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Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems., Perivascular pathways: pseudolymphatic vessels of the brain? In peripheral organs, colloids are extravasated across a fenestrated capillary bed, and these proteins, as well as excess tissue fluid, are returned to [...]

The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. [...]

Migraine is an episodic headache disorder affecting as many as 10% of people worldwide. Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of severe migraine accompanied by visual disturbances known as aura. Migrainous aura is caused by cortical spreading depression (CSD)--a slowly advancing wave of tissue depolarization in the cortex. More than half of FHM cases are caused by mutations in the CACNA1A gene, which encodes a neuronal [Ca.sub.v]2.1 [Ca.sup.2+] channel, resulting in increased [Ca.sup.2+] flow into dendrites and excessive release of the excitatory neurotransmitter glutamate. In this issue of the JCI, Eikermann-Haerter et al. show that transgenic mice with FHM-associated mutations in Cacna1a have increased susceptibility to CSD compared with wild-type animals, likely due to augmentation of excitatory neurotransmission (see the related article beginning on page 99). Additional as-yet-undefined channel mutations may similarly render the migraine brain more susceptible to the initiation of CSD, with implications not only for the genesis of migraine but also for the hypoxic injury that accompanies its worst manifestation, complicated migraine., Cortical spreading depression as a trigger of migraine pain Written accounts of migraine are nearly as old as writing itself. Descriptions of headaches, dating to roughly 3000 BCE, have been [...]