The diagnostic implications of measuring the full set of CSF dynamics parameters in pediatric PTCS are highlighted in this paper, in order to provoke further investigation and to encourage the use of this approach more widely in clinical practice. CSF dynamics could provide information on the contents of CSFp that are not obvious from CSFp as a solitary number, accurately differentiating between the clinically and radiologically derived entities of PTCS.
We have highlighted that (A) a single recording of a raised CSFp is not necessarily a representative value for a patient’s ICP and (B) a raised CSFp value does not give a full understanding of a patient’s CSF circulation, including venous drainage. Despite its limitations, we acknowledge that CSFp is a diagnostic criterion in current guidelines and we have therefore described our precise methodology for maximizing the reliability of this single CSF dynamics variable. This methodology includes the measurement of “steady-state” CSFp ([8, 9, 42]) and simultaneous measurement of the blood circulation with CSF pressure recordings, as it is known that there is a complicated interaction between the CSF circulation and the cerebral blood circulation in CSF disorders ([7, 9, 43]). We also aim to minimize the impact of other confounding factors such as stress, position, and sedation [1, 4, 11, 47]. These factors and how they influence the CSFp cannot be studied and comprehended without analysis of the CSFp components, preferably with cerebral multi-modality monitoring [11, 25, 42].
Studies have already shown that there is a lack of reliability in the manometry reading of a CSFp [8, 11], something which is also partially shown by the lack of correlation between manometry and baseline CSFp from a computerized infusion test in our cohort. However, these readings were not taken at a very close time, but up to 3 months apart. Nonetheless, they represent the clinical reality of trying to make a diagnosis and a treatment plan from separated LPs and/or drainages, often weeks and month apart from each other.
The CSFp at baseline was by definition raised > 20 mmHg in pediatric PTCS and on average in our group > 25 mmHg. In the group of children with definite PTCS, there were 3 children with a CSFp > 30 mmHg, and 2 of them had critical levels of CSFp with compromised cerebral perfusion. Although infusion was not possible in these children, the CSF dynamics parameters that could be measured were revealing; a pattern of negative AMP-CSFp relationship was observed, indicating low-cerebral perfusion pressure. It has been reported in traumatic brain injury that when ICP reaches critical levels (usually > 25 mmHg in head injury), the AMP-ICP relationship becomes negative [9, 11], which appears to also be the case with these 2 patients. However, more data are needed in order to confirm this pattern and association in pediatric PTCS. These cases, although seemingly rare, highlight the importance of an extended multi-parametric monitoring of the cerebral circulation, including systemic arterial pressure and possibly cerebral autoregulation, blood flow, and oxygenation. It would be interesting, for future purposes, to adopt at a research setting initially a multi-parameter monitoring approach, especially in suspicion of serious disease and explore the clinical implications of possible cerebral hypoperfusion.
The difficulty in diagnosing and classifying pediatric PTCS lies in the probable group, where the CSFp was not raised (average 15 mmHg) and did not differ to the children in whom PTCS was excluded. In these cases, it is of significance to investigate the dynamics of the CSFp. Neither CSFp nor AMP at baseline seemed to help in differentiating between those probable and not PTCS. However, both elasticity and SSp were significantly lower in group C and could potentially provide a key in the differentiation between the two groups. Both elasticity and SSp were elevated in children with definite as well as probable PTCS, showing further potential markers of the disease besides CSFp. However, it is important to bear in mind that both of these parameters are subject to calculation errors and SSp represents a value derived from mathematical modeling of the CSF circulation and not the patient’s actual SSp. Unfortunately, it is not possible to understand or confirm what the probable PTCS group represents, as compared with definite PTCS and normal children, until at least some further follow-up and perhaps investigations are performed. Higher SSp as well as higher elasticity could perhaps highlight a tendency or the beginning of the syndrome that has not reached the severity of the definite group.
Besides elasticity and SSp, and partially RAP, none of the other infusion-derived parameters were above the reported normal thresholds (0.6 for RAP—lowered to 0.4 for the this cohort of patients, 0.16 for the amp-p line, 4 mmHg for AMPp, 10–13 mmHg*min/ml for Rout), with the exception of slow waves of CSFp at plateau, the magnitude of which exceeded 1.5 mmHg in groups A and B, but not in group C. Also, the absolute rise in CSFp during infusion was the same in all groups. This rise, divided by infusion rate, denotes the resistance to CSF outflow. As PTCS SSp follows the rise in CSFp, this way of estimation gives an overestimated value of resistance. Nevertheless, in PTCS, CSF circulation is probably normal, as the gradient CSFpp–CSFpb is low .
For slow waves in particular, there is no well-described threshold in any of the CSF disorders [24, 26, 48]. Although the differences in the magnitude of slow waves between groups were not significant, there seems to be a tendency of higher magnitude in group A than in groups B and C, group C possibly having the lowest magnitude. Perhaps an increased magnitude of slow waves when the CSF circulation is challenged could reveal a disturbed CSF circulation and assist in differentiating between definite, probable PTCS and mimics. This will need further confirmation. Another finding that could provide interesting information in excluding or confirming PTCS is the presence or absence of a LBP in the AMP-P line. None of the children in the definite group presented with such a breakpoint, whereas it was observed in 2 children for each of the other groups.
