Abnormal Cerebral Blood Flow Velocity Research Articles

Improving Completion Rates of Transcranial Doppler Ultrasounds in Children with Sickle Cell Disease Using Quality Improvement Efforts: In-Clinic Vs. Population-Based Assessments

Introduction:People living with sickle cell disease (SCD) are at risk for stroke due to progressive cerebral vasculopathy. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) study showed that transfusion therapy in patients with abnormal cerebral blood flow velocities measured by transcranial doppler (TCD) ultrasound significantly reduced the risk for stroke. Based on the STOP and STOP II studies, the National Heart, Lung and Blood Institute (NHLBI) and American Society of Hematology (ASH) recommend annual TCD screenings for children with HbSS and HbSb0 genotypes from age 2-16. Despite this recommendation, studies show that fewer than half of eligible children with SCD complete annual TCD screening. Recently, Cabana and Treadwell et al. (2020) found high TCD referral and completion rates in a multi-site quality improvement (QI) initiative (85% baseline) using chart review. Another feasible approach to tracking guideline adherence uses administrative claims data which are derived from diagnostic and billing codes from statewide claims. Claims data can be used to assess population estimates for a clinic or a state, for all eligible patients, including those who may not routinely access care. In this study, we use administrative claims to assess TCD completion rates in the same clinics participating in the aforementioned QI initiative. We hypothesized that, population level rates would be lower than those assessed via chart review and that QI strategies may not lead to sustained TCD completion rates.Methods:Between August 2017 to August 2018, a QI initiative within the Pacific Sickle Cell Regional Collaborative (PSCRC) was conducted to improve referral and completion rates of TCD screenings. Site leads participated in a monthly QI learning collaborative, implementing and reporting on Plan-Do-Study-Act (PDSA) cycles, with bimonthly chart review data collection. Medicaid administrative claims from the four states with participating clinics, from 2017, 2018 (to assess baseline and post-QI initiative performance) and 2019 (to assess sustainability), were used to assess rates of TCD completion in the eligible pediatric population, using the specifications of a previously validated quality measure by Reeves et al (2019). Annual TCD completion rates and changes in completion rates over time were assessed for each site and state.Results:Five sites from four states in the PSCRC were included in the analysis. There was large variability in the number of eligible patients in each clinic (13-75) and state (23-588). Based on administrative claims, TCD clinic-level completion rates at baseline ranged from 41.7% to 69.2% at individual clinics. After 12 months of QI participation, TCD completion rates improved at allsites (range 4.6% to 29.2%). The site with the largest change improved TCD completion rate from 41.7% to 70.8% (n=24). All but one site had a decrease in TCD completion rate after completing the QI initiative and in 2019, TCD completion rates were within 10% of baseline completion rates at all sites (range -8.2% to 8.3%). At the statewide level, one state had a sustained improvement in TCD completion (improvement from baseline: 8.8%). In three of the four states providing data, TCD completion rates decreased from baseline (range -0.7% to -12.6%).Discussion:In a regional collaborative, we found improvements in TCD completion in the setting of a QI initiative focused on TCD, which were not sustained in the year after. This suggests the need for a systems-level approach to improvement, leading to feasible sustainability when no longer the focus of a collaborative. In addition, our data show that, when using administrative claims, rates of TCD completion are lower than rates when using chart review data (41.7% to 69.2% vs. 85% by chart review noted in prior publication). Thus, while site-specific medical record review provides insight into the quality of care for patients seen in the clinic, administrative claims data allow for a global understanding of the quality of care for the clinic population at risk, including those who do not attend clinic regularly. This suggests additional potential focus for quality improvement initiatives, such as systems to optimize outreach to patients who may not routinely access care. This type of outreach may best be done by health plans, potentially in partnership with sickle cell specialists, and would be an important tool for improving health for children with SCD. DisclosuresVissa: Global Blood Therapeutics Inc: Research Funding. Treadwell: National Alliance of Sickle Cell Centers: Other: Early Evaluation of the Use of Crizanlizumab in Sickle Cell Disease.

Transcranial Doppler to detect early abnormalities in cerebral hemodynamics following traumatic brain injury in adult patients

Background Transcranial Doppler (TCD) can be a valuable tool in detecting early changes in cerebral blood flow (CBF) velocities following traumatic brain injury (TBI). We designed this prospective observational study to screen for early abnormalities in CBF following TBI using TCD and to evaluate its ability to predict the patients’ outcome. Patients and methods The study was carried out on 66 adult patients admitted to the ICU with TBI. TCD was performed on admission by insonating the middle cerebral arteries and extracranial internal carotid arteries, and flow velocities were recorded, and pulsatility index (PI) and Lindegaard ratio were calculated. End-diastolic velocity (EDV) less than 25 cm/s and PI more than 1.3 were considered abnormal. The patient outcome was evaluated at discharge from the hospital using the Glasgow Outcome Scale. Results Admission TCD revealed that EDV less than 25 cm/s was present in 11.1% of the patients with mild-to-moderate TBI [Glasgow Coma Score (GCS)>8] and in 46.7% of the patients with severe TBI (GCS≤8). PI more than 1.3 was present in 16.7% of the patients with GCS more than 8 and in 46.7% of the patients with GCS less than or equal to 8. The incidence of vasospasm was highest on the fifth day after trauma as it was detected in 16.7% of the patients with GCS more than 8 and in 40% of the patients with GCS less than or equal to 8. The logistic regression analysis of outcome predictors showed that the initial PI more than 1.3 had 91% sensitivity and 89% specificity and EDV less than 25 cm/s had 88% specificity and sensitivity 85% in predicting poor outcome; meanwhile, cerebral vasospasm had 84% sensitivity and 75% specificity in poor outcome prediction. Conclusion Early abnormal CBF velocity detected by TCD following TBI can predict poor outcome at discharge from the hospital.

