebral artery blood velocity (MCAv) dynamic response to an acute bout of exercise in humans at 3- and 6-months poststroke. As a secondary objective, we grouped individuals according to the MCAv dynamic response to the exercise bout as responder or nonresponder. We tested whether physical activity, aerobic fitness, and exercise mean arterial blood pressure differed between groups. Methods and Results Transcranial Doppler ultrasound measured MCAv during a 90-second baseline followed by a 6-minute moderate intensity exercise bout. Heart rate, mean arterial blood pressure, and end-tidal CO2 were additional variables of interest. The MCAv dynamic response variables included the following: baseline, time delay, amplitude, and time constant. Linear mixed model revealed no significant differences in our selected outcomes between 3- and 6-months poststroke. Individuals characterized as responders demonstrated a faster time delay, higher amplitude, and reported higher levels of physical activity and aerobic fitness when compared with the nonresponders. No between-group differences were identified for baseline, time constant, or exercise mean arterial blood pressure. In the nonresponders, we observed an immediate rise in MCAv following exercise onset followed by an immediate decline to near baseline values, while the responders showed an exponential rise until steady state was reached. Conclusions The MCAv dynamic response profile has the potential to provide valuable information during an acute exercise bout following stroke. Individuals with a greater MCAv response to the exercise stimulus reported statin use and regular participation in exercise.

BackgroundIntracranial atherosclerotic disease (ICAD) is a common cause of ischemic stroke with a high risk of clinical stroke recurrence. Multiple mechanisms may underlie cerebral ischemia in this condition. The study's objective is to discern the mechanisms of recurrent ischemia in ICAD through imaging biomarkers of impaired antegrade flow, poor distal perfusion, abnormal vasoreactivity, and artery-to-artery embolism.MethodsThis prospective multicenter observational study enrolled patients with recent (≤21 days) ischemic stroke or transient ischemic attack (TIA) caused by ICAD with 50-99% stenosis treated medically. We obtained baseline quantitative MRA (QMRA), perfusion MRI (PWI), transcranial Doppler vasoreactivity (VMR), and emboli detection studies (EDS). The primary outcome was ischemic stroke in the territory of the stenotic artery within 1 year of follow-up; secondary outcomes were TIA at 1 year and new infarcts in the territory on MRI at 6-8 weeks.ResultsAmongst 102 of 105 participants with clinical follow-up (mean 253±131 days), the primary outcome occurred in 8.8% (12.7/100 patient-years), while 5.9% (8.5/100 patient-years) had a TIA. A new infarct in the territory of the symptomatic artery was noted in 24.7% at 6-8 weeks. A low flow state on QMRA was noted in 25.5%, poor distal perfusion on PWI in 43.5%, impaired vasoreactivity on VMR in 67.5%, and microemboli on EDS in 39.0%. No significant association was identified between these imaging biomarkers and primary or secondary outcomes.ConclusionsDespite intensive medical management in ICAD, there is a high risk of clinical cerebrovascular events at 1 year and an even higher risk of new imaging-evident infarcts in the subacute period after index stroke. Hemodynamic and plaque instability biomarkers did not identify a higher risk group. Further work is needed to identify mechanisms of ischemic stroke and infarct recurrence and their consequence on long-term physical and cognitive outcomes.Trial registrationClinicalTrials.gov: NCT02121028.

The leptomeningeal collateral status is an independent predictor of stroke outcome. By means of optical coherent tomography angiography to compare two mouse strains with different extent of native leptomeningeal collateralization, we determined the spatiotemporal dynamics of collateral flow and downstream hemodynamics following ischemic stroke. A robust recruitment of leptomeningeal collateral flow was detected immediately after middle cerebral artery (MCA) occlusion in C57BL/6 mice, with continued expansion over the course of seven days. In contrast, little collateral recruitment was seen in Balb/C mice during- and one day after MCAO, which coincided with a greater infarct size and worse functional outcome compared to C57BL/6, despite a slight improvement of cortical perfusion seven days after MCAO. Both strains of mice experienced a reduction of blood flow in the penetrating arterioles (PA) by more than 90% 30-min after dMCAO, although the decrease of PA flow was greater and the recovery was less in the Balb/C mice. Further, Balb/C mice also displayed a prolonged greater heterogeneity of capillary transit time after dMCAO in the MCA territory compared to C57BL/6 mice. Our data suggest that the extent of native leptomeningeal collaterals affects downstream hemodynamics with a long lasting impact in the microvascular bed after cortical stroke.

RationaleIntracranial atherosclerotic disease (ICAD) is the most common cause of ischemic stroke with the highest rate of recurrence, despite aggressive medical management. Diverse mechanisms may be responsible for ICAD-related cerebral ischemia, with potential therapeutic implications. Here we present the rationale, design and methods of the Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease (MyRIAD) study. The aim of MyRIAD is to determine the mechanisms of stroke in ICAD through physiologic imaging biomarkers that evaluate impaired antegrade flow, poor distal perfusion, abnormal vasoreactivity, artery to artery embolism, and their interaction.Methods and designThis is a prospective observational study of patients with recently symptomatic (

Cerebral Blood Flow Velocity waveforms acquired via Transcranial Doppler (TCD) can provide evidence for cerebrovascular occlusion and stenosis. Thrombolysis in Brain Ischemia (TIBI) flow grades are widely used for this purpose, but require subjective assessment by expert evaluators to be reliable. In this work we seek to determine whether TCD morphology can be objectively assessed using an unsupervised machine learning approach to waveform categorization. TCD beat waveforms were recorded at multiple depths from the Middle Cerebral Arteries of 106 subjects; 33 with Large Vessel Occlusion (LVO). From each waveform, three morphological features were extracted, quantifying onset of maximal velocity, systolic canopy length, and the number/prominence of peaks/troughs. Spectral clustering identified groups implicit in the resultant three-dimensional feature space, with gap statistic criteria establishing the optimal cluster number. We found that gap statistic disparity was maximized at four clusters, referred to as flow types I, II, III, and IV. Types I and II were primarily composed of control subject waveforms, whereas types III and IV derived mainly from LVO patients. Cluster morphologies for types I and IV aligned clearly with Normal and Blunted TIBI flows, respectively. Types II and III represented commonly observed flow-types not delineated by TIBI, which nonetheless deviate from normal and blunted flows. We conclude that important morphological variability exists beyond that currently quantified by TIBI in populations experiencing or at-risk for acute ischemic stroke, and posit that the observed flow-types provide the foundation for objective methods of real-time automated flow type classification.

