Blood-cerebrospinal fluid (CSF) barrier dysfunction means reduced CSF flow not barrier leakage - conclusions from CSF protein data / Disfunção da barreira hemato-liquórica significa redução do fluxo de líquido cefalorraquidiano, e não quebra de barreira - conclusões a partir de estudos sobre as proteínas do LCR

ABSTRACT Background: Increased concentrations of serum proteins in cerebrospinal fluid (CSF) are interpreted as blood-CSF barrier dysfunction. Frequently used interpretations such as barrier leakage, disruption or breakdown contradict CSF protein data, which suggest a reduced CSF flow rate as the cause. Results: Even the severest barrier dysfunctions do not change the molecular size-dependent selectivity or the interindividual variation of the protein transfer across barriers. Serum protein concentrations in lumbar CSF increase with hyperbolic functions, but the levels of proteins that do not pass the barrier remain constant (brain proteins) or increase linearly (leptomeningal proteins). All CSF protein dynamics above and below a lumbar blockade can also be explained, independent of their barrier passage, by a reduced caudally directed flow. Local accumulation of gadolinium in multiple sclerosis (MS) is now understood as due to reduced bulk flow elimination by interstitial fluid (ISF). Nonlinear change of the steady state in barrier dysfunction and along normal rostro-caudal gradients supports the diffusion/flow model and contradicts obstructions of diffusion pathways. Regardless of the cause of the disease, pathophysiological flow blockages are found in bacterial meningitis, leukemia, meningeal carcinomatosis, Guillain-Barré syndrome, MS and experimental allergic encephalomyelitis. In humans, the fortyfold higher albumin concentrations in early fetal development decrease later with maturation of the arachnoid villi, i.e., with beginning CSF outflow, which contradicts a relevant outflow to the lymphatic system. Respiration- and heartbeat-dependent oscillations do not disturb net direction of CSF flow. Conclusion: Blood-CSF and blood-brain barrier dysfunctions are an expression of reduced CSF or ISF flow rate.

RESUMO Introdução: Concentrações aumentadas de proteínas séricas no líquido cefalorraquidiano são interpretadas como disfunção da barreira (hemato-liquórica) sanguínea do LCR. Interpretações frequentemente usadas, como vazamento de barreira (quebra ou rompimento de barreira), rompimento ou quebra, contradiz os dados de proteína do LCR, que sugerem uma taxa de fluxo reduzida do LCR como a causa. Resultados: Mesmo as disfunções de barreira mais graves não alteram a seletividade dependente do tamanho molecular nem a variação interindividual da transferência de proteína através de barreiras. As concentrações de proteínas séricas no LCR lombar aumentam com as funções hiperbólicas, mas as proteínas que não passam a barreira permanecem constantes (proteínas do cérebro) ou aumentam linearmente (proteínas leptomeningeais). Toda a dinâmica das proteínas do LCR acima e abaixo de um bloqueio lombar também pode ser explicada, independente de sua passagem pela barreira, por um fluxo caudal reduzido. O acúmulo local de gadolínio na esclerose múltipla (EM) é agora entendido como decorrente da redução da eliminação do bulk flow pelo fluido intersticial (FIS). A mudança não linear do estado estacionário na disfunção da barreira e ao longo dos gradientes rostro-caudais normais apoia o modelo de difusão/fluxo e contradiz as obstruções das vias de difusão. Independentemente da causa da doença, os bloqueios fisiopatológicos do fluxo são encontrados na meningite bacteriana, leucemia, carcinomatose meníngea, síndrome de Guillain-Barré, EM e encefalomielite alérgica experimental. Em humanos, as concentrações de albumina quarenta vezes mais altas no desenvolvimento fetal inicial diminuem tarde com a maturação das vilosidades aracnoides, isto é, com o início do fluxo de LCR, o que contradiz um fluxo relevante para o sistema linfático. As oscilações dependentes da respiração e do batimento cardíaco não perturbam a direção do fluxo do LCR. Conclusão: As disfunções das barreiras hemato-liquórica e hemato-encefálica são uma expressão da redução da taxa de fluxo do LCR ou FIS.