Association of small fiber neuropathy and post treatment Lyme disease syndrome.

ObjectivesTo examine whether post-treatment Lyme disease syndrome (PTLDS) defined by fatigue, cognitive complaints and widespread pain following the treatment of Lyme disease is associated with small fiber neuropathy (SFN) manifesting as autonomic and sensory dysfunction.MethodsThis single center, retrospective study evaluated subjects with PTLDS. Skin biopsies for assessment of epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD) and functional autonomic testing (deep breathing, Valsalva maneuver and tilt test) were performed to assess SFN, severity of dysautonomia and cerebral blood flow abnormalities. Heart rate, end tidal CO2, blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery using transcranial Doppler were monitored.Results10 participants, 5/5 women/men, age 51.3 ± 14.7 years, BMI 27.6 ± 7.3 were analyzed. All participants were positive for Lyme infection by CDC criteria. At least one skin biopsy was abnormal in all ten participants. Abnormal ENFD was found in 9 participants, abnormal SGNFD in 5 participants, and both abnormal ENFD and SGNFD were detected in 4 participants. Parasympathetic failure was found in 7 participants and mild or moderate sympathetic adrenergic failure in all participants. Abnormal total CBFv score was found in all ten participants. Low orthostatic CBFv was found in 7 participants, three additional participants had abnormally reduced supine CBFv.ConclusionsSFN appears to be associated with PTLDS and may be responsible for certain sensory symptoms. In addition, dysautonomia related to SFN and abnormal CBFv also seem to be linked to PTLDS. Reduced orthostatic CBFv can be associated with cerebral hypoperfusion and may lead to cognitive dysfunction. Autonomic failure detected in PTLDS is mild to moderate. SFN evaluation may be useful in PTLDS.

Cerebral Infarcts and Cerebrovascular Disease in Neurologically Intact Tanzanian Children with Sickle Cell Anaemia

