In this study, we conducted a literature review of CSF dynamics in IIH and investigated different lumbar CSF pressure parameters in a well-described retrospective cohort. The systematic review of the literature mainly revealed consistently increased CSF pressure and increased resistance to CSF outflow. Our analysis of the retrospective cohort showed that mean lumbar CSF pressure and BMI were higher in verified IIH patients compared to symptomatic controls, and that both fast and slow dynamic changes in lumbar CSF pressure were increased. We confirmed that psychiatric comorbidity is common in IIH and found that lumbar CSF pressure was more often higher in cases with such comorbidity. We observed that the use of acetazolamide may have obscured an increase in RAP and SLOW measures in true IIH patients.
Literature review of CSF dynamic findings in IIH
In our literature review of CSF dynamic findings in IIH, we found that lumbar CSF pressure or ICP was elevated in IIH patients [5, 8, 9, 15, 16, 19,20,21, 23, 24, 27, 29, 30, 38, 39, 48, 51], and the resistance to CSF outflow increased [5, 14, 20, 27, 42]. CSF pressure and AMP were associated with linear direct relationship . Also, a positive linear relationship between ICP and resistance of CSF outflow has been identified . Moreover, elevated SSP is a common finding in IIH patients [4, 21, 24, 29, 38, 47], although only recently prospective attempts have been made to verify the range of normal variation in non-IIH populations (ClinicalTrials.gov ID: NCT03948971). CSF pressure and SSP appears to be coupled in IIH and when CSF pressure increases during CSF infusion, it produces an increase in SSP  and its vasogenic components . During drainage, both pressures decrease until a certain point, when CSF pressure may decrease further, while SSP remains constant [23, 38]. Opening pressure appears to be increased in the presence of MR venography assessed transverse sinus compression . In one study, CSF formation rate tended to decrease on IIH patients with higher than average ICP values . One study illustrated the so-called B waves during the continuous CSF pressure monitoring, present for at least 50% of the time . The craniospinal elastance appears to be higher in IIH patients [9, 16, 24, 42], corresponding to a reduced craniospinal compliance, since this is the inverse of elastance. PVI represents the calculated volume required to raise the CSF pressure (or ICP) by a factor of 10 and describes the relationship between pressure and compliance . One previous study also found that PVI was decreased in IIH , which could suggest that the observed changes in craniospinal elastance or compliance are not only secondary to an increased pressure, but also reflect a change in the overall pressure/volume curve. That study also investigated the relationship between lumbar CSF opening pressure and PVI, and found no dependency . However, another study found a negative linear relationship between lumbar CSF opening pressure and PVI in IIH , which could complicate the comparison of PVI between IIH and other groups. Recent studies thus suggest that the craniospinal compliance dynamics may differ in patients with IIH, which could provide insight into the disease pathogenesis. However, further studies confirming these results and comparing similar measurements in patients with and without IIH are needed to determine whether potential differences in craniospinal compliance in IIH reflect expected variations due to the changes in pressure or may be related to pathophysiologic changes in IIH . Additionally, all the reported findings regarding compliance or elastance were based on measurements of lumbar CSF pressure, rather than intracranial pressure. It should be noted that the observations are of changes in craniospinal compliance, which includes the compliance of both the intracranial and spinal CSF compartments, and thus it is not possible to draw distinct conclusions about changes in the intracranial compliance. When these compartments are communicating, as is generally the case in IIH, measurements in the two compartments should be closely related, but it could be of interest to confirm these findings with intracranial measurements.
Increased venous sinus pressure has been regarded as one of the possible causes of IIH. In addition, changes of the cerebral cortical capillaries and blood–brain barrier dysfunction are associated with evolvement of IIH [12, 18]. Classically, it is thought that the majority of the drainage of CSF into the venous compartment takes place through the arachnoid granulations that penetrate the sagittal sinus but also alternative routes have been described . Recently found cerebral lymphatic system has been thought to also support the CSF outflow . Thus, an increased resistance to CSF outflow in IIH could be indicative of a disturbance in any of these suggested absorption routes. Furthermore, the rate of absorption of CSF depends on the pressure gradient between the subarachnoid space and venous sinus, hence with an increase in venous pressure a concomitant increase in CSF pressure is needed to maintain absorption rates . Because of this relationship between absorption and venous pressure, the observed coupling of SSP and CSF pressure during infusion in IIH [23, 38] could affect the measurement of resistance to CSF outflow in IIH subjects, since this measurement depends on an assumption of a stable SSP during the infusion. If SSP rises during the infusion the estimated resistance could be falsely high, thus, in order to confirm an increased resistance in IIH infusion investigations should be performed with simultaneous measurement of SSP.