Sickle cell disease (SCD) is characterized by deoxygenation-induced polymerization of hemoglobin in red blood cells, leading to hemolytic anemia, vaso-occlusion, and the development of multiple clinical complications. To characterize the clinical burden associated with differences in hemoglobin concentration and hemolysis measures, a systematic literature review of MEDLINE, EMBASE, and related meta-analyses was undertaken. For quantitative analyses related to hemoglobin concentration, pooled results were analyzed using random effects models to control for within-and between-study variability. To derive risk ratios associated with hemoglobin concentration change, we combined ratios of means from select studies, which reported hazard and odds ratios in meta-analyses for hemoglobin concentration-related outcomes and changes between groups. Forty-one studies were identified for inclusion based on relating hemoglobin concentration to clinical outcomes. Meta-analyses demonstrated that mean hemoglobin concentration was significantly lower in patients with cerebrovascular disease (0.4 g/dL), increased transcranial Doppler velocity in cerebral arteries (0.6 g/dL), albuminuria (0.6 g/dL), elevated estimated pulmonary artery systolic pressure (0.9 g/dL), and in patients that subsequently died (0.6 g/dL). In a risk reduction meta-analysis, modeled increased hemoglobin concentrations of 1 g/dL or greater resulted in decreased risk of negative clinical outcomes of 41% to 64%. In conclusion, chronic anemia is associated with worse clinical outcomes in individuals with SCD and even modest increases in hemoglobin concentration may be beneficial in this patient population. This systematic review has been registered on Prospero (Registration number CRD42018096860; https://www.crd.york.ac.uk/prospero/).

Over 50% of patients who rapidly ascend to extreme altitudes develop various symptoms known as acute mountain sickness (AMS), which rarely can be life threatening. It is unclear why some patients are more susceptible to AMS than others. Our objective was to determine whether patent foramen ovale (PFO) is a risk factor for AMS. Subjects who had hiked to altitudes above 10,000' (∼3,000 meters) on the John Muir Trail in California were recruited. Participants completed a questionnaire and 2-physician adjudication was performed in regard to AMS status. A transcranial Doppler with agitated saline contrast injection was performed to evaluate the presence or absence of PFO. The primary outcome was the development of AMS. From 2016 to 2018, 137 hikers were recruited into the study. There was a higher prevalence of PFO in hikers with AMS 15 of 24 (63%) compared with hikers without AMS 44 of 113 (39%); p = 0.034. In the multivariate model, the presence of a PFO significantly increased the risk for developing AMS: odds ratio 4.15, 95% confidence intervals 1.14 to 15.05; p = 0.030. In conclusion, hikers with a PFO had significantly higher risk of developing AMS relative to hikers without a PFO. Clinicians should consider PFO a risk factor in patients who plan to hike to high altitudes.

The low cost, simple, noninvasive, and continuous measurement of cerebral blood flow velocity (CBFV) by transcranial Doppler is becoming a common clinical tool for the assessment of cerebral hemodynamics. CBFV monitoring can also help with noninvasive estimation of intracranial pressure and evaluation of mild traumatic brain injury. Reliable CBFV waveform analysis depends heavily on its accurate beat-to-beat delineation. However, CBFV is inherently contaminated with various types of noise/artifacts and has a wide range of possible pathological waveform morphologies. Thus, pulse onset detection is in general a challenging task for CBFV signal. In this paper, we conducted a comprehensive comparative analysis of three popular pulse onset detection methods using a large annotated dataset of 92,794 CBFV pulses-collected from 108 subarachnoid hemorrhage patients admitted to UCLA Medical Center. We compared these methods not only in terms of their accuracy and computational complexity, but also for their sensitivity to the selection of their parameters values. The results of this comprehensive study revealed that using optimal values of the parameters obtained from sensitivity analysis, one method can achieve the highest accuracy for CBFV pulse onset detection with true positive rate (TPR) of 97.06% and positive predictivity value (PPV) of 96.48%, when error threshold is set to just less than 10 ms. We conclude that the high accuracy and low computational complexity of this method (average running time of 4ms/pulse) makes it a reliable algorithm for CBFV pulse onset detection.