Introduction:Children and adolescents with sickle cell anemia (SCA) without history of neurological manifestations remain at risk of stroke and require cost effective screening as evidence-based stroke prevention interventions are developed. Although there are data on the prevalence of Transcranial Doppler (TCD) abnormality, there are relatively few studies on the prevalence of silent cerebral infarction (SCI) on magnetic resonance imaging (MRI) and vasculopathy on MR angiography (MRA), paricularly in Africa, where the burden of disease is greatest. In this study in Africa, we determined the prevalence of SCI on MRI and cerebral vasculopathy on MRA, and explored associations with age, sex, internal carotid/middle cerebral artery (ICA/MCA) and basilar cerebral blood flow velocities (CBFV) on TCD, and hematological variables.Patients and methods:We prospectively studied children with homozygous SCA (HbSS) without prior clinically overt stroke or TIA or seizures. Clinical information and blood for full blood count was collected for all patients. All were offered TCD using non-imaging equipment (Compumedics) and MRI and MRA of intracranial arteries on a Philips 1.5 Tesla scanner. MRA was graded as 1 Turbulence, 2 Stenosis, 3 Occlusion, 4 Occlusion with collaterals (moyamoya). Imaging was reviewed by 2 neuroradiologists (MJ and DS) and consensus was reached.Results:Within a period of 12 months, 395 children with SCA were recruited. Mean age was 12.7+/-4 (range 5-19 years); 199 (50.4%) were male. Mean hemoglobin was 7.6±1.1 (range 4.1-13.5) g/dl. 381 had TCD, of whom 227 (57%) have had brain MRI and MRA so far.Only 14/395 (3.5%) of patients had abnormal CBFV, 8 (2%) with maximum CBFV <50 cm/sec, 3 with CBFV 150-169 cm/sec, 1 with conditional (170-199 cm/sec) and 2 (0.5%) with abnormal CBFV (>200cm/sec).Prevalence of silent cerebral infarction was 29% (65/227) and was similar in males (30%; 34/114) and females (28%; 31/110) but was lower in children aged <9 years (20%; 10/51) than in those aged 10-14 years (33%; 27/83) or those aged 15-19 years (32%; 28/89); this was not significant (p=0.2).The prevalence of cerebral vasculopathy on MRA, defined as stenosis (Grade 2), occlusion (Grade 3) or occlusion with collaterals (moyamoya; Grade 4), was 9% (20/227). The internal carotid and/or middle cerebral artery was affected in all 20 and the anterior cerebral artery was affected in 7 patients. Vasculopathy was not observed on MRA in the posterior cerebral artery and no patients had moyamoya. An additional 9 (4%) patients had turbulence (Grade 1) in at least one artery on MRA.SCI were more common in those with MRA vasculopathy Grades 2-3 (12/64; 19%) and in those with Grade 1 Turbulence (2/9; 22%) than in those with normal MRA (8/165; 5%) (p<0.05). Patients with Grade 1 Turbulence had higher ICA/MCA CBFv (mean 122+/-36 cm/sec) than those with normal MRA (mean 101+/-25 cm/sec) or Grades 2-3 (mean 109+/-21 cm/sec) vasculopathy. The difference in those with Grade 1 turbulence compared with those with normal MRA was significant (mean difference 20 cm/sec, 95% confidence intervals 1, 39 cm/sec; p=0.037). Basilar velocity was also significantly higher in those with Grade 1 turbulence (87+/-21 cm/sec) than in those with normal MRA (76+/-14 cm/sec) and those with Grade 2-3 vasculopathy (80+/-11 cm/sec)(mean difference 11.5 cm/sec, 95% confidence intervals 0.3, 22.6 cm/sec; p=0.043). Basilar velocity weakly correlated with hemoglobin (r=-0.18) but the relationships between hemoglobin and ICA/MCA CBFV or either presence of SCI or MRA abnormality were not significant.Conclusions:The prevalence of SCI on MRI is high in children with SCA without neurological history living in Africa even when TCD CBFV is normal. Children and adolescents with all grades of vasculopathy on MRA are at higher risk of brain parenchymal injury. The lack of association between SCI and hemoglobin may be related to the relatively severe anemia in our African study. As MRA contrast depends on velocity of blood flowing in vessels, it is not surprising that Grade 1 turbulence on MRA appears to reflect high CBFV on TCD. Importantly, high TCD velocity and Grade 1 turbulence may reflect the potentially reversible early stages in the development of SCA vasculopathy when cerebral blood flow is high before stenosis and occlusion supervene. TCD is operator dependent and there may be a case for MRI and MRA screening if follow-up shows that these measures predict stroke. DisclosuresNo relevant conflicts of interest to declare.

Transcranial Doppler-based modeling of hemodynamics using delay differential equations

Approximately 40,000 people suffer brain aneurysm rupture and 2.5 million suffer a traumatic brain injury (TBI) each year in the USA. Cerebral vasospasm (CV) occurs as a complication of brain hemorrhage resulting from cerebral aneurysm rupture and TBI. CV causes further cerebral injury and is the primary cause of death and disability in aneurysmal hemorrhage and TBI. Consequently, it is critical to design a model for diagnosing and analyzing the abnormal cerebral blood flow velocity hemodynamics associated with CV. By generating such a model, it would be possible to design machine learning mechanisms for earlier prediction of CV. In previous studies, cerebrovascular models of blood flow behavior for different disorders were established. Unfortunately, those models are disorder specific and have too many parameters to tune. We have established a model for the signal envelope of the cerebral blood flow velocity that was produced by transcranial Doppler (TCD). We have applied it to simulate CV behavior, and it is general enough to be applied to other cerebrovascular disorders. The model is based on the delay differential equation as a representative modeling equation for three diagnostic categories: control (no CV or hyperemia), hyperemia, and CV. The model has only four tunable parameters and allows switching from one case to another by changing those parameters. After validation of the model, the generated envelope signals compared to spectrograms recorded by transcranial Doppler, demonstrated good concordance in all three categories between the model and signals acquired with TCD. This result could be used for modeling cerebral blood velocity abnormalities and lead to early detection of CV in TBI and aneurysmal hemorrhage.

Characteristics of cardio-Cerebrovascular modulation in patients with generalized anxiety disorder: an observational study

BackgroundGeneralized anxiety disorder (GAD) has been shown in previous studies to display abnormal cerebral blood flow velocity (CBFV); however, the characteristics of cardio-cerebrovascular modulation are unknown. We aimed to analyze cardio-cerebrovascular modulation using parameters from a supine-to-standing test.MethodsThere are 2 parts to this study; in Part 1, 125 participants with Hamilton Anxiety scale scores ≥14 were enrolled, and 33 age- and sex-matched medically and psychiatrically healthy volunteers were recruited as control participants. Patients were divided by score into mild, moderate, and severe anxiety groups. The cardio-cerebrovascular modulation using the parameters of dynamic changes of CBFV and heart rate in response to an orthostatic challenge were investigated. In Part 2, we followed up the severe GAD patients for 6 months and repeated the supine-to-standing test, and severe GAD patients were divided into recovery and non-recovery groups.ResultsIn part 1, the GAD group displayed more marked CBFV and heart rate changes than the healthy group, but there was no difference in the CBFV and heart rate changes from the supine to upright position in mild, moderate, and severe anxiety groups. In part 2, The recovery group demonstrated significant improvement in changes in the CBFV and heart rate values from the supine to the upright position after treatment compared with before treatment. In the non-recovery group, the CBFV and heart rate changes were significantly higher than the healthy group regardless of treatment.ConclusionsCardio-cerebrovascular modulation is compromised in patients with GAD, however, this impairment can be restored to normal after the disappearance of anxiety.