Retrospective cohort analysis: baseline patient characteristics and lumbar CSF pressure parameters
The mean age and CSF protein count at diagnosis was similar in both groups. The presenting symptoms were similar and most commonly these patients presented with headache and visual disturbances. Neuroradiological findings did not differ between verified IIH patients and symptomatic controls, most commonly these patients presented with empty sella or increased CSF around the optic nerve. However, the mean measured opening pressure and BMI were significantly higher for the verified IIH patients, as compared with the symptomatic controls, as expected. In addition, the true IIH patients more often had severe optic nerve findings and visual field defects at diagnosis, but there was no difference in visual acuity at presentation.
When comparing verified IIH cases versus symptomatic controls, all lumbar CSF pressure parameters differed significantly between the groups except RAP index, power of slow waves and RPPC. When all cases who were on acetazolamide during the pressure measurement were excluded, the RAP index and slow waves were also significantly higher in IIH patients than controls. Increased fast and slow waves in lumbar CSF pressure (AMP, RESP, SLOW) as well as increased RAP index likely reflect reduced craniospinal compliance in IIH, as would be expected at the increased lumbar CSF pressure level. These results are not entirely unexpected but have not been previously established in the literature. Amplitudes of CSF pressure waves, specifically pulse amplitudes, measured via the lumbar route, with the methodology used in this study, are typically somewhat smaller than if measured intracranially, though there is a very strong correlation. This is because the pressure waves, which originate intracranially, are dampened somewhat as they are transmitted along the spinal compartment. Thus, the amplitude levels measured here are not directly comparable to intracranial amplitude levels. While the significant differences between the two groups in our cohort likely reflect a genuine difference in intracranial amplitudes as well, the magnitude of that difference may be not be the same, since the dampening may depend slightly on the pressure level. The observed increase of P0 in IIH patients compared to symptomatic controls could support the previous finding of increased sagittal sinus pressure in IIH [21, 29, 38], since this pressure constant has been suggested to depend on venous pressure — and at least venous flow . According to the mathematical model of CSF dynamics, P0 sets the “baseline” for the lumbar CSF pressure level, i.e. a change in P0 results in an equal change in (mean) lumbar CSF pressure. In terms of the classical exponential pressure/volume curve for CSF pressure, a change in P0 corresponds to moving the entire curve along the pressure axis, rather than moving the state of the patient along the curve. Accordingly, craniospinal compliance decreases as the difference between lumbar CSF pressure and P0 increases, i.e. an increased lumbar CSF pressure would not result in reduced craniospinal compliance if P0 increased in parallel. Based on our results, the increase in P0 in IIH was less than half of the increase in lumbar CSF pressure (Table 3), which explains how we also found evidence of decreased craniospinal compliance. Thus, in IIH, there may be an effect on both the baseline of lumbar CSF pressure and on the volume-related aspect of lumbar CSF pressure, i.e. a shift of both the pressure/volume curve and of the state of the patient along the curve. Additionally, as revealed in the literature review, there may be an effect on the steepness of the pressure/volume curve, as indicted by a reduction of PVI , which we did not measure in our cohort. PVI is closely related to RPPC, which we did measure and found not to be altered in IIH, but RPPC also depends on the change of cerebral arterial blood volume with each heartbeat, which could be a confounder in this comparison. Also, we were not able to assess RPPC in all subjects, because we assessed this parameter based on natural pressure variability rather than with infusion tests.
The increased value of SLOW we found in the IIH cases without acetazolamide treatment could stem from a decreased craniospinal compliance, resulting in higher amplitudes, but it could also mean that SLOW waves appear more often in IIH. The power of slow waves reflects both the degree of occurrence and the amplitude of the waves, i.e. the power can increase if waves occur during a higher proportion of time or if the amplitude of the waves increase. Since slow waves are expected to appear in response to variations in intracranial blood volume or blood pressure, this could potentially indicate an issue with cerebral autoregulation in IIH. However, without simultaneous measurement of arterial blood pressure, the origin of the waves cannot be confirmed, and thus, autoregulation was not specifically assessed. Also, with the relatively short duration of measurement of this study, i.e. < 1 h, it was not possible to reliably determine if there is more slow wave activity in IIH in general, though such results would be in line with Gjerris et al . These results warrant studies on other indicators of cerebral autoregulation in future IIH research.
In IIH patients, there was significant correlation between power of respiratory waves and BMI, but not between any other lumbar CSF pressure parameters and BMI or between lumbar CSF pressure parameters and CSF protein levels. When analysing only the IIH subjects that were not using acetazolamide at the measurement occasion, the correlation between RESP and BMI increased further. The respiratory waves reflect variations in venous cerebral blood volume and/or CVP, so this observation could relate to increased venous pressure or increased respiratory variation in venous pressure in subjects with high BMI.