BACKGROUND AND PURPOSE: External counterpulsation improves cerebral perfusion velocity in acute stroke and may stimulate collateral artery growth. However, whether (non-acute) at-risk patients with high-grade carotid artery disease may benefit from counterpulsation needs to be validated. METHODS: Twenty-eight patients (71 ± 6.5 years, five women) with asymptomatic unilateral chronic severe internal carotid artery stenosis (>70%) or occlusion were randomized to receive 20 min active counterpulsation followed by sham treatment or vice versa. Cerebral blood flow velocity (CBFV) (measured bilaterally by transcranial middle cerebral artery Doppler), tissue oxygenation index (TOI) (measured over the bilateral prefrontal cortex by near-infrared spectroscopy) and cerebral hemodynamic parameters, such as relative pulse slope index (RPSI), were monitored. RESULTS: Ipsilateral mean CBFV (ΔVmean +3.5 ± 1.2 cm/s) and tissue oxygenation (ΔTOI +2.86 ± 0.8) increased significantly during active counterpulsation compared to baseline, whilst the sham had little effect (ΔVmean +1.13 ± 1.1 cm/s; ΔTOI +1.25 ± 0.65). On contralateral sides, neither counterpulsation nor sham control had any effect on either parameter. During counterpulsation, early dynamic changes in ΔRPSI of the ipsilateral CBFV signal predicted improved tissue oxygenation during counterpulsation (odds ratio 1.179, 95% confidence interval 1.01-1.51), whilst baseline cerebrovascular reactivity to hypercapnia failed to show an association. CONCLUSIONS: In patients with high-grade carotid disease, ipsilateral cerebral oxygenation and blood flow velocity are increased by counterpulsation. This is a necessary condition for the stimulation of regenerative collateral artery growth and thus a therapeutic concept for the prevention of cerebral ischaemia. This study provides a rationale for further clinical investigations on the long-term effects of counterpulsation on cerebral hemodynamics and collateral growth.

BACKGROUND AND PURPOSE:Individuals with migraine are at higher risk for stroke, but the mechanism has not been established. On the basis of the association between migraine and intracardiac right-to-left shunt, it has been proposed that stroke in migraineurs could be caused by a paradoxical embolus passing through a patent foramen ovale (PFO) or pulmonary arteriovenous malformation. The aim of this study was to determine the prevalence of PFO with right-to-left shunt in patients who presented with cryptogenic stroke and had a history of migraine. METHODS:Patients between 18 and 60 years old who presented with an ischemic stroke were characterized based on ASCOD phenotyping (atherosclerosis; small-vessel disease; cardiac pathology; other causes; dissection). A migraine diagnosis was identified by reviewing physician notes, and frequent aura was defined if present in at least 50% of attacks. A PFO with right-to-left shunt diagnosis was identified by the presence of a positive bubble contrast study with either transcranial Doppler, transthoracic, or transesophageal echocardiography. RESULTS:Of the 712 patients who presented with ischemic stroke, 127 (18%) were diagnosed as cryptogenic; 68 patients had adequate testing for PFO and a documented migraine history. The prevalence of PFO in patients with cryptogenic stroke without migraine was elevated (59%) compared with the general population (18%). Patients with both cryptogenic stroke and migraine had a higher prevalence of PFO (79%). In patients with cryptogenic stroke who had migraine with frequent aura, the prevalence of PFO was 93%. Only 5 patients (4%) had a history compatible with migrainous infarction. CONCLUSIONS:In patients with cryptogenic stroke who have migraine, there is a high prevalence (79%) of PFO with right-to-left shunt. The timing of the stroke in migraineurs is usually not related to a migraine attack. These observations are consistent with the hypothesis that the mechanism of stroke in migraineurs is most likely because of a paradoxical embolus. Future cryptogenic stroke classification schemes should consider including PFO as a separate etiologic category.

Once deemed benign, patent foramen ovale (PFO)-mediated right-to-left shunting has now been linked to stroke, migraine, and hypoxemia. Contrast transesophageal echocardiography is considered the standard technique for identifying a PFO, allowing visualization of the atrial septal anatomy and differentiation from non-PFO right-to-left shunts. Transthoracic echocardiography is the most common method for PFO imaging, being cost-effective, but has the lowest sensitivity. Transcranial Doppler is highly sensitive but is unable to differentiate cardiac from pulmonary shunts; it is the best method to quantitate shunt severity, being more sensitive than transthoracic or transesophageal echocardiography so is our preferred screening method for PFO.

BackgroundThe reproducibility of transcranial Doppler (TCD) ultrasound measurements in Sturge-Weber syndrome (SWS) and TCD's ability to predict neurological progression is unknown.MethodsIn 14 individuals with SWS, TCD measured mean flow velocity, pulsatility index, peak systolic velocity, and end-diastolic velocity in the middle, posterior, and anterior cerebral arteries of the affected and unaffected hemisphere. TCD was performed either once (n = 5) or twice in one day (n = 9). We assessed the reproducibility of the measurements performed twice on the same day on subjects and compared the TCD measurements to previously published age-matched controls. Clinically obtained neuroimaging was scored for extent and severity of SWS brain involvement. Patients were prospectively assigned SWS neuroscores.ResultsMiddle cerebral artery velocity (r = 0.79, P = 0.04, n = 7), posterior cerebral artery velocity (r = 0.90, P = 0.04, n = 5), and anterior cerebral artery pulsatility index (r = 0.82, P = 0.02, n = 7) were reproducible TCD measurements comparing same-day percent side-to-side differences. In subjects with SWS, affected and unaffected mean peak systolic velocity and end-diastolic velocity in the middle, posterior, and anterior cerebral arteries were globally lower compared with age-matched control subjects. Subjects with the lowest affected middle cerebral artery velocity had the greatest worsening in the total neurological score between time 1 and 2 (r = -0.73, P = 0.04, n = 8) and the most severe magnetic resonance imaging involvement of the affected frontal lobe (r = -0.82, P = 0.007, n = 9).ConclusionsTCD may be a reliable measure with potential clinical value, indicating that blood flow may be globally decreased in SWS patients with unilateral brain involvement.