Haemoglobin oxygen saturation, leucocyte count and lactate dehydrogenase are predictors of elevated cerebral blood flow velocity in Nigerian children with sickle cell anaemia

Background: Transcranial Doppler ultrasound (TCD) scan, which measures blood flow velocity through the time-averaged mean of maximum velocities (TAMMVs) in the internal carotid arteries and middle cerebral arteries, is a useful screening tool for predicting stroke risk in children with sickle cell anaemia (SCA).Aim: To investigate which clinical and laboratory indices predict abnormal TCD velocity in children with SCA.Methods: Fifty-four SCA patients with normal TCD (TAMMV < 170 cm/s), classified as negative TCD (NTCD), and 93 patients with conditional and abnormal TCD velocities (TAMMV ≥ 170 cm/s) classified as positive TCD were recruited. The haemoglobin oxygen saturation, haematological variables, nitric oxide metabolites and lactate dehydrogenase activity of the patients were analysed.Results: The mean (SD) age was 7.16 (3.84) years (range 2–16). The median SpO2 of the patients in the positive TCD group was significantly lower than that of the negative TCD group (p = 0.002). Multivariate logistic regression analysis indicated that the MCV [odds ratio (OR) 1.12, 95% confidence interval (CI) 1.04–1.22, p = 0.01)], MCH (OR 1.34, 95% CI 1.02–1.77, p = 0.04), leucocyte count (OR 1.26, 95% CI 1.07–1.49, p = 0.01) and lactate dehydrogenase (LDH) level (OR 1.00, 95% CI 1.00–1.01, p = 0.01) were independent predictors of high cerebral blood flow velocities.Conclusions: These clinical and laboratory indices are characteristic of chronic hypoxia and severe anaemia and are predictors of abnormal cerebral blood flow velocity. They can be used to predict stroke risk in children with SCA when access to TCD screening is limited.

Abstract TP115: Cerebral Hemodynamic Changes in Military Personnel With Long-term Effects of Concussions

Service members (SMs) suffer from repeated exposure to concussions or mild TBI, which can disrupt cerebral blood flow. This effect is seen in the acute phase of TBI, but the development of vascular wall abnormalities, which can lead to luminal narrowing and abnormally elevated cerebral blood flow velocities (CBFV), has not been studied in the post concussive phase. The purpose of this study was to evaluate the transcranial Doppler (TCD) determined incidence of abnormal cerebral hemodynamics in patients with long-term effects of mTBI. Material and Methods: TCD recordings of mean CBFV in cm/sec and Pulsatility Indices (PI) were recorded from 431 SMs (9 females; ages 24-54, mean age 39.2 ± 6.4 years) who were admitted to the National Intrepid Center of Excellence 4-week Interdisciplinary Outpatient Program. TCD data were analyzed to determine whether SMs exhibited abnormal CBFV s in the middle cerebral artery, internal carotid artery (ICA), and basilar artery. All subjects consented to protocol #362504 prior to any data collection or analysis. Two standard deviation from the mean CBFV in any direction labeled as an abnormal and PI was assumed normal with values between 0.7 and 0.9 Patients with one or more vessels with abnormal CBFV’s and PI’s were labeled as abnormal. Results: Average time since last TBI was 5.1 ± 3.4 years. We observed abnormal CBFV values in 33% of SMs. 149 (35%) and 48 (11%) demonstrated abnormally high CBFV and PIs in one or more vessels, respectively. Abnormal CBFV was observed most frequently in the ICA (48%). Majority of studied patients had patchy pattern of abnormal data presented in one or few vessels. The presence of abnormal cerebral hemodynamics was inversely related to the time since the last mTBI exposure: the likelihood of abnormal CBFV values deceased with increasing time since last head injury was sustained but was still present. Conclusions: Our data reveal that a large proportion of SMs have elevated CBFVs following mTBI exposure in many years after last mTBI. We believe that head injuries due to combat and training blast and blunt force trauma exposure cause early atherosclerotic or fibrotic changes in the large vessel walls of the Circle of Willis, which results in vascular lumen narrowing and increased CBFV’s.