Comparing lumbar CSF pressure parameters in IIH cases with and without empty sella turcica did not reveal any differences. In IIH subjects with excess CSF around the optic nerve, RPPC and power of respiratory waves were significantly lower than for subjects without this radiological finding. The implications of these results are unclear; though a reduced RPPC may be indicative of a worsened pressure-independent component of craniospinal compliance, i.e. the aspect of compliance that defines the steepness of the pressure/volume curve, which is often described by the PVI .
Lumbar CSF pressure and outcome in IIH patients
Only about half of the IIH patients benefitted from acetazolamide treatment, and further surgical intervention was required for eleven patients. After conservative and operative treatments, the overt outcome improved slightly as 60% of patients reported themselves to be symptomless, hence having favourable outcome. The visual acuity at diagnosis was better for the IIH patients with favourable outcome as compared with IIH patients with unfavourable outcome. This finding might suggest that if the IIH is diagnosed early and the treatment has been started promptly, the IIH-related symptoms have progressed less leading to better outcome. No lumbar CSF pressure parameters differed significantly between these groups. Neuro-ophthalmological outcome was assessed as a degree of resolution of papilledema, and up to 65.7% of all patients had physiological papillae at the end of follow-up, there were no differences in lumbar CSF pressure parameters when stratified by neuro-ophthalmological outcome.
When comparing results from IIH subjects who were taking acetazolamide to those who were not, there were trends toward higher lumbar CSF pressure, power of slow waves (SLOW) and RAP index in subjects without acetazolamide. While not statistically significant, the trends for RAP index and SLOW motivate the post hoc analysis comparing only verified IIH cases and symptomatic controls without acetazolamide treatment, where these two parameters showed significant differences between the groups that were not revealed in the original comparison. Our findings suggest that in some cases the lumbar CSF pressure was reduced by acetazolamide, as is expected , and that craniospinal compliance increased accordingly. As discussed above, the power of slow waves reflects both the degree of occurrence and the magnitude of these waves. The trend regarding slow waves could reflect improved craniospinal compliance with treatment, resulting in reduced wave amplitudes. However, it is also possible that in subjects treated with acetazolamide there was an decrease in the occurrence of slow waves, which is in line with a previous study that observed reduced slow wave activity in cerebral blood flow velocity after administration of acetazolamide . This finding and its implications could be of interest for further research, particularly in relation to cerebral blood flow and autoregulation.
Previously, we have reported that psychiatric disorders are very common in IIH patients compared to general population . In this cohort of IIH patients who had undergone CELDA investigation, almost half of them had pre-existing psychiatric diagnosis. The most common psychiatric diagnosis was MDD. We found no differences in the baseline characteristics between IIH patients with or without psychiatric comorbidity, however the IIH patients with psychiatric comorbidity had significantly worse outcome as compared to patients without such history as shown in our previous study . Comparisons between IIH subjects with or without psychiatric comorbidity showed higher lumbar CSF pressure for subjects with psychiatric comorbidity, as well as trends toward higher power of respiratory waves and lower RPPC.
Strengths and weaknesses
Our retrospective analysis is limited by factors inherent to a secondary analysis of retrospectively collected data as well as the small sample size. Nevertheless, this issue is addressed in limited amount of previous data, as our systematic literature review shows. This study represents a detailed investigation, including continuous lumbar CSF pressure measurements, based on a well-defined cohort, which ensures a clinically comprehensive analysis and long follow-up times for these patients, which we regard as strengths of this study.
The major concern of this study is the risk for circular reasoning with the definition of symptomatic controls. Somewhat surprisingly some of these patients had also slight papilledema without visual field defects. Perhaps, this could represent early stage of IIH patients who have part of the time lumbar CSF pressure above 25 cm H2O. The cutoff point for lumbar CSF pressure might not unambiguously separate IIH patients from symptomatic controls, especially in patients with increased AMP and decreased craniospinal compliance.
Henceforth, the definition of symptomatic control is somewhat controversial. To overcome this problem, in the future, patients with suspected IIH and borderline lumbar CSF pressure, might benefit from control lumbar CSF pressure measurement.
Further studies, focusing on the role of CSF dynamics in patients with IIH in larger patient cohorts are needed. In 2017, we initiated a prospective collaborative multicentre study on IIH (www.iih.fi). In this study, we prospectively perform continuous lumbar CSF pressure measurement, collect biological samples for further metabolomics and genetic studies to advance understanding of the complex pathophysiology of the IIH disease, in addition to gathering all clinical variables and administrating validated questionnaires to screen and follow-up on mental well-being of patients with IIH, quality of life, and impact of their possible residual symptoms.