In children with Sickle Cell Disease, the combination of risk stratification with Transcranial Doppler Ultrasound (TCD) and selective chronic red cell transfusion (CRCT-the STOP Protocol) is one of the most effective stroke prevention strategies in medicine. How fully it is being implemented is unclear. Nineteen of 26 sites that conducted the two pivotal clinical trials (STOP and STOP II) participated in Post STOP, a comprehensive medical records review assessing protocol implementation in the 10-15 years since the trials ended. Professional abstractors identified medical records in the Post STOP era in 2851 (74%) of the 3,840 children who took part in STOP and/or STOP II, and documented TCD rescreening, maintenance of CRCT in those at risk, and stroke. Among 1,896 children eligible for TCD rescreening (target group), evidence of any rescreening was found in 1,090 (57%). There was wide site variation in TCD rescreening ranging from 18% to 91% of eligible children. Both younger age and having a conditional TCD during STOP/II were associated with a higher likelihood of having a TCD in Post STOP. Sixty eight new abnormal, high risk cases were identified. Despite clear evidence of benefit the STOP protocol is not fully implemented even at experienced sites. Site variation suggests that system improvements might remove barriers to implementation and result in even greater reduction of ischemic stroke in children with SCD. Am. J. Hematol. 91:1191-1194, 2016. © 2016 Wiley Periodicals, Inc.

Transcranial Doppler (TCD) screening rates remain low among children with sickle cell disease (SCD). We assessed TCD screening rates and missed opportunities for TCD screening. Children 2 to 16 years old with SCD enrolled in Michigan Medicaid for ≥1 year (2007-2011) were identified through newborn screening. Receipt of TCD screening and presence of a missed opportunity (≥1 SCD-related outpatient visit, no TCD screening) were identified through administrative claims. Potential correlates of missed opportunities included SCD-related health services, comorbidities, and demographics. Logistic regression with generalized estimating equations modeled associations between a missed opportunity and correlates. Overall, 353 children contributed 1066 person-years. TCD screening was low yearly (10%-32%); missed opportunities occurred in 73% of the person-years. Increasing age (odds ratio [OR] = 1.11; confidence interval CI = 1.07, 1.15), previous TCD screening (OR = 0.26; CI = 0.16, 0.41), and 4 to 5 (OR = 0.48; CI = 0.26, 0.87) or ≥6 outpatient visits (OR = 0.26; CI = 0.14, 0.49) were associated with a missed opportunity. Reduction of missed opportunities is a potential strategy to increase TCD screening rates.

BackgroundTranscranial Doppler (TCD) with agitated saline has been shown to be an alternative for the detection of right-to-left shunts (RLS) with similar diagnostic accuracies as transesophageal echocardiography (TEE). It is hypothesized that the addition of blood to agitated saline increases the sensitivity of TCD for the detection of RLS. The aim of this meta-analysis was to determine whether agitated saline with blood increases the sensitivity of TCD for the detection of RLS compared to agitated saline alone and other contrast agents.MethodA systematic review of Medline, Cochrane, and Embase was performed to look for all prospective studies assessing intracardiac RLS using TCD compared with TEE as the reference; both tests were performed with a contrast agent and a maneuver to provoke RLS in all studies.ResultsA total of 27 studies (29 comparisons) with 1,968 patients met the inclusion criteria. Of 29 comparisons, 10 (35%) used echovist contrast during TCD, 4 (14%) used a gelatin-based solution, 12 (41%) used agitated saline, and 3 (10%) utilized 2 different contrast agents. The addition of blood to agitated saline improved the sensitivity of TCD to 100% compared to agitated saline alone (96% sensitivity, P = 0.161), echovist (94% sensitivity, P = 0.044), and gelatin-based solutions (93% sensitivity, P = 0.041).ConclusionThe addition of blood to agitated saline improves the sensitivity of TCD for the detection of RLS to 100% when compared to other conventional contrast agents; these findings support the addition of blood to agitated saline during TCD bubble studies.

The aim of this study was to assess transcranial Doppler (TCD) as a screening test for pulmonary arteriovenous malformation (PAVM) in patients with hereditary hemorrhagic telangiectasia (HHT). This retrospective study included suspected patients with HHT who were screened for PAVM with a TCD and a chest computed tomography (CT) study. The results of TCD and CT were compared to evaluate the usefulness of TCD for detecting PAVM. A TCD Spencer grade ≥3 was defined as positive for a significant right-to-left shunt (RLS). The diameter of the pulmonary arteries feeding the PAVM was measured by calipers from the CT study. In 86 subjects from 74 families with HHT, the sensitivity of TCD for identifying a PAVM at rest was 98% and post-Valsalva was 100%. Specificity was 58% and 35%, respectively, presumably due to pulmonary shunts too small to recognize on CT. Of the patients with HHT who were referred for embolization therapy for their PAVMs, all 20 had TCD grade ≥3. In patients who were diagnosed with a PAVM by chest CT, patients with TCD grade ≥5 had a significantly larger sum of artery diameters feeding the PAVMs compared to those with grade ≤4 (5.0 ± 3.2 mm vs 2.6 ± 1.9 mm, p = 0.01). In conclusion, a TCD examination for evaluating RLS is sensitive for identifying PAVM in patients with HHT and is useful in quantitating the degree of RLS flow. The sensitivity of the TCD examination makes it a useful screening test without radiation in HHT subjects to determine which patients need to undergo CT evaluation to identify PAVMs.

The incidence of traumatic brain injury (TBI) in the United States was 3.5 million cases in 2009, according to the Centers for Disease Control and Prevention. It is a contributing factor in 30.5% of injury-related deaths among civilians. Additionally, since 2000, more than 260,000 service members were diagnosed with TBI, with the vast majority classified as mild or concussive (76%). The objective assessment of TBI via imaging is a critical research gap, both in the military and civilian communities. In 2011, the Department of Defense (DoD) prepared a congressional report summarizing the effectiveness of seven neuroimaging modalities (computed tomography [CT], magnetic resonance imaging [MRI], transcranial Doppler [TCD], positron emission tomography, single photon emission computed tomography, electrophysiologic techniques [magnetoencephalography and electroencephalography], and functional near-infrared spectroscopy) to assess the spectrum of TBI from concussion to coma. For this report, neuroimaging experts identified the most relevant peer-reviewed publications and assessed the quality of the literature for each of these imaging technique in the clinical and research settings. Although CT, MRI, and TCD were determined to be the most useful modalities in the clinical setting, no single imaging modality proved sufficient for all patients due to the heterogeneity of TBI. All imaging modalities reviewed demonstrated the potential to emerge as part of future clinical care. This paper describes and updates the results of the DoD report and also expands on the use of angiography in patients with TBI.

ObjectivesTo assess the presence of right-to-left shunting (RLS) in patients with obstructive sleep apnea (OSA), and compare clinical characteristics and parameters of the sleep studies of patients with and without RLS.BackgroundThe most common cause of RLS is due to intermittent flow through a patent foramen ovale (PFO). PFO occurs more frequently in patients with OSA and may be involved in the exacerbation of OSA.MethodsPatients with an abnormal polysomnogram seen at UCLA-Santa Monica Sleep Medicine Clinic were enrolled. A diagnosis of RLS was made using a transcranial Doppler (TCD) bubble study. Gender and age-matched controls were drawn from patients referred for cardiac catheterization who underwent a TCD. The frequency of RLS in OSA patients and the controls was evaluated. Clinical characteristics and polysomnogram parameters were compared between OSA patients with and without a RLS.ResultsA total of 100 OSA patients and 200 controls participated in the study. The prevalence of RLS was higher in patients with OSA compared to the control group (42% versus 19%; p < 0.0001). Patients with OSA and a RLS had a lower apnea-hypopnea index (AHI), less obstructive apnea, and fewer hypopnea episodes than patients with OSA without a RLS. The baseline and nadir SpO2 were similar in both groups and did not correlate with the level of RLS assessed by TCD. The degree of desaturation for a given respiratory disturbance, as measured by oxygen desaturation index (ODI)/AHI ratio, was higher in OSA patients with RLS versus OSA patients without RLS (0.85 ± 0.07 versus 0.68 ± 0.04; p < 0.0001).ConclusionRLS, most commonly due to a PFO, occurs 2.2 times more frequently in OSA patients compared to a control population that was matched for age and gender. The severity of sleep apnea is not greater in OSA patients who have a PFO. However, patients with OSA and a PFO are more likely to become symptomatic at a younger age with an equivalent decrease in nocturnal SpO2, and have greater arterial desaturation in proportion to the frequency of respiratory disturbances.

We examined the reliability and ease of use of a novel automated transcranial Doppler (TCD) system in comparison to a conventional TCD system. TCD ultrasound allows non-invasive monitoring of cerebral blood flow, and can predict arterial vasospasm after a subarachnoid hemorrhage (SAH). The Presto 1000 TCD system (PhysioSonics, Bellevue, WA, USA) is designed for monitoring flow through the M1 segment of the middle cerebral artery (MCA) via temporal windows. The Presto 1000 system was tested across multiple preclinical and clinical settings in parallel with a control predicate TCD system. In a phantom flow generating device, both the Presto 1000 and Spencer system (Spencer Technologies, Redmond, WA, USA) were able to detect velocities with high accuracy. In nine volunteer patients, the Presto system was able to locate the MCA in 14 out of 18 temporal windows, in an average of 12.5s. In the SAH cohort of five patients with a total of 25 paired measurements, the mean absolute difference in flow velocities of the M1 segment, as measured by the two systems, was 17.5 cm/s. These data suggest that the Presto system offers an automated TCD that can reliably localize and detect flow of the MCA, with relative ease of use. The system carries the additional benefit of requiring minimal training for the operator, and can be used by many providers across multiple bedside settings. The mean velocities that were generated warrant further validation across an extended group of patients, and the predictive value for vasospasm should be checked against the current standard of angiography.

Cerebral dominance of language function and hand preference are suggested to be heritable traits with possible shared genetic background. However, joined genetic studies of these traits have never been conducted. We performed a genetic linkage study in 37 multigenerational human pedigrees of both sexes (consisting of 355 subjects) enriched with left-handedness in which we also measured language lateralization. Hand preference was measured with the Edinburgh Handedness Inventory, and language lateralization was measured with functional transcranial Doppler during language production. The estimated heritability of left-handedness and language lateralization in these pedigrees is 0.24 and 0.31, respectively. A parametric major gene model was tested for left-handedness. Nonparametric analyses were performed for left-handedness, atypical lateralization, and degree of language lateralization. We did not observe genome-wide evidence for linkage in the parametric or nonparametric analyses for any of the phenotypes tested. However, multiple regions showed suggestive evidence of linkage. The parametric model showed suggestive linkage for left-handedness in the 22q13 region [heterogeneity logarithm of odds (HLOD) = 2.18]. Nonparametric multipoint analysis of left-handedness showed suggestive linkage in the same region [logarithm of odds (LOD) = 2.80]. Atypical language lateralization showed suggestive linkage in the 7q34 region (LODMax = 2.35). For strength of language lateralization, we observed suggestive linkage in the 6p22 (LODMax = 2.54), 7q32 (LODMax = 1.93), and 9q33 (LODMax = 2.10) regions. We did not observe any overlap of suggestive genetic signal between handedness and the extent of language lateralization. The absence of significant linkage argues against the presence of a major gene coding for both traits; rather, our results are suggestive of these traits being two independent polygenic complex traits.