Laboratorial and Genetic Biomarkers Associated to Cerebral Blood Flow Velocity on Hemoglobin SC Disease

INTRODUCTIONClinical complications in hemoglobin SC disease (HbSC) are mild compared to sickle cell anemia (SCA), the most severe type of sickle cell disease. However, HbSC individuals have 100 times greater risk of stroke compared to the healthy population. The lack of studies to determine reference values for transcranial Doppler (TCD) velocities in HbSC is still a limitation considering that we have been used TCD velocities previously determined for the SCA and having as standard the one described by Adams et al. (1992). Other studies described cerebral blood flow velocities (CBFV) for HbSC individuals, and considered as abnormal values that exceed 128 cm/s and 143.5 cm/s respectively. Studies show the association of abnormal TCD with distinct laboratorial biomarkers, despite the controversial results. To our knowledge, there are no published studies based on specific biomarkers and abnormal CBFV for HbSC individuals. Thus, we aim to investigate the association of genetic, hematological and biochemical data with CBFV in HbSC. METHODSA cross-sectional study comprising 68 HbSC individuals, with an average age of 6.96 ± 3.90 years, whom 40 (58.82 %) were female, attended the Pediatric Cerebrovascular Disease Outpatient Center at the Hospital Universitario Professor Edgar Santos (HUPES) of the Universidade Federal da Bahia (UFBA) was conducted. All procedures were in accordance with the 1964 Helsinki declaration and its later amendments. The CBFV was estimated with TCD, and the time-averaged maximum mean velocity (TAMMV) in the middle cerebral arteries, anterior cerebral artery and distal intracranial internal carotid was assessed. Hematological and biochemical parameters, nitric oxide (NO) measurement and genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) 677C>T (rs1801133), vascular cell adhesion molecule (VCAM)-833T>C (rs1041163)and VCAM 1238G>C genes, α3.7Kb thalassemia (-α3.7-thal) and Beta S (βS) haplotypes were investigated. Statistical analyses were performed using SPSS version 18.0 software, Graphpad Prism version 6.0 and JMP software. P values <0.05 were considered significant. RESULTSThe median of TAMMV in the HbSC individuals was 111.50 cm/s, the 25th percentile was 101.50 cm/s and the 75th percentile was 125.75 cm/s. The TAMMV was negatively correlated to red blood cells (RBC) (R= -0.2734; P= 0.0315), hemoglobin (Hb) (R= -0.3390; P= 0.0070), hematocrit (Ht) (R= -0.3470; P= 0.0057) and direct bilirubin (R= -0.2545; P= 0.0363) and positively correlated to monocytes (R= 0.2533; P= 0.0470) and ferritin (R= 0.3044; P= 0.0145). Based on previous protocol for SCA established by Adams and colleagues, we found two individuals with low TCD, 64 with normal TCD, one with abnormal TCD and one with inconclusive TCD. Noteworthy, this classification is not suitable for HbSC individuals. Using a cut off value of 128 cm/s, defined by Deane and colleagues (2008), we found significant decreased RDW (p=0.035) and NO (p=0.017) values in HbSC individuals with TAMMV higher than 128 cm/s. Vieira and colleagues (2014) defined a cut off value of 143.50 cm/s for HbSC individuals in the same population of this study. We found significant decrease of Hb (p=0.008) and Ht (p=0.008) concentration and increased ferritin levels (p=0.023) in HbSC individuals with TAMMV higher than 143.50 cm/s. Value of TAMMV at 75th percentile (125.75 cm/s) was used in order to evaluate the laboratorial markers. We found significant differences in Hb, Ht, RDW and NO levels, which were decreased, and in the ferritin, which was elevated in HbSC individuals with TAMMV above 125.75 cm/s (Table 1). The multivariate analysis adjusted by age and sex showed that Ht (< 33.35%), RDW (> 15.55%) and NO (< 29.86 uM) were independently associated with TAMMV values higher than 125.75 cm/s (75th percentile) (Table 2). CONCLUSIONSWe suggest that RBC, Hb, Ht, RDW, monocyte, direct bilirubin, NO, ferritin, polymorphism on the MTHFR 677C>T gene and the absence of α3.7Kb thalassemia are associated with TAMMV on HbSC individuals. The TAMMV 125.75cm/s is lower than the those proposed by Deane et al. (2008) and Vieira et al. (2014), but have shown to be associated with hematological and biochemical changes found in both velocities 128 cm/s and 143.50 cm/s respectively. Thus, we also suggest that TAMMV of 125.75 cm/s should be investigated in additional studies as a cut-off point for stroke risk in HbSC individuals. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Haptoglobin, alpha‐thalassaemia and glucose‐6‐phosphate dehydrogenase polymorphisms and risk of abnormal transcranial Doppler among patients with sickle cell anaemia in Tanzania

Transcranial Doppler ultrasonography measures cerebral blood flow velocity (CBFv) of basal intracranial vessels and is used clinically to detect stroke risk in children with sickle cell anaemia (SCA). Co-inheritance in SCA of alpha-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) polymorphisms is reported to associate with high CBFv and/or risk of stroke. The effect of a common functional polymorphism of haptoglobin (HP) is unknown. We investigated the effect of co-inheritance of these polymorphisms on CBFv in 601 stroke-free Tanzanian SCA patients aged <24years. Homozygosity for alpha-thalassaemia 3·7 deletion was significantly associated with reduced mean CBFv compared to wild-type (β-coefficient -16·1cm/s, P=0·002) adjusted for age and survey year. Inheritance of 1 or 2 alpha-thalassaemia deletions was associated with decreased risk of abnormally high CBFv, compared to published data from Kenyan healthy control children (Relative risk ratio [RRR]=0·53 [95% confidence interval (CI):0·35-0·8] & RRR=0·43 [95% CI:0·23-0·78]), and reduced risk of abnormally low CBFv for 1 deletion only (RRR=0·38 [95% CI:0·17-0·83]). No effects were observed for G6PD or HP polymorphisms. This is the first report of the effects of co-inheritance of common polymorphisms, including the HP polymorphism, on CBFv in SCA patients resident in Africa and confirms the importance of alpha-thalassaemia in reducing risk of abnormal CBFv.

Feasibility and efficacy of chronic transfusion for stroke prevention in children with sickle cell disease

In children with sickle cell disease (SCD), chronic transfusion to maintain haemoglobin S (HbS) below 30% markedly decreases both the risk of a first stroke when transcranial Doppler (TCD) ultrasonography shows abnormal cerebral blood flow velocities and the risk of recurrent stroke. Maintaining HbS below 30% may be difficult, especially in countries where blood donors and recipients belong to different ethnic groups and where the availability of closely matched blood products is limited. We assessed the feasibility and efficacy of chronic transfusion with an HbS target of 30% in children with SCD living in the Paris area. We retrospectively studied 29 children aged 6.8 +/- 3.0 yr (3-15 yr) at inclusion who received chronic transfusion either because of abnormal TCD findings (primary prevention group, PPG, n = 17) or because of a previous cerebrovascular event (secondary prevention group, SPG, n = 12 including nine with a history of stroke and three of transient ischaemic attacks). Mean follow-up was 3.5 +/- 3.0 yr (0.5-12 yr). No cases of stroke occurred in the PPG. In the SPG, one patient with a history of stroke and severe cerebrovascular disease had a recurrence after 11 yr of chronic transfusion, when the HbS level was 20%. The stroke recurrence rate (SPG group) was 1.6/100 patient-years. Mean HbS levels before and after transfusion were 30 +/- 10% and 20.6 +/- 7%, respectively. Two patients acquired red-cell alloantibodies. Of the 29 patients, 22 required iron chelation. Regular transfusion maintaining HbS below 30% is feasible and safe in children with SCD in France and protects from overt stroke.

Risk factors for high cerebral blood flow velocity and death in Kenyan children with Sickle Cell Anaemia: role of haemoglobin oxygen saturation and febrile illness

High cerebral blood flow velocity (CBFv) and low haemoglobin oxygen saturation (SpO2) predict neurological complications in sickle cell anaemia (SCA) but any association is unclear. In a cross-sectional study of 105 Kenyan children, mean CBFv was 120 ± 34·9 cm/s; 3 had conditional CBFv (170–199 cm/s) but none had abnormal CBFv (>200 cm/s). After adjustment for age and haematocrit, CBFv ≥150 cm/s was predicted by SpO2 ≤ 95% and history of fever. Four years later, 10 children were lost to follow-up, none had suffered neurological events and 11/95 (12%) had died, predicted by history of fever but not low SpO2. Natural history of SCA in Africa may be different from North America and Europe.

The Visually-Evoked Cerebral Blood Flow Response in Women with a Recent History of Preeclampsia and/or Eclampsia

Several studies provide evidence for altered cerebral hemodynamics during (pre)eclampsia. Whether (pre)eclampsia has a persistent negative impact on cerebral hemodynamics, possibly contributing to an elevated risk of premature stroke, is unknown. The aims of this study were (i) to refine and apply a control system-based method previously introduced by Rosengarten to quantify the visually-evoked blood flow response of the posterior cerebral artery (PCA); and (ii) to test the hypothesis with this method that cerebral hemodynamics in women with a recent history of (pre)eclampsia is abnormal relative to that in parous controls. Hereto, we recorded cerebral blood flow velocity (CBFV) in the PCA by transcranial Doppler (TCD) sonography during cyclic visual stimulation in 15 former preeclamptics, 13 former eclamptics and 13 controls. The typical CBFV response was fitted with the step response of a second-order-linear model enabling quantification by parameters K (gain), ζ (damping), ω (natural frequency), T v (rate time) and T d (time delay). The method refinement introduced here consisted of response filtering before quantification and of considering the individual instead of group-averaged response patterns. Application of this refinement reduced the fitting errors (1.4 ± 1.2 vs. 3.2 ± 1.8, p < 0.01). Intergroup differences in model parameters were not found. Although statistically not significant, a trend was observed that critical damping (ζ>1) occurred more frequently in the combined group of former patients than in the controls (7 of 28 vs.1 of 13, p = 0.16). Critical damping (ζ>1) reflects an abnormal response, which is either compensated for by a rise in rate time (“intermediate”; ζ>1; T v > 20) or remains uncompensated (“sluggish”; ζ>1; T v < 20). Critical damping increased significantly ( p = 0.039) with (pre-)eclampsia-to-test-interval in the PE+E patients with abnormal responses (ζ>1), suggesting that (pre)eclampsia might induce diminishing cerebral hemodynamic function over time. Based on a system-analytical classification approach, the data of this study provide evidence for individual CBFV responses to be abnormal in former (pre)eclamptics compared with controls. Further study is needed to reveal how the abnormal CBFV response classification reflects cerebrovascular dysfunction. (E-mail: esther.martens@mumc.nl)