Evaluation of Aqueductal Patency in Patients with Hydrocephalus: Three-Dimensional High-Sampling-Efficiency Technique (SPACE) versus Two-Dimensional Turbo Spin Echo at 3 Tesla

OBJECTIVE: To compare the accuracy of diagnosing aqueductal patency and image quality between high spatial resolution three-dimensional (3D) high-sampling-efficiency technique (sampling perfection with application optimized contrast using different flip angle evolutions [SPACE]) and T2-weighted (T2W) two-dimensional (2D) turbo spin echo (TSE) at 3-T in patients with hydrocephalus. MATERIALS AND METHODS: This retrospective study included 99 patients diagnosed with hydrocephalus. T2W 3D-SPACE was added to the routine sequences which consisted of T2W 2D-TSE, 3D-constructive interference steady state (CISS), and cine phase-contrast MRI (PC-MRI). Two radiologists evaluated independently the patency of cerebral aqueduct and image quality on the T2W 2D-TSE and T2W 3D-SPACE. PC-MRI and 3D-CISS were used as the reference for aqueductal patency and image quality, respectively. Inter-observer agreement was calculated using kappa statistics. RESULTS: The evaluation of the aqueductal patency by T2W 3D-SPACE and T2W 2D-TSE were in agreement with PC-MRI in 100% (99/99; sensitivity, 100% [83/83]; specificity, 100% [16/16]) and 83.8% (83/99; sensitivity, 100% [67/83]; specificity, 100% [16/16]), respectively (p < 0.001). No significant difference in image quality between T2W 2D-TSE and T2W 3D-SPACE (p = 0.056) occurred. The kappa values for inter-observer agreement were 0.714 for T2W 2D-TSE and 0.899 for T2W 3D-SPACE. CONCLUSION: Three-dimensional-SPACE is superior to 2D-TSE for the evaluation of aqueductal patency in hydrocephalus. T2W 3D-SPACE may hold promise as a highly accurate alternative treatment to PC-MRI for the physiological and morphological evaluation of aqueductal patency.

CSF Flow Quantification of the Cerebral Aqueduct in Normal Volunteers Using Phase Contrast Cine MR Imaging

OBJECTIVE: To evaluate whether the results of cerebrospinal fluid (CSF) flow quantification differ according to the anatomical location of the cerebral aqueduct that is used and the background baseline region that is selected. MATERIALS AND METHODS: The CSF hydrodynamics of eleven healthy volunteers (mean age = 29.6 years) were investigated on a 1.5T MRI system. Velocity maps were acquired perpendicular to the cerebral aqueduct at three different anatomical levels: the inlet, ampulla and pars posterior. The pulse sequence was a prospectively triggered cardiac-gated flow compensated gradient-echo technique. Region-of-interest (ROI) analysis was performed for the CSF hydrodynamics, including the peak systolic velocity and mean flow on the phase images. The selection of the background baseline regions was done based on measurements made in two different areas, namely the anterior midbrain and temporal lobe, for 10 subjects. RESULTS: The mean peak systolic velocities showed a tendency to increase from the superior to the inferior aqueduct, irrespective of the background baseline region, with the range being from 3.30 cm/sec to 4.08 cm/sec. However, these differences were not statistically significant. In the case of the mean flow, the highest mean value was observed at the mid-portion of the ampulla (0.03 cm3/sec) in conjunction with the baseline ROI at the anterior midbrain. However, no other differences were observed among the mean flows according to the location of the cerebral aqueduct or the baseline ROI. CONCLUSION: We obtained a set of reference data of the CSF peak velocity and mean flow through the cerebral aqueduct in young healthy volunteers. Although the peak systolic velocity and mean flow of the CSF differed somewhat according to the level of the cerebral aqueduct at which the measurement was made, this difference was not statistically significant.

Clinical Applications of Cine MR

Evaluation of intracranial CSF flow was accomplished by the use of cine MR technique. In the cine MR, there were two methods of evaluation in CSF flow pattern. Qualitative and quantitative methods were called magnitude reconstruction and phase contrast mapping method, respectively. The image of magnitude reconstruction method can demonstrate areas of decreased CSF flow and help explain the cause of hydrocephalus. The image of phase contrast mapping method is more sensitive to fluid motion and may increase utility in the future for analysis of fluid flow. Cine MR is capable of showing both normal and abnormal intracranial CSF flow. Such a study can be easily added as an extra pulse sequence at the end of a routinely acquired MR examination. We evaluated 2 cases of the normal pattern of pulsatile flow within subarachnoid space and 3 cases of abnormal patterns of CSF flow(communicating hydrocephalus: 2 cases, arachnoid cyst in posterior fossa: 1 case). These observations were compared with pre- and post-operative CSF flow state. In conditions which result in alterations of flow, cine MR shows either obstruction or excessively turbulent flow within the CSF pathways. In our studies, the most distinctive pathological finding was bulk flow in the aqueduct of Sylvius. The authors suggest that this technique can be applied in a wide range of conditions where CSF pathway is altered including hydrocephalus, evaluation of the function of the shunt system and communication between arachnoid cyst and subarachnoid space . Moreover correct diagnosis is possible in patients with hydrocephalus, in whom the exact level of CSF obstruction can be determined. We believe that surgical decisions can be aided by careful analysis of these CSF cine MR studies. We discuss the normal and abnormal CSF flow findings and indications of cine MR CSF flow technique with literature review.