Improved Cerebral Glymphatic Flow after Transvenous Embolization of CSF-Venous Fistula

DISCUSSION

It is entirely unknown whether glymphatic clearance is altered in patients with SIH due to CSFVF and if/how it may contribute to symptomatology or pathophysiology. In this brief report, all 3 patients demonstrated impaired baseline glymphatic clearance (ALPS Index, 1.029–1.078) compared with a literature normal reference value (ALPS Index, ∼1.29).¹⁰ If a minimum literature ALPS Index value is considered to be approximately 0.93, this suggests that patients with CSFVF may have <50% of baseline glymphatic outflow compared with healthy patients. Additionally, in all 3 patients, CSFVF embolization at least partially recovered glymphatic function, suggesting that the observed low ALPS values might be attributed to the CSFVF.

Although the mechanism underlying the presented observation is unknown, it has been previously shown that abnormal intracranial pressure alters CSF clearance pathways, suggesting a possible connection between intracranial pressure homeostasis and cerebral glymphatic flow.¹³ Likewise, it is also possible that glymphatic function may be pressure-dependent, in which a decrease in outflow might parallel the decreased CSF volume. Additionally, we hypothesize that general brain sagging due to low intracranial CSF volume may structurally distort the cerebral venoglymphatic system and could result in the observed impaired flow. Furthermore, venous sinus engorgement, a common neuroimaging fining in SIH, could possibly compress and compromise the adjacent cerebral perivascular glymphatics. Last, low CSF intracranial volume could conceivably alter the homeostasis of the cerebral interstitial space, which may compromise cerebral interstitial compliance and the glymphatic system.¹⁴

While purely theoretical, one potential implication of this study is that it could explain some CSFVF symptoms that are not as well-explained by gross structural abnormalities such as brain sag. In general, it is accepted that brain sag with resultant traction of pain-sensitive fibers or trigeminal nerve ganglia is the possible reason for headaches. However, other common SIH symptoms and complications including drowsiness, brain fog, and frontotemporal dementia are not as well-explained by brain sag. Given that impaired glymphatic flow has been implicated as the final common pathway for dementia, it is possible that this may be a mechanism for some of the harder-to-localize symptoms of SIH due to CSFVF.⁷

In addition to possibly implicating the glymphatic system in SIH due to CSFVF, the DTI-ALPS method could be used for diagnostic purposes. It is feasible that the extent of impaired glymphatic flow could function as a quantitative neuroimaging marker for patients with CSFVF and may theoretically be combined with the Bern Score to aid in the diagnosis. However, impaired glymphatic flow is nonspecific to SIH and can be seen in other conditions, which may limit this possibility.^9,10 Regardless, given the diagnostic challenge of SIH and CSFVF, a low ALPS index obtained noninvasively from a brain MR imaging could serve as an additional data point for further work-up, including a diagnostic myelogram. Similarly, while not previously investigated, the ALPS index could also assist in the diagnosis and management in patients with a low Bern Score, which could be explored in future studies.

While the DTI-ALPS method is noninvasive and can be completed retrospectively, additional techniques have been described to image the glymphatic system. For example, following IV or intrathecal administration of gadolinium-based contrast, MR cisternography can be used to track CSF transport and measure glymphatic clearance along the paravascular routes.¹⁵ Meningeal lymphatic vessels can also be directly imaged via FLAIR MR imaging following contrast administration, when the rate of meningeal lymphatic efflux reflects the rate of paravascular/glymphatic outflow.¹⁵ Additional advanced MR imaging techniques include intravoxel incoherent motion and chemical exchange saturation transfer to measure cerebral interstitial fluid transport.¹⁵ These methods, among others, could also be used to study the glymphatic system in patients with SIH.

While the obvious limitation of this study is the modest sample size of 3 patients and absence of age-matched controls, in all instances, glymphatic flow increased following transvenous embolization. Most interesting, we also observed that in the 2 patients with symptomatic improvement, the postembolization glymphatic flow increase was notably higher than the minimal increase in patient 3, who demonstrated a mild radiographic improvement and no appreciable symptomatic improvement (Online Supplemental Data, Fig 2). This finding could suggest that the extent of glymphatic clearance rescue may at least partially reflect/explain the substantial radiographic and clinical improvement that is often observed with transvenous embolization.^4⇓-6 Alternatively, normalized intracranial volume after CSFVF embolization may structurally restore the venoglymphatic system, resulting in at least partially normalized glymphatic flow. Nonetheless, a change in glymphatic clearance could conceivably function as a quantitative marker of treatment success based on our modest n = 3. An additional limitation is that we only included patients with SIH with an identified CSFVF. It is possible that SIH due to other mechanisms (ventral tear and so forth) may not have impaired glymphatic clearance as suggested here. Future studies researching the glymphatic system in SIH should investigate CSF leaks of different etiologies and with appropriate controls.