Cerebral and Systemic Hemodynamics Changes During Upright Tilt in Chronic Fatigue Syndrome

During head-up tilt (HUT), patients with chronic fatigue syndrome (CFS) have higher rates of neurally mediated hypotension (NMH) and postural tachycardia syndrome (POTS) than healthy controls. The authors studied whether patients with CFS were also more likely to have abnormal cerebral blood flow velocity (CBFV) compared with controls in response to orthostatic stress. Transcranial Doppler monitoring of middle cerebral artery (MCA) CBFV was performed during 3-stage HUT prospectively in 26 patients with CFS and 23 healthy controls. At the same time, continuous monitoring of arterial blood pressure (BP), heart rate (HR), endtidal CO2 (ET-CO2) were performed. Results are reported as mean +/- SD. NMH developed in 21 patients with CFS and in 14 controls (P = .22). POTS was present in 9 CFS patients and 7 controls (P = .76). Supine HR was higher in CFS patients, but all other hemodynamics and CBFV measures were similar at baseline. The median time to hypotension did not differ, but the median time to onset of orthostatic symptoms was shorter in those with CFS (P < .001). The CBFV did not differ between groups in the supine posture, at 1 or 5 minutes after upright tilt, at 5 or 1 minute before the end of the test, or at termination of the test. Mean CBFV fell at termination of tilt testing in those with CFS and controls. ET-CO2 was lower at termination of the test in those with CFS versus controls (P = .002). The results of this study are not consistent with the hypothesis that patients with CFS have a distinctive pattern of MCA CBFV changes in response to orthostatic stress.

Elevated Cerebral Blood Flow Velocities in Fabry Disease With Reversal After Enzyme Replacement

Fabry disease is an X-linked inherited disorder resulting from a deficiency of alpha-galactosidase A. Cerebrovascular disease in Fabry disease includes small-vessel disease and larger-vessel ectasia in a predominantly posterior distribution. We assessed transcranial Doppler (TCD) blood flow velocities in naive and enzyme-treated Fabry patients. TCD was used to noninvasively examine patients with Fabry disease for abnormal cerebral blood flow velocities. TCD measurements were also made during CO2 retention by breathholding to examine cerebrovascular vessel reactivity. Twenty-six patients were enrolled in a 6-month, double-blind, placebo-controlled trial of enzyme replacement therapy consisting of biweekly intravenous alpha-galactosidase A infusions, with a subsequent 18-month follow-up in an open-label trial. Statistical analysis consisted of applying a mixed-effects ANOVA model for correlated outcomes. Peak velocity, mean velocity, pulsatility index, and resistance index were found to be significantly higher in patients compared with control subjects. When the individual vessels were considered, elevated flow velocities were found in the middle cerebral M1 branch and the posterior cerebral artery. Enzyme replacement therapy significantly decreased peak, mean, and end-diastolic velocities and flow acceleration at the 18-month follow-up time point. Patients with Fabry disease have elevated cerebral blood flow velocities. These velocities significantly improved with enzyme replacement therapy.

Maternal cerebral circulation in normal and abnormal pregnancies.

Abnormal pregnancies are usually associated with an impairment of maternal cerebral circulation which is mainly a consequence of generalized vasospasm and cerebral edema. The pathogenesis of vasospasm has still been a matter of controversy. The aim of this study was to evaluate maternal cerebral blood flow velocity (CBFV) changes in normal and abnormal pregnancies, and to correlate CBFV findings with the severity of symptoms in abnormal pregnancies. A group of 40 gravidas (aged between 25 and 32 years) with pre-eclampsia were analyzed by Transcranial Doppler (TCD), Color Doppler Flow Imaging of carotid arteries and Transcranial Color Coded System once a week, starting from 32nd week of pregnancy and followed 2 months after delivery. The study was performed from the January 1996 to June 1996. The results showed 70% of abnormal pregnancies to have impaired TCD findings, mostly increased CBFV. The degree of toxemia measured by Goecke's index significantly correlated with abnormal CBFV Nine gravidas with increased CBFV on the first examination developed vasospasm during 34 to 36 weeks of gravidity. No statistically significant difference of the M1 segment of MCA diameters was found between normal (3.8 +/- 0.7 mm) and abnormal pregnancies (4.1 +/- 0.9 mm). The increase in the maternal CBFV was the most frequent observation in abnormal pregnancies. It was progressive during late pregnancy, when vasospasm may develop, although the presence of vasospasm is still the matter of controversy. The most important observation was that significant changes in CBFV preceded neurologic symptoms, emphasizing the predictive role of TCD in abnormal pregnancies.

