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intracranial hypotension, by taking into consideration not only the symptoms but, Rethink the classical view of above all, the responsible mechanisms. There is a reply to this letter by Wardlaw cerebrospinal fluid production et al. Nat. Rev. Neurol. https://doi.org/10.1038/ s41582-021-00539-z (2021). Margaux Roques , Amaury De Barros and Fabrice Bonneville Margaux Roques 1 ✉ , Amaury De Barros2 and Fabrice Bonneville1 1Department of Neuroradiology, Hôpital Pierre Paul In their brilliant review, Joanna Wardlaw force for CSF pulsatile motion5. These in vivo Riquet CHU Purpan, Toulouse, France. 2Department of Neurosurgery, Hôpital Pierre Paul and colleagues describe those well-known findings support a new model, in which CSF Riquet CHU Purpan, Toulouse, France. but poorly understood CNS features, the is produced by water filtration across capillary ✉e-mail: [email protected] perivascular spaces (Wardlaw, J. M. et al. walls throughout the CNS and is subjected to https://doi.org/10.1038/s41582-021-00538-0 Perivascular spaces in the brain: anatomy, a combination of multidirectional motions, physiology, and pathology. Nat. Rev. Neurol. 16, where hydrodynamic and osmotic changes 1. Wardlaw, J. M. et al. Perivascular spaces in the brain: 137–153 (2020)1). Questions persist on the role play a crucial role6. anatomy, physiology and pathology. Nat. Rev. Neurol. 16, 137–153 (2020). of these spaces in interstitial fluid–cerebrospinal Another line of evidence that suggests 2. Dandy, W. E. Experimental hydrocephalus. Ann. Surg. fluid (ISF–CSF) metabolite clearance, such as that the choroid plexus is not the only site of 70, 129–142 (1919). 3. Milhorat, T. H., Hammock, M. K., Fenstermacher, J. D., drainage pathways, the role of aquaporin 4 CSF production is the failure of plexectomy Rall, D. P. & Levin, V. A. Cerebrospinal fluid production in water transport, and the effects of sleep on to treat paediatric hydrocephalus. This by the choroid plexus and brain. Science 173, 330–332 (1971). their function. In their discussion, the authors approach, which was used for decades, has 4. Mehemed, T. M. et al. Dynamic oxygen-enhanced accurately indicate that the occurrence of CSF largely been replaced by shunt or endoscopic MRI of cerebrospinal fluid. PLoS ONE 9, e100723 (2014). drainage via arachnoid granulations in humans ventriculostomy owing to its lack of efficacy in 5. Matsumae, M. et al. Changing the currently held 7 has been questioned. We believe that their all but exceptional cases of CP hyperplasia . concept of cerebrospinal fluid dynamics based on shared findings of cerebrospinal fluid motion in the statement that CSF is “produced continuously In addition, the combination of choroid cranial cavity using various types of magnetic resonance in the choroid plexus” should be examined too. plexus cauterization with ventriculostomy imaging techniques. Neurol. Med. Chir. 59, 133–146 The traditional ‘bulk flow’ theory of active does not improve outcomes for children with (2019). 6. Oreškovic´, D., Radoš, M. & Klarica, M. New concepts 8 production of CSF in the choroid plexus post-infectious hydrocephalus . Inflammation of cerebrospinal fluid physiology and development of and its passive absorption via arachnoid has recently been proved to play a prominent hydrocephalus. Pediatr. Neurosurg. 52, 417–425 (2017). granulations — historically presented as the role in acquired hydrocephalus, but further 7. Limbrick, D. D., Baird, L. C., Klimo, P., Riva-Cambrin, J. ‘third circulation’ — mostly originates from experiments are required for greater clarity9. & Flannery, A. M. Pediatric hydrocephalus: systematic literature review and evidence-based guidelines. a single experiment by Dandy published in In summary, the oversimplified bulk flow Part 4: Cerebrospinal fluid shunt or endoscopic 1919 that has not been reproduced since. He theory is commonly presented as fact in third ventriculostomy for the treatment of hydrocephalus in children. J. Neurosurg. Pediatr. 