Pathophysiology of the lymphatic drainage of the central nervous system: Implications for pathogenesis and therapy of multiple sclerosis  R.O. Weller, I. Galea, R.O. Carare, A. Minagar  Pathophysiology  Volume 17, Issue 4, Pages 295-306 (September 2010) DOI: 10.1016/j.pathophys.2009.10.007 Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 1 Diagram to show the largely separate pathways of lymphatic drainage of interstitial fluid (ISF) and CSF from the brain. (1) Blood flows into the brain along branches of the carotid (and vertebral) arteries (red) and forms a network of capillaries (red) that are the sites of the blood-brain barrier through which nutrients enter brain tissue. ISF and solutes appear to drain from the brain along perivascular pathways (curved blue line) in the walls of capillaries and in the tunica media (brown) and adventitia (light blue) of arteries to cervical lymph nodes. (2) Blood flows into post-capillary venules (blue) from which lymphocytes and monocytes (***) enter the brain by receptor-mediated mechanisms, gather in perivenular and perivenous spaces and migrate into brain tissue. (3) CSF is formed in the ventricles (yellow), flows into the subarachnoid space from which it drains via nasal lymphatics to cervical lymph nodes or into venous sinuses through arachnoid villi or granulations. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.) Pathophysiology 2010 17, 295-306DOI: (10.1016/j.pathophys.2009.10.007) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 2 Perivascular lymphatic drainage of interstitial fluid and solutes from the brain. ISF and solutes (green) diffuse through the narrow extracellular spaces of the brain parenchyma to enter the bulk flow pathways in the 100–150nm-thick basement membranes of capillary walls (green) and then into the basement membranes (green) surrounding smooth muscle cells in the tunica media of arteries. ISF and solutes do not appear to drain along the basement membranes (blue) of endothelial cells or along the basement membranes (blue) on the outer aspect of the vessel wall. Some tracer injected into the ISF is taken up by smooth muscle cells and by perivascular macrophages during its passage out of the brain. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.) Pathophysiology 2010 17, 295-306DOI: (10.1016/j.pathophys.2009.10.007) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 3 Lymphatic drainage of CSF through the cribriform plate of the ethmoid bone. The diagram shows that distinct channels pass from the subarachnoid space through the cribriform plate alongside olfactory nerves to join lymphatics in the nasal mucosa. It is by this route that CSF drains to cervical lymph nodes; the channels are large enough for antigen presenting cells (APC) to migrate from CSF to cervical lymph nodes. Pathophysiology 2010 17, 295-306DOI: (10.1016/j.pathophys.2009.10.007) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 4 Summary of lymphatic drainage of the brain. Left: the route for drainage of ISF and solutes from the brain parenchyma. The perivascular pathway is too narrow for the migration of APCs from brain to cervical lymph nodes. Right: CSF drains from the brain along relatively wide channels, potentially large enough for the migration of APCs from CSF to cervical lymph nodes. Whether APCs do migrate to cervical lymph nodes via this route to an immunologically significant extent is unclear. Pathophysiology 2010 17, 295-306DOI: (10.1016/j.pathophys.2009.10.007) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 5 MR imaging of the brain of a 22-year-old patient with relapsing remitting multiple sclerosis (MS). Axial FLAIR image that shows ovoid MS lesions (white) in the cerebral white matter of both hemispheres. Pathophysiology 2010 17, 295-306DOI: (10.1016/j.pathophys.2009.10.007) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 6 T2-weighted axial brain MR image that demonstrates MS plaques as hyperintense lesions (white). Pathophysiology 2010 17, 295-306DOI: (10.1016/j.pathophys.2009.10.007) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions

Fig. 7 Post-contrast T1-weighted axial brain MR image of the same patient as in Fig. 6; it demonstrates enhancement of one MS lesion, that appears bright (white) after contrast enhancement. Under normal circumstances, gadolinium does not appear within the brain parenchyma and its active accumulation by the MS lesion indicates disruption of the blood-brain barrier and may serve as an indicator for the early stages of inflammation. Contrast enhancement is a transient phenomenon that usually resolves within 8 weeks. Pathophysiology 2010 17, 295-306DOI: (10.1016/j.pathophys.2009.10.007) Copyright © 2009 Elsevier Ireland Ltd Terms and Conditions