Coupling of CSF and sagittal sinus pressure in adult patients with pseudotumour cerebri

Funder: University of CambridgeAbstract: Objective: Pseudotumour cerebri syndrome (PTCS including idiopathic intracranial hypertension) is characterised by the symptoms and signs of raised cerebrospinal fluid pressure (CSFp) in the absence of ventricular dilatation or an intracranial mass lesion. Its aetiology is unknown in the majority of cases but there is much evidence for impaired CSF absorption. Traditionally, sagittal sinus pressure has been considered to be independent of CSF pressure in adults. However, the discovery of stenoses of intracranial venous sinuses and introduction of venous sinus stenting has highlighted the importance of the venous drainage in PTCS. In this study, we have explored the relationship between CSFp and SSp before and during a CSF infusion test and during CSF drainage. Materials and methods: Ten patients (9 females:1 male) with PTCS underwent infusion studies in parallel with direct retrograde cerebral venography. Both SSp and CSFp were recorded at a baseline and during CSFp elevation in a course of a CSF infusion test. The drainage of CSF after the CSF infusion was performed in 7 patients. In 5 cases, jugular venous pressure was also measured. Results: CSFp and SSp including their amplitudes correlated significantly and strongly both at baseline (R = 0.96; p = 0.001) and during infusion (R = 0.92; p = 0.0026). During drainage, this correlation was maintained until SSp reached a stable value, whereas CSFp continued to decrease. Conclusions: In this series of ten patients with PTCS, CSFp and SSp were coupled, both at baseline and during infusion. The implications of such coupling for the calculation of CSF outflow resistance are discussed

Cerebrospinal fluid dynamics in non-acute post-traumatic ventriculomegaly

Abstract: Background: Post-traumatic hydrocephalus (PTH) is potentially under-diagnosed and under-treated, generating the need for a more efficient diagnostic tool. We aim to report CSF dynamics of patients with post-traumatic ventriculomegaly. Materials and methods: We retrospectively analysed post-traumatic brain injury (TBI) patients with ventriculomegaly who had undergone a CSF infusion test. We calculated the resistance to CSF outflow (Rout), AMP (pulse amplitude of intracranial pressure, ICP), dAMP (AMPplateau-AMPbaseline) and compensatory reserve index correlation coefficient between ICP and AMP (RAP). To avoid confounding factors, included patients had to be non-decompressed or with cranioplasty > 1 month previously and Rout > 6 mmHg/min/ml. Compliance was assessed using the elasticity coefficient. We also compared infusion-tested TBI patients selected for shunting versus those not selected for shunting (consultant decision based on clinical and radiological assessment and the infusion results). Finally, we used data from a group of shunted idiopathic Normal Pressure Hydrocephalus (iNPH) patients for comparison. Results: Group A consisted of 36 patients with post-traumatic ventriculomegaly and Group B of 45 iNPH shunt responders. AMP and dAMP were significantly lower in Group A than B (0.55 ± 0.39 vs 1.02 ± 0.72; p < 0.01 and 1.58 ± 1.21 vs 2.76 ± 1.5; p < 0.01. RAP baseline was not significantly different between the two. Elasticity was higher than the normal limit in all groups (average 0.18 1/ml). Significantly higher Rout was present in those with probable PTH selected for shunting compared with unshunted. Mild/moderate hydrocephalus, ex-vacuo ventriculomegaly/encephalomalacia were inconsistently reported in PTH patients. Conclusions: Rout and AMP were significantly lower in PTH compared to iNPH and did not always reflect the degree of hydrocephalus or atrophy reported on CT/MRI. Compliance appears reduced in PTH