There was a correlation between CSFpb and SSp, but not CSFpp. This finding could be similar to what has been shown in adults with PTCS , whereby SSp and CSFp are coupled at baseline and during infusion. This relationship, however, cannot be validated in children without direct SSp measurement and there is ethical equipoise currently between the risks and benefits of exposing them to invasive cerebral venous investigation. The correlation between SSp and elasticity found mainly in our definite PTCS patients could also demonstrate part of the pathophysiology of PTCS, whereby “faulty” venous sinuses allow the transmission of the CSF pressure onto the sinuses, leading to a coupling of the two pressure and thereby a “stiffer” brain. It is therefore possible in children with normal CSFp but abnormal CSF dynamics (e.g., a depleted compensatory reserve) or an abnormal cerebral venous sinus system  that CSFp levels can rise with minimal perturbation of the current equilibrium state.
It was intriguing to find out that no single CSF pressure or dynamics parameter on its own could accurately differentiate between the 3 groups with an AUC > 0.80. Our findings from the ROC analysis show a potential overlap between diagnosis and classification from clinical examination and neuroradiology, with CSF dynamics parameters, in particular, CSFpb, SSP, and elasticity. The main discrepancy between CSF dynamics and the Friedman classification lie in the patient in group C with no papilledema and disturbed CSF dynamics and in group B, where there is a lot of heterogeneity among the patients. We therefore could speculate that monitoring and infusion, not just baseline parameters, are possibly essential for accurate patient classification and characterization of the disturbance in the CSF circulation. In this context, it is of interest to look into the case of one out of the 5 patients without PTCS, whose CSFp was 27 mmHg and did not meet the criteria for PTCS from the Friedman classification. Therefore, in the absence of papilledema, even a confirmed intracranial hypertension perhaps is not synonymous to the actual syndrome and the venous compartment in such cases could merit further investigation. Moreover, it may be possible to distinguish between these two entities both clinico-radiologically, as well as with monitoring of CSF dynamics, and more patients will be needed to make these distinctions.
Finally, the influence of GA on CSF dynamics could not be clearly demonstrated in this small cohort. It has been reported in NPH and TBI patients that GA possibly has no effect on baseline CSFp or elasticity, but significantly dampens the magnitude of slow waves . This study was derived from the same center and therefore included the same GA protocol as the NPH group (propofol + remifentanil and a muscle relaxant, usually rocuronium, naturally with different doses in adults vs pediatric patients). The fact that CSFpb was increased in definite PTCS under GA vs conscious children could be a random finding, or show that anesthetic agents could increase CSFp in pediatric PTCS patients, which is not justified from the literature on the influence of anesthetic agents such as propofol on cerebral blood flow and metabolism. Additionally, this finding, as well as similar previous reports [4, 25, 47], could highlight that children needing GA are usually the ones with a higher BMI, that in our experience is less likely to tolerate a LP, and could reflect the known relationship with BMI in PTCS severity as well as the influence of increased abdominal pressure on CSFp. Preliminarily derived from our set, 7/14 children needed GA in group A, 3/3 with CSFp> 30 mmHg. In comparison, our adult and pediatric hydrocephalus children normally require GA when their symptoms are very prominent, which prohibits them from complying with investigations. Similarly, the lower SSp and elasticity in anesthetized probable PTCS patients could mean several things, but this study is not adequately powered to identify if this effect is real. Notably, 14/39 (36%) of our total children (including the ones diagnosed with secondary PTCS and were excluded from this analysis) that underwent an infusion test had GA during the investigation. This percentage was lower compared with a reported national average of 45% , and we utilized our longer term average CSFp technique that allowed for reliable CSF pressure measurement on a truly continuous scale.
Our main limitation is the small number of patients in each group and subgroup. Although we were able to show statistically significant results with p < 0.001, suggesting that the effect sizes are large, analysis of a larger cohort is needed to generalize these results to all children with PTCS. Even though we tried to avoid further confusion by excluding secondary PTCS and selecting well-matched control groups, there were still a lot of different patterns and cases that will need further elaboration in the future, as well as more thoroughly designed studies on the influence of GA on CSF dynamics.
Connected to the above is the fact that to date we have no definitive normative data for CSF dynamics in children. We only performed an infusion test in 5 children without PTCS—initially, they were considered to have a disc appearance that was considered to be borderline for edema, but this was later clarified and confirmed to not be disc edema. As such, the “abnormal” thresholds for the CSF dynamics parameters have mainly been described in hydrocephalus and TBI. From this preliminary study, thresholds appear similar; however, more studies, adequately powered, are needed to validate these parameters.
RAP has got a calculation window of 4 min, and in the short time of the infusion test, the smallest artifacts could make the calculation unreliable; however, calculation without artifacts was possible in all 31 patients. Longer term monitoring is preferred, and RAP is most reliable then; however, a good 10-min baseline with stable variables could give us an estimation of RAP and the compensatory reserve. The magnitude of slow waves is strongly influenced by GA  and would require further investigation in awake pediatric PTCS patients.