Although transcranial Doppler (TCD) screening assesses the need for stroke prevention efforts among children with sickle cell disease (SCD), screening rates remain low across many parts of the United States. We sought to identify neighborhoods with low TCD screening rates and neighborhood-level factors related to screening to inform the utility of community-level interventions to improve TCD screening. Children ages 2 to 16 years with SCD (HbSS/HbS/β-thalassemia) living in Wayne County, MI, were identified in Michigan Medicaid (2007 to 2011) through newborn screening records. Children were enrolled for ≥ 1 year and could contribute multiple years. We determined receipt of ≥ 1 TCD screening and neighborhood (census tract) each year. The proportion of children receiving TCD in the tract was calculated and investigated for spatial patterns across tracts (Moran's I). Median household income, % unemployment, % black residents, and % less than high school education within each tract were ascertained from the American Community Survey. Logistic regression with generalized estimating equations was used to model associations between TCD screening and neighborhood-level factors. Overall, 329 children contributed 532 person-years and screening rates increased from 7% to 36% from 2007 to 2011. Median screening rate in tracts was 0% (interquartile range = 29%) and there was no spatial pattern of TCD screening across tracts (Moran's I Z-score = -0.94, P-value = 0.35). No associations were found between neighborhood characteristics and receipt of TCD screening in this disadvantaged Michigan county. Additional research is needed to inform interventions to increase TCD screening in this high stroke-risk population.

ObjectiveWe explored factors that may influence physician adherence to transcranial Doppler (TCD) screening guidelines among children with sickle cell disease.MethodsPediatric hematologists, neurologists, and primary care physicians (n = 706) responded to a mailed survey in May 2012 exploring factors hypothesized to influence physician adherence to TCD screening guidelines: physician (internal) barriers and physician-perceived external barriers. Responses were compared by specialty using chi-square tests.ResultsAmong 276 physicians (44%), 141 currently treated children with sickle cell disease; 72% recommend screening. Most primary care physicians (66%) did not feel well informed regarding TCD guidelines, in contrast to neurologists (25%) and hematologists (6%, P < .0001). Proportion of correct answers on knowledge questions was low (13%-35%). Distance to a vascular laboratory and low patient adherence were external barriers to receipt of TCD screening.ConclusionsAdditional research regarding physicians' lack of self-efficacy and knowledge of recommendations could help clarify their role in recommendation of TCD screening.

BackgroundLambl's excrescences (LEx) are detected by transesophageal echocardiography (TEE) and are characterized as thin, elongated, and hypermobile structures located at the leaflets' coaptation point of the heart valves. The association of LEx with cerebrovascular disease (CVD) is still undefined and yet patients with LEx and suspected CVD receive unproven effective antiplatelet or anticoagulant therapy or even undergo valve surgery. Also, the association of LEx with aging and atherogenic, inflammatory, or thrombogenic parameters has not been reported.MethodsSeventy-seven patients with systemic lupus erythematosus (SLE) (71 women, age 37 ± 12 years) and 26 age- and sex-matched healthy controls (22 women, age 34 ± 11 years) prospectively underwent routine history and physical exam, transcranial Doppler, brain MRI, TEE, carotid duplex, and clinical and laboratory evaluations of atherogenesis, inflammation, platelet activity, coagulation, and fibrinolysis. Subjects without stroke/TIA on enrollment (with and without LEx) had a median follow-up of 57 months.ResultsOn enrollment, 33 (43%) of 77 patients had CVD manifested as acute stroke/TIA (23 patients), cerebromicroembolism by transcranial Doppler (17 patients), or cerebral infarcts by MRI (14 patients). Mitral or aortic valve LEx were equally frequent in healthy controls (46%) as in patients with and without any CVD (39 and 43%), stroke/TIA (35 and 43%), cerebromicroembolism (41 and 42%), or cerebral infarcts (36 and 43%) (all p ≥ 0.72). Also, other mechanisms for CVD other than LEx such as Libman-Sacks vegetations, patent foramen ovale or interatrial septal aneurysm, aortic or carotid atherosclerosis, or thrombogenesis were found in ≥94% of patients with CVD. In addition, 36 subjects with and 44 without LEx had similar low incidence of stroke/TIA (1 (1.3%) and 2 (2.5%), respectively, p = 1.0) during follow-up. Finally, LEx were not associated with aging, atherogenic risk factors, atherosclerosis, inflammation, or thrombogenesis.ConclusionsIn this study, LEx are similarly prevalent in healthy controls and SLE patients, are not associated with CVD, and are not associated with pathogenic risk factors. Therefore, the study findings suggest that LEx may not be cardioembolic substrates, may not represent pathologic valve structures, and may not require therapy.

BackgroundTranscranial Doppler (TCD) can detect a right-to-left shunt (RLS) with high sensitivity but has a 5% chance of a false negative study. TCD is usually performed with injection of agitated saline into an arm vein. We compared the sensitivity of TCD performed from the brachial versus femoral veins.MethodsPatients presenting to the cardiac catheterization laboratory for percutaneous closure of a patent foramen ovale (PFO) were enrolled. Power M-mode Transcranial Doppler (Terumo 150 PMD) was conducted. After injection of a mixture of 8 cc of agitated saline, 0.5 cc of air, and 1 cc of blood into the brachial vein, embolic tracks were counted over the middle cerebral arteries. The degree of RLS was evaluated by TCD at rest, and with Valsalva at 40 mmHg aided by visual feedback with a manometer device. The test was repeated using femoral venous injections.ResultsSixty five patients were enrolled, mean age 52, 43% male. TCD grades were significantly higher with femoral injections compared to brachial injections at rest (p

BackgroundPostmenopausal hormone therapy (HT) increases the risk of venous thrombosis and ischemic stroke.ObjectivesWe postulated that HT might increase the risk of ischemic stroke by promoting venous clots that travel to the brain through a right to left shunt (RLS).MethodsA total of 2,389 records were studied. After eliminating the premenopausal patients, and those with TIAs and non-ischemic strokes, the medical records of 1846 postmenopausal women hospitalized at four institutions for ischemic stroke were reviewed to identify those who had undergone an adequate study to assess for RLS. The proportion of women with a shunt in users and non-users of HT was compared in stroke patients and in a reference population consisting of postmenopausal women undergoing elective cardiac catheterization.ResultsThere were 363 (20%) records that had complete data and were included in the analysis. A shunt was more prevalent in patients with a cryptogenic stroke than in patients with a stroke of known cause (55/88 (63%) vs. 53/275 (19%), P