Cerebrospinal fluid dynamics in non-acute post-traumatic ventriculomegaly

Abstract: Background: Post-traumatic hydrocephalus (PTH) is potentially under-diagnosed and under-treated, generating the need for a more efficient diagnostic tool. We aim to report CSF dynamics of patients with post-traumatic ventriculomegaly. Materials and methods: We retrospectively analysed post-traumatic brain injury (TBI) patients with ventriculomegaly who had undergone a CSF infusion test. We calculated the resistance to CSF outflow (Rout), AMP (pulse amplitude of intracranial pressure, ICP), dAMP (AMPplateau-AMPbaseline) and compensatory reserve index correlation coefficient between ICP and AMP (RAP). To avoid confounding factors, included patients had to be non-decompressed or with cranioplasty > 1 month previously and Rout > 6 mmHg/min/ml. Compliance was assessed using the elasticity coefficient. We also compared infusion-tested TBI patients selected for shunting versus those not selected for shunting (consultant decision based on clinical and radiological assessment and the infusion results). Finally, we used data from a group of shunted idiopathic Normal Pressure Hydrocephalus (iNPH) patients for comparison. Results: Group A consisted of 36 patients with post-traumatic ventriculomegaly and Group B of 45 iNPH shunt responders. AMP and dAMP were significantly lower in Group A than B (0.55 ± 0.39 vs 1.02 ± 0.72; p < 0.01 and 1.58 ± 1.21 vs 2.76 ± 1.5; p < 0.01. RAP baseline was not significantly different between the two. Elasticity was higher than the normal limit in all groups (average 0.18 1/ml). Significantly higher Rout was present in those with probable PTH selected for shunting compared with unshunted. Mild/moderate hydrocephalus, ex-vacuo ventriculomegaly/encephalomalacia were inconsistently reported in PTH patients. Conclusions: Rout and AMP were significantly lower in PTH compared to iNPH and did not always reflect the degree of hydrocephalus or atrophy reported on CT/MRI. Compliance appears reduced in PTH

Assessment of cerebral autoregulation indices – a modelling perspective

Abstract: Various methodologies to assess cerebral autoregulation (CA) have been developed, including model - based methods (e.g. autoregulation index, ARI), correlation coefficient - based methods (e.g. mean flow index, Mx), and frequency domain - based methods (e.g. transfer function analysis, TF). Our understanding of relationships among CA indices remains limited, partly due to disagreement of different studies by using real physiological signals, which introduce confounding factors. The influence of exogenous noise on CA parameters needs further investigation. Using a set of artificial cerebral blood flow velocities (CBFV) generated from a well-known CA model, this study aims to cross-validate the relationship among CA indices in a more controlled environment. Real arterial blood pressure (ABP) measurements from 34 traumatic brain injury patients were applied to create artificial CBFVs. Each ABP recording was used to create 10 CBFVs corresponding to 10 CA levels (ARI from 0 to 9). Mx, TF phase, gain and coherence in low frequency (LF) and very low frequency (VLF) were calculated. The influence of exogenous noise was investigated by adding three levels of colored noise to the artificial CBFVs. The result showed a significant negative relationship between Mx and ARI (r = −0.95, p < 0.001), and it became almost purely linear when ARI is between 3 to 6. For transfer function parameters, ARI positively related with phase (r = 0.99 at VLF and 0.93 at LF, p < 0.001) and negatively related with gain_VLF(r = −0.98, p < 0.001). Exogenous noise changed the actual values of the CA parameters and increased the standard deviation. Our results show that different methods can lead to poor correlation between some of the autoregulation parameters even under well controlled situations, undisturbed by unknown confounding factors. They also highlighted the importance of exogenous noise, showing that even the same CA value might correspond to different CA levels under different ‘noise’ conditions

Shunt infusion studies: impact on patient outcome, including health economics

Funder: University of CambridgeAbstract: Objectives: The diagnosis of shunt malfunction is often not straightforward. We have explored, in symptomatic shunted patients with hydrocephalus or pseudotumour cerebri syndrome (PTCS), the accuracy of CSF infusion tests in differentiating a functioning shunt from one with possible problems, and the health economic consequences. Methods: Participants: hydrocephalus/PTCS patients with infusion tests performed from January 2013 until December 2015. We followed patients up after 6 and 12 months from the test to determine whether they had improved, had persisting symptoms or had required urgent revision. We calculated the total cost savings of revision versus infusion tests and standard protocol of revision and ICP monitoring versus infusion tests. Results: Three hundred sixty-five shunt infusion tests had been performed where a shunt prechamber/reservoir was present. For hydrocephalus patients, more than half of the tests (~ 55%, 155 out of 280) showed no shunt malfunction versus 125 with possible malfunction (ages 4 months to 90 years old). For PTCS patients aged 10 to 77 years old, 47 had possible problems and 38 no indication for shunt malfunction. Overall, > 290 unnecessary revisions were avoided over 3 years’ time. Two hundred fifty-eight (> 85%) of those non-surgically managed, remained well, did not deteriorate and did not require surgery. No infections were associated with infusion studies. For Cambridge, the overall savings from avoiding revisions was £945,415 annually. Conclusions: Our results provide evidence of the importance of shunt testing in vivo to confirm shunt malfunction. Avoiding unnecessary shunt revisions carries a strong health benefit for patients that also translates to a significant financial benefit for the National Health Service and potentially for other healthcare systems worldwide