Comparison of cerebral blood flow velocity estimation with cranial ultrasound imaging for early prediction of outcome in preterm infants

Seventy-four low birth weight infants underwent serial measurements of cerebral blood flow velocity (CBFV) using Doppler ultrasound together with ultrasound imaging of the brain. Surviving infants were examined and assessed using the Bayley scales of mental and motor development at 18 months post-term. There were no significant differences in mean CBFV between normal and impaired infants. Infants with abnormal neurological signs (n = 6) or developmental delay (n = 3) did not show the usual steady rise in CBFV during the first few days of life. Four of nine had a rise, then a fall in CBFV compared with 4 of 31 with complete data in the normal group. This difference is significant (chi 2 = 4.3, p = 0.03). The magnitude of the percentage increase between day 1 and day 3 was also smaller in the abnormal group (median 0% vs. 39%, Mann-Whitney p = 0.03). A structural abnormality seen on the cranial ultrasound image was a better predictor of adverse outcome than an abnormal CBFV pattern, with a better sensitivity and specificity (66% and 97% for imaging compared to 44% and 87% for CBFV). The addition of serial ultrasound Doppler measurements of CBFV did not improve the prediction of outcome obtained using ultrasound imaging alone.

15 CERBRAL BLOOD FLOW VELOCITY IN THE HIGH RISK NEWBORN – AN INDICATOR OF EARLY PROGNOSIS

In 175 high risk neonates (87:>2500 g; 50:2500–1500 g; 38: <1500 g) cerebral blood flow velocities (CBFV)were measured by transcranial Doppler in the basal cerebral arteries on the 1st, 3rd to 5th and 8th to 10th day of life. They were compared with values of healthy neonates. Cranial ultrasound was performed on all babies. On the 1st day 66% of the babies had normal, 23% decreased, and 12% increased CBFV. On day 8 to 10 87% had normal, 6% decreased, and 7% increased CBFV. In babies below 1500 g, normal CBFV were associated with the lowest incidence of cerebral hemorrhage (h) and death (d) (6/23 h; no d) while increased CBFV indicated poor prognosis (8/12 h; 7/12 d). Babies with decreased CBFV showed more hemorrhages and deaths than those with normal CBFV. A similar incidence of hypoxic ischemic encephalopathies, hemorrhages and deaths was found in neonates more than 1500 g with both normal or abnormal CBFV. Conclusion: CBFV measured by Doppler are useful as an early prognostic parameter in infants below 2500 g; in higher birth weights they may be useful for prognosis only in selected cases.

Severe birth asphyxia and abnormal cerebral blood-flow velocity.

Thirty-four fullterm infants with postasphyxial encephalopathy (PAE) were studied with ultrasound to assess cerebral blood-flow velocity (CBFV). A control group of 126 healthy infants also had CBFV recordings during the first week of life. Measurements for the majority of the asphyxiated group fell into two abnormal patterns in relation to the control group: four had low CBFV (less than 2 SD below the mean) and 17 had high CBFV (greater than or equal to 2 SD above the mean); all had severe PAE. Median age at the first high measurement was 26 hours. There were no statistically significant differences between infants with normal and abnormal CBFV in measurements of PaCO2 or mean arterial blood-pressure. A Pourcelot Resistance Index (PRI) less than 0.55 was common in the presence of high CBFV, but never seen with low measurements. 21 of the 34 infants died of their asphyxial insult and four of the survivors have severe cerebral palsy at a median age of two years. Three of the four with low CBFV died, and no infant with CBFV greater than 3 SD survived without severe impairment. The positive predictive value of CBFV measurements less than 2 SD or greater than 3 SD for death or severe impairment is 94 per cent, compared with 83 per cent for low PRI alone. The authors believe that high CBFV is the result of vasoparalysis of cerebral arterioles and that it represents a form of irreversible cerebral injury.

1328 NEONATAL CEREBRAL HEMORRHAGE (CH)/HEMODYNAMICS AND OUTCOME

To correlate the severity of CH and its associated cerebral hemodynamic changes with long-term outcome, we prospectively evaluated survivors with birth weight ≤1500 gnu The population was drawn from 155 low birth weight inborn infants who were assessed for CH by echoencephalography and for abnormal cerebral blood flow velocity (CBFV) patterns by Doppler ultrasound technique. Of these 155 infants, 100 survived; 70 returned for child development evaluation at a mean age of 16 ± 5 mo; in 40, valid Bayley scores were obtained. The incidence of neurological handicaps was higher with those with CH (47%) vs those with no CH (26%). The table shows that incidence of moderate to severe handicaps was highest with Grade 3-4 CH. Abnormal neurological findings were observed in 13/42 (31%) who had normal CBFV patterns and in 15/28 (54%) who had pulsatility index values ≥ .90 during the first week of life (p 0.05). The mean mental development index (MDI) corrected for gestational age was 84 ± 24 in the CH and 96 ± 12 in no-CH group. 10/24 had MDI <80 in the CH babies compared to 0/15 in no-CH babies (X2 = 8.4 df = 1 p <.005). Preliminary data show that the severity of CH and abnormal CBFV patterns appear to correlate with long-term outcome.