BackgroundSignificant alterations in autonomic nervous system (ANS) function, vasomotor reactivity, and cerebral blood flow may develop from damage to brain ANS regulatory areas in heart failure (HF). This preferentially right-sided injury occurs largely in autonomic structures perfused by the middle cerebral artery. Indications of altered, asymmetrical perfusion raise the potential for further neural damage.ObjectiveTo determine whether the extent of middle cerebral artery blood flow velocity and vasomotor reactivity is altered on one side of the brain over the other in HF versus control subjects, three ANS challenges were administered-each challenge recruited ANS regulatory areas potentially injured in HF.MethodsTranscranial Doppler ultrasonography was used to measure cerebral blood flow velocity and vasomotor reactivity in 40 HF (mean age = 52.7 years, SD = 7.5; 27 men; left ventricular ejection fraction = 26.8, SD = 8.3) and 42 control subjects (mean age = 48.3 years, SD = 6.0; 22 men) during 5% CO2 and hyperventilation, Valsalva, and orthostatic (upper body tilt) challenges.ResultsLower cerebral blood flow velocity and abnormal vasomotor reactivity (p < .01) were noted in HF middle cerebral arteries during all challenges. More right-sided flow velocity reductions appeared in HF, with laterality differences noted during CO2 and orthostatic (p < .05), but not Valsalva challenges.DiscussionDiminished cerebral blood flow velocity and altered vasomotor reactivity were associated with HF, changes being preferentially on the right side; the asymmetry was more pronounced during CO2 and orthostatic challenges. The impaired blood flow regulation may contribute to the lateralized brain pathology in ANS areas, undermining autonomic control in HF.

ObjectivesThe aim of this meta-analysis was to determine the accuracy of transcranial Doppler (TCD) compared with transesophageal echocardiography (TEE) as the reference.BackgroundRight-to-left shunting (RLS), usually through a patent foramen ovale (PFO), has been associated with migraine, cryptogenic stroke, and hypoxemia. With emerging observational studies and clinical trials on the subject of PFO, there is a need for accurate diagnosis of PFO in patients with these conditions, and those being considered for transcatheter closure. Although a TEE bubble study is the current standard reference for diagnosing PFO, the TCD bubble study may be a preferable alternative test for RLS because of its high sensitivity and specificity, noninvasive nature, and low cost.MethodsA systematic review of Medline, the Cochrane Library, and Embase was done to look for all the prospective studies assessing intracardiac RLS using TCD compared with TEE as the reference; both tests were performed with a contrast agent and a maneuver to provoke RLS in all studies.ResultsA total of 27 studies (29 comparisons) with 1,968 patients (mean age 47.8 ± 5.7 years; 51% male) fulfilled the inclusion criteria. The weighted mean sensitivity and specificity for TCD were 97% and 93%, respectively. Likewise, the positive and negative likelihood ratios were 13.51 and 0.04, respectively. When 10 microbubbles was used as the embolic cutoff for a positive TCD study, TCD produced a higher specificity compared with when 1 microbubble was used as the cutoff (p = 0.04); there was, however, no significant change in sensitivity (p = 0.29).ConclusionsTCD is a reliable, noninvasive test with excellent diagnostic accuracies, making it a proficient test for detecting RLS. TCD can be used as a part of the stroke workup and for patients being considered for PFO closure. If knowledge of the precise anatomy is required, then TEE can be obtained before scheduling a patient for transcatheter PFO closure.

BACKGROUND: We aimed to provide information on whether or not the correlation between body tilt and the pulse amplitude of transcranial ultrasonic time-of-flight waveform can be observed in the anterior-posterior skull direction. Also, we asked the question whether or not the skull pulsation can be detected since the cranial bones involved are thicker. METHODS: The experimental model of body tilt that alters intracranial pressure by shifting body fluid headward was employed. Transcranial ultrasound waveforms were examined in 15 healthy volunteers positioned at five tilt angles of +30 degrees, 0 degrees, -30 degrees, -60 degrees, and -90 degrees from the horizontal body position. A pulse-echo transducer was placed on the middle forehead and ultrasound waveforms were recorded. Synchronized variations in the ultrasonic time-of-flight with heartbeats were monitored using the pulsed phase locked loop technique for the output voltage of the ultrasound transducer. Simultaneous effects of body tilt on cardiovascular parameters were also evaluated. RESULTS: Pulse amplitudes of ultrasonic time-of-flight waveforms were found to vary with body tilt. Repeated-measures ANOVA and regression analysis showed a negative correlation between body tilt angle and pulse amplitude. The regression line has the equation: pulse amplitude = (1.158-0.01023 x tilt angle) x 10(-4) voltage. There was no such relationship between head-down body tilt and altered mean blood pressure or heart rate. CONCLUSION: An increase in the pulse amplitude of the anterior-posterior transcranial ultrasonic time-of-flight waveform can be detected when the head-down body tilt angle increases.