14, performed a unilateral choroid plexectomy textbooks and medical schools but should be 30–34 (2014). and obstruction of the foramen of Monro presented as one of several models, along with 8. Kulkarni, A. V. et al. Endoscopic treatment versus shunting for infant hydrocephalus in Uganda. N. Engl. on one dog, which led to the collapse of the its limitations and flaws. Examination of the J. Med. 377, 2456–2464 (2017). plexectomized ventricle and dilation of entire ISF–CSF pathway from production to 9. Karimy, J. K. et al. Inflammation in acquired 2 hydrocephalus: pathogenic mechanisms and the ventricle containing a choroid plexus . clearance is essential for improving treatment therapeutic targets. Nat. Rev. Neurol. 16, By contrast, in 1969, Milhorat et al.3 obstructed of conditions that involve altered CSF 285–296 (2020). the ventricular system of 76 monkeys, which dynamics, such as obstructive hydrocephalus, Competing interests caused hydrocephalus independently of normal pressure hydrocephalus and even The authors declare no competing interests. choroid plexectomy, suggesting a role for extra-choroidal sites in CSF production. The function of the choroid plexus has frequently been investigated in in vitro and Reply to: Rethink the classical view ex vivo experiments, the conditions of which could differ from physiological conditions. of cerebrospinal fluid production However, MRI can be used to explore CSF dynamics in vivo. Use of dynamic oxygen- enhanced MRI has demonstrated that Joanna M. Wardlaw , Helene Benveniste, Maiken Nedergaard , inhaled oxygen predominantly diffuses into Berislav V. Zlokovic, Serge Charpak, Kenneth J. Smith and Sandra E. Black the sulcal CSF rather than the ventricular CSF4. This observation could be explained We thank Roques and colleagues for their s41582-021-00538-0 (2021)2). We agree that by the abundance of pial arterioles relative to comments on our Review (Wardlaw, J. M. et al. the questions of how much cerebrospinal fluid intraventricular vessels and the direct crossing Perivascular spaces in the brain: anatomy, (CSF) is produced and from which structures of intra-arterial molecules through the physiology, and pathology. Nat. Rev. Neurol. remain unanswered. In our Review, we noted blood–CSF barrier to form CSF. In addition, 16, 137–153 (2020)1), in which they correctly that there are several potential sources of CSF, use of several imaging techniques in which point out some textbook dogma that needs to including the choroid plexus, but information CSF motion is directly visualized has be re-evaluated (Roques, M., De Barros, A. about the relative contributions of each source demonstrated no motion around the choroid & Bonneville, F. Rethink the classical is unfortunately limited. plexus, which contradicts the notion that view of cerebrospinal fluid production. In our Review1, we focused on perivascular choroid plexus arterial pulsation is the driving Nat. Rev. Neurol. https://doi.org/10.1038/ spaces as seen in vivo on human brain
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imaging, how these relate to perivascular exiting via one of the several exit routes (the 6Zilkha Neurogenetic Institute, Keck School of Medicine, spaces as described histologically, and arachnoid granulations to venous sinuses, University of Southern California, their role in brain fluid management. the meningeal lymphatics along the dural Los Angeles, CA, USA. Perivascular spaces themselves have been sinuses, or the nasal lymphatics5), which com 7INSERM, CNRS, Institute de la Vision, a controversial topic since the 1800s, and pounds the difficulties of measuring the source Paris, France. 8 clarification of their role, along with a full of fluid. Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, UK. understanding of brain fluid management, Measurement of intracranial fluid pro- 9Department of Medicine (Neurology), Sunnybrook would be of great value. duction is difficult. In humans, opening of Health Sciences Centre, University of Toronto, Some evidence supports the existence the cranial cavity, even with small burr holes, Toronto, ON, Canada. of several sources of interstitial fluid and disturbs the usual pressure balance between 10Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook CSF and several sites of their drainage from intravascular and extravascular compart- Research Institute, University of Toronto, Toronto, 8 the cranial cavity, including a return to the ments , so might also perturb blood and fluid ON, Canada. venous circulation via arachnoid granulations transit through the various compartments. ✉e-mail: [email protected] and intradural channels3, and drainage Cranial windows in rodents affect brain https://doi.org/10.1038/s41582-021-00539-z 1,4 via meningeal lymphatics , including via temperature, thus altering blood flow and 1. Wardlaw, J. M. et al. Perivascular spaces in the brain: skull base lymphatics to nasal lymphatics5. cellular activity9, so might also affect fluid anatomy, physiology and pathology. Nat. Rev. Neurol. 16, 137–153 (2020). However, the major remaining questions production and movement. The temperature 2. Roques, M., De Barros, A. & Bonneville, F. Rethink concern how much fluid is produced and effects persist after re-closure of the cranial the classical view of cerebrospinal fluid production. Nat. Rev. Neurol. https://doi.org/10.1038/s41582- removed by each route, and whether the cavity with a glass window that is sealed with 021-00538-0 (2021). function of these pathways differs by age, sex, dental cement or by substituting the window 3. Fox, R. J., Walji, A. H., Mielke, B., Petruk, K. C. & 9 Aronyk, K. E. Anatomic details of intradural channels brain and physical activity (including sleep by thinning the cranium , and these processes in the parasagittal dura: A possible pathway for flow and wakefulness) and disease states. could also affect pressures, as the properties of cerebrospinal fluid. Neurosurgery 39, 84–91 The choroid plexus is generally agreed to of these materials differ from those of the (1996). 4. Rasmussen, M. K., Mestre, H. & Nedergaard, M. 4 be a key site of CSF production , although intact skull. Improvements in non-invasive Fluid transport in the brain. Physiol. Rev. the relative contributions of choroid plexus medical imaging techniques, such as recent https://doi.org/10.1152/physrev.00031.2020 (2021). in the lateral ventricle versus that in the non-invasive approaches to the measurement 5. Ahn, J. H. et al. Meningeal lymphatic vessels at the fourth ventricle are uncertain and may differ of fluid crossing the blood–brain barrier and skull base drain cerebrospinal fluid. Nature 572, 62–66 (2019). 10 between species. There are also longstanding blood–CSF barrier , the use of multi-pronged 6. Liu, G. et al. Direct measurement of cerebrospinal arguments that interstitial fluid contributes to approaches, and awareness of the limitations fluid production in mice. Cell Rep. 33, 108524 (2020). the CSF and ultimately to lymphatic drain- of each approach, will clarify the impor- 7. Bradbury, M. W., Cserr, H. F. & Westrop, R. J. age4,6,7. Water is a byproduct of metabolic tance of each intracranial fluid production Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am. J. Physiol. 240, reactions in the brain, so excess needs to be and drainage route in the near future. F329–336 (1981). removed. Filtration at the level of capillaries Joanna M. Wardlaw 1 ✉ , Helene Benveniste2, 8. Wardlaw, J. M., Cannon, J., Statham, P. F. X. & Price, R. Does the size of intracranial aneurysms Maiken Nedergaard 3,4, Berislav V. Zlokovic5,6, via the blood–brain barrier also allows fluid change with intracranial pressure? Observations 7 8 to enter the brain interstitial space, a process Serge Charpak , Kenneth J. Smith and based on colour “power” transcranial Doppler Sandra E. Black 9,10 ultrasound. J. Neurosurg. 88, 846–850 that might subtly increase in many disease 1Centre for Clinical Brain Sciences, UK Dementia (1998). states, including Alzheimer disease and small Research Institute, University of Edinburgh, 9. Roche, M. et al. In vivo imaging with a water immersion objective affects brain temperature, vessel disease. Fluid can enter the interstitial Edinburgh, UