Glymphatic and Lymphatic Functions in Patients with Chronic Migraine

By Alina Masters-Israilov, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: Patients with chronic migraine have dysfunction of their glymphatic and meningeal lymphatic systems, which may play a role in the pathogenesis of migraine.

SOURCE: Wu CH, Chang FC, Wang YF, et al. Impaired glymphatic and meningeal lymphatic functions in patients with chronic migraine. Ann Neurol 2024;95:583-595.

The glymphatic and meningeal lymphatic systems are involved in the transport of cerebrospinal fluid, intracranial waste clearance, and immunomodulation. Dysfunction of these systems has been implicated as part of the pathophysiology of various neurological disorders, including migraine.

Wu et al conducted a prospective study on patients with migraine to determine whether the glymphatic system is dysfunctional in patients with migraine when compared to healthy controls. They also studied meningeal lymphatic vessel (mLV) function in participants with chronic migraine (CM) and compared them to those with
episodic migraine (EM) using specific magnetic res-onance imaging (MRI) techniques (diffusion tensor imaging [DTI] and dynamic contrast-enhanced MRI [DCE-MRI]).

Patients with migraine between the ages of 20 and 60 years were recruited from headache clinics and completed questionnaires, which included information on headache frequency and intensity and disability from migraine. Healthy controls were recruited as well. Several headache specialists diagnosed these patients with their appropriate headache diagnosis, including EM vs. CM, and an additional assessment for medication overuse headache (MOH); only headache preventive treatment-naïve patients were included.

Participants were asked not to take any pain medications for two days prior to their MRI. On the day of their MRI, they were asked about their headache status and when their last migraine attack was; those with significant headache on the day of MRI were excluded and allowed to treat their symptoms appropriately. All participants, including healthy controls, underwent DTI MRI and other sequences for information on glymphatic function (Bundle 1). Those who agreed to then receive gadolinium underwent DCE-MRI and other sequences for information on mLV function (Bundle 2).

Participants who underwent DCE-MRI were randomized into three models (Models A-C), each focusing on different lymphatic vessels/structures and, thus, necessitating different MRI orientations (coronal vs. sagittal vs. axial, respectively). Participants found to have structural lesions or suboptimal image quality then were excluded. The MRI data mentioned earlier then were processed and analyzed using VolumeViewer software to obtain the DTI analysis along the perivascular space (DTI-ALPS) index for glymphatic function. VolumeViewer and two neuroradiologists who were blinded to the clinical history of participants were used to describe the mLV function (depicted as time to peak [TTP], enhancement integral [EI], and mean time to enhance [MTE]). The potential clinical effects of glymphatic dysfunction as discovered in Bundle 1 were explored further by correlating the DTI-ALPS index with the clinical parameters of the participants.

By analyzing the images of 112 patients with migraine and 63 healthy controls (175 subjects in total), the authors found that the DTI-ALPS index was significantly lower in participants with CM than in healthy controls and participants with EM (there was not a significant difference in DTI-ALPS index between healthy controls and participants with EM). Interestingly, among participants with CM, those with MOH had a significantly lower DTI-ALPS index than those without MOH. A total of 105 participants with migraine received gadolinium and underwent the DCE-MRI protocol. The TTP was significantly longer in participants with CM than in those with EM in Models A and B, the EI values were significantly higher in CM than in EM in Model A, and the MTE was significantly longer in CM compared to EM in Models A and B.

Finally, the DTI-ALPS index was negatively correlated with the Migraine Disability Assessment and Pittsburgh Sleep Quality Index. There also was a negative correlation between DTI-ALPS and headache frequency, headache severity, and extent of bodily pain.

COMMENTARY

This study demonstrated decreased glymphatic and meningeal lymphatic function in patients with CM and especially those with MOH. In addition to other proposed pathophysiologic mechanisms, the authors speculate that chronically disrupted glymphatic systems in patients with migraine may decrease calcitonin gene-related peptide clearance from perivascular glymphatic spaces and increase the risk of chronification of migraine.

The authors also hypothesized that meningeal lymphatic dysfunction may lead to the accumulation of immune cells in the meninges, which may activate meningeal trigeminovascular afferents and trigger migraine further. Because of the findings in the study, the authors questioned whether it would be helpful for patients with glymphatic dysfunction to be preferentially treated with medications and modalities that may modulate glymphatic function, such as beta-blockers and vagus nerve stimulation.

Limitations of the study were exclusion of patients who have tried preventive medications and not monitoring sleep the night before the MRI (sleep likely affects glymphatic function). One important point made in this study is that we should consider more consistently offering migraine prevention to those with five or more migraine episodes per month, given the reduced glymphatic function seen in these participants.