BackgroundWe aimed to provide information on whether or not the correlation between body tilt and the pulse amplitude of transcranial ultrasonic time-of-flight waveform can be observed in the anterior-posterior skull direction. Also, we asked the question whether or not the skull pulsation can be detected since the cranial bones involved are thicker.MethodsThe experimental model of body tilt that alters intracranial pressure by shifting body fluid headward was employed. Transcranial ultrasound waveforms were examined in 15 healthy volunteers positioned at five tilt angles of +30 degrees, 0 degrees, -30 degrees, -60 degrees, and -90 degrees from the horizontal body position. A pulse-echo transducer was placed on the middle forehead and ultrasound waveforms were recorded. Synchronized variations in the ultrasonic time-of-flight with heartbeats were monitored using the pulsed phase locked loop technique for the output voltage of the ultrasound transducer. Simultaneous effects of body tilt on cardiovascular parameters were also evaluated.ResultsPulse amplitudes of ultrasonic time-of-flight waveforms were found to vary with body tilt. Repeated-measures ANOVA and regression analysis showed a negative correlation between body tilt angle and pulse amplitude. The regression line has the equation: pulse amplitude = (1.158-0.01023 x tilt angle) x 10(-4) voltage. There was no such relationship between head-down body tilt and altered mean blood pressure or heart rate.ConclusionAn increase in the pulse amplitude of the anterior-posterior transcranial ultrasonic time-of-flight waveform can be detected when the head-down body tilt angle increases.

The purpose of this study was to understand why patients with adult congenital heart disease (CHD) but no obvious shunt have an increased frequency of migraine headaches (MH). CHD patients with no known cardiac shunts (CHD-NKS), based on their echocardiographic or angiographic procedures, were tested for a right-to-left shunt using agitated saline contrast transcranial Doppler (TCD). Medical records of 2,920 patients from the UCLA Adult CHD Center were screened to participate in a study to evaluate the prevalence of MH in adults with CHD; 182 patients (6.23%) had CHD-NKS; of these, 60 (30%) underwent a TCD; 23 (38%) tested positive and 37 (62%) tested negative for a right-to-left shunt (P = 0.01 compared with controls). The frequency of MH was 43% in CHD-NKS compared with 11% in controls (P < 0.0001). TCD demonstrated right-to-left shunting in approximately 2/3 of patients with pulmonary stenosis, the Marfan syndrome and congenitally corrected transposition of great vessels, 1/4 of patients with bicuspid aortic valve, 1/5 of patients with mitral valve prolapse and all patients with Ebstein's anomaly. Approximately half of these experienced MH. Patients who had MH did not show a higher frequency of right-to-left shunt when compared with patients without MH (P = 0.57). In conclusion, CHD patients with conditions usually not associated with a shunt have a higher than expected prevalence of PFO which permits intermittent right-to-left shunting undetected by standard non-contrast TTE and TEE; the increased prevalence of right-to-left shunting may partially explain the higher than expected frequency of migraines.

ObjectivesThe aim of this study was to assess the prevalence of right-to-left (R to L) shunt in patients with visual aura and evaluate the effect of shunt closure on resolution of aura.BackgroundRight-to-left shunting is associated with migraine headache (MH) with aura. Some patients present with visual aura without headaches. It is unclear whether visual aura without headache is a form of migraine or a transient neurologic dysfunction.MethodsOf patients referred to the University of California, Los Angeles for suspected patent foramen ovale (PFO), 225 had visual aura with or without MH. Patients were assessed for a shunt and evaluated for MH and/or visual aura. They were divided into 3 groups: 1) visual aura associated with MH; 2) visual aura unrelated in time to MH; and 3) visual aura without MH. The frequency of R to L shunt was compared with a control group of 200 patients. Eighty patients underwent PFO closure. Residual shunts, MH, and visual aura were reassessed after 3 and 12 months.ResultsThe prevalence of R to L shunt in Groups A, B, and C was 96%, 72%, and 67%, respectively, versus 18% in the control group (p < 0.0001). The frequency of shunting was similar in Group B versus Group C, but much higher in all 3 groups compared with control subjects. Twelve months after PFO closure, symptoms of aura were resolved in 52%, 75%, and 80% of patients in Groups A, B, and C, respectively (p = NS).ConclusionsThe similar distribution of R to L shunting in all 3 patient groups and the correlation between PFO closure and improvement of aura suggests a similar pathophysiology between the presence of PFO and the visual aura phenomenon, whether or not headache is present in the symptom complex.

ObjectivesThe purpose of this study was to understand the reason for variation in the sensitivity of different methods of detecting right-to-left shunts (RLS).BackgroundPatent foramen ovale (PFO) is implicated in the pathogenesis of cryptogenic stroke, decompression illness, and migraine headaches. Intravenous agitated saline injections with tomographic imaging (transthoracic, transesophageal, and intracardiac echocardiography) has been used for detecting intracardiac shunts. Some patients with a high clinical suspicion of PFO have inconclusive echocardiographic study results. Transcranial Doppler (TCD) is an alternative method for detecting RLS that is not dependent on tomographic imaging.MethodsThirty-eight consecutive patients who were undergoing PFO closure had simultaneous transcranial Doppler and intracardiac echocardiography performed. Agitated saline injections were performed at rest, with Valsalva maneuver, and with forced expiration into a manometer to 40 mm Hg before and after closure, as well as 3 or more months after closure. Right atrial pressures were measured in the periprocedural period, and RLS were graded according to standard methods during these maneuvers.ResultsRight atrial pressures were significantly higher with Valsalva maneuver compared with rest (before closure 21.6 +/- 11.9 mm Hg vs. 6.6 +/- 2.6 mm Hg, p < 0.001; after closure 28.4 +/- 13.9 mm Hg vs. 6.8 +/- 2.6 mm Hg, p < 0.001) and with manometer compared with Valsalva maneuver (before closure 38.7 +/- 6.6 mm Hg vs. 21.6 +/- 11.9 mm Hg, p < 0.001; after closure 44.0 +/- 9.5 mm Hg vs. 28.4 +/- 13.9 mm Hg, p < 0.001). Intracardiac echocardiography underestimated shunting in 34% of patients with Valsalva maneuver or manometer after closure compared with TCD.ConclusionsTranscranial Doppler with immediate feedback provided by forced expiration against a manometer to 40 mm Hg is more sensitive than echocardiographic imaging for the detection of RLS. These observations have significant implications for determining the incidence of RLS in patients with stroke or migraine.