Shunt infusion studies: impact on patient outcome, including health economics

Funder: University of CambridgeAbstract: Objectives: The diagnosis of shunt malfunction is often not straightforward. We have explored, in symptomatic shunted patients with hydrocephalus or pseudotumour cerebri syndrome (PTCS), the accuracy of CSF infusion tests in differentiating a functioning shunt from one with possible problems, and the health economic consequences. Methods: Participants: hydrocephalus/PTCS patients with infusion tests performed from January 2013 until December 2015. We followed patients up after 6 and 12 months from the test to determine whether they had improved, had persisting symptoms or had required urgent revision. We calculated the total cost savings of revision versus infusion tests and standard protocol of revision and ICP monitoring versus infusion tests. Results: Three hundred sixty-five shunt infusion tests had been performed where a shunt prechamber/reservoir was present. For hydrocephalus patients, more than half of the tests (~ 55%, 155 out of 280) showed no shunt malfunction versus 125 with possible malfunction (ages 4 months to 90 years old). For PTCS patients aged 10 to 77 years old, 47 had possible problems and 38 no indication for shunt malfunction. Overall, > 290 unnecessary revisions were avoided over 3 years’ time. Two hundred fifty-eight (> 85%) of those non-surgically managed, remained well, did not deteriorate and did not require surgery. No infections were associated with infusion studies. For Cambridge, the overall savings from avoiding revisions was £945,415 annually. Conclusions: Our results provide evidence of the importance of shunt testing in vivo to confirm shunt malfunction. Avoiding unnecessary shunt revisions carries a strong health benefit for patients that also translates to a significant financial benefit for the National Health Service and potentially for other healthcare systems worldwide

Assessment of cerebral autoregulation indices – a modelling perspective

Abstract: Various methodologies to assess cerebral autoregulation (CA) have been developed, including model - based methods (e.g. autoregulation index, ARI), correlation coefficient - based methods (e.g. mean flow index, Mx), and frequency domain - based methods (e.g. transfer function analysis, TF). Our understanding of relationships among CA indices remains limited, partly due to disagreement of different studies by using real physiological signals, which introduce confounding factors. The influence of exogenous noise on CA parameters needs further investigation. Using a set of artificial cerebral blood flow velocities (CBFV) generated from a well-known CA model, this study aims to cross-validate the relationship among CA indices in a more controlled environment. Real arterial blood pressure (ABP) measurements from 34 traumatic brain injury patients were applied to create artificial CBFVs. Each ABP recording was used to create 10 CBFVs corresponding to 10 CA levels (ARI from 0 to 9). Mx, TF phase, gain and coherence in low frequency (LF) and very low frequency (VLF) were calculated. The influence of exogenous noise was investigated by adding three levels of colored noise to the artificial CBFVs. The result showed a significant negative relationship between Mx and ARI (r = −0.95, p < 0.001), and it became almost purely linear when ARI is between 3 to 6. For transfer function parameters, ARI positively related with phase (r = 0.99 at VLF and 0.93 at LF, p < 0.001) and negatively related with gain_VLF(r = −0.98, p < 0.001). Exogenous noise changed the actual values of the CA parameters and increased the standard deviation. Our results show that different methods can lead to poor correlation between some of the autoregulation parameters even under well controlled situations, undisturbed by unknown confounding factors. They also highlighted the importance of exogenous noise, showing that even the same CA value might correspond to different CA levels under different ‘noise’ conditions

Zebrafish ProVEGF-C Expression, Proteolytic Processing and Inhibitory Effect of Unprocessed ProVEGF-C during Fin Regeneration

BACKGROUND: In zebrafish, vascular endothelial growth factor-C precursor (proVEGF-C) processing occurs within the dibasic motif HSIIRR(214) suggesting the involvement of one or more basic amino acid-specific proprotein convertases (PCs) in this process. In the present study, we examined zebrafish proVEGF-C expression and processing and the effect of unprocessed proVEGF-C on caudal fin regeneration. METHODOLOGY/PRINCIPAL FINDINGS: Cell transfection assays revealed that the cleavage of proVEGF-C, mainly mediated by the proprotein convertases Furin and PC5 and to a less degree by PACE4 and PC7, is abolished by PCs inhibitors or by mutation of its cleavage site (HSIIRR(214) into HSIISS(214)). In vitro, unprocessed proVEGF-C failed to activate its signaling proteins Akt and ERK and to induce cell proliferation. In vivo, following caudal fin amputation, the induction of VEGF-C, Furin and PC5 expression occurs as early as 2 days post-amputation (dpa) with a maximum levels at 4-7 dpa. Using immunofluorescence staining we localized high expression of VEGF-C and the convertases Furin and PC5 surrounding the apical growth zone of the regenerating fin. While expression of wild-type proVEGF-C in this area had no effect, unprocessed proVEGF-C inhibited fin regeneration. CONCLUSIONS/SIGNIFICANCES: Taken together, these data indicate that zebrafish fin regeneration is associated with up-regulation of VEGF-C and the convertases Furin and PC5 and highlight the inhibitory effect of unprocessed proVEGF-C on fin regeneration

Crustal structure of the Trans-Atlantic Geotraverse (TAG) segment (Mid-Atlantic Ridge, 26°10′N) : implications for the nature of hydrothermal circulation and detachment faulting at slow spreading ridges

Author Posting. © American Geophysical Union, 2007. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 8 (2007): Q08004, doi:10.1029/2007GC001629.New seismic refraction data reveal that hydrothermal circulation at the Trans-Atlantic Geotraverse (TAG) hydrothermal field on the Mid-Atlantic Ridge at 26°10′N is not driven by energy extracted from shallow or mid-crustal magmatic intrusions. Our results show that the TAG hydrothermal field is underlain by rocks with high seismic velocities typical of lower crustal gabbros and partially serpentinized peridotites at depth as shallow as 1 km, and we find no evidence for low seismic velocities associated with mid-crustal magma chambers. Our tomographic images support the hypothesis of Tivey et al. (2003) that the TAG field is located on the hanging wall of a detachment fault, and constrain the complex, dome-shaped subsurface geometry of the fault system. Modeling of our seismic velocity profiles indicates that the porosity of the detachment footwall increases after rotation during exhumation, which may enhance footwall cooling. However, heat extracted from the footwall is insufficient for sustaining long-term, high-temperature, hydrothermal circulation at TAG. These constraints indicate that the primary heat source for the TAG hydrothermal system must be a deep magma reservoir at or below the base of the crust.This research was supported by NSF grant OCE-0137329

Self-reported data: a major tool to assess compliance with anti-malarial combination therapy among children in Senegal

Background: Although there are many methods available for measuring compliance, there is no formal gold standard. Different techniques used to measure compliance were compared among children treated by the anti-malarial amodiaquine/sulphadoxine-pyrimethamine (AQ/SP) combination therapy, in use in Senegal between 2004 and 2006. Methods: The study was carried out in 2004, in five health centres located in the Thies region (Senegal). Children who had AQ/SP prescribed for three and one day respectively at the health centre were recruited. The day following the theoretical last intake of AQ, venous blood, and urine samples were collected for anti-malarial drugs dosage. Caregivers and children above five years were interviewed concerning children's drug intake. Results: Among the children, 64.7% adhered to 80% of the prescribed dose and only 37.7% were strict full adherent to the prescription. There was 72.7% agreement between self-reported data and blood drug dosage for amodiaquine treatment. Concerning SP, results found that blood dosages were 91.4% concordant with urine tests and 90% with self-reported data based on questionnaires. Conclusion: Self-reported data could provide useful quantitative information on drug intake and administration. Under strict methodological conditions this method, easy to implement, can be used to describe patients' behaviors and their use of new anti-malarial treatment. Self-reported data is a major tool for assessing compliance in resource poor countries. Blood and urine drug dosages provide qualitative results that confirm any drug intake. Urine assays for SP could be useful to obtain public health data, for example on chemoprophylaxis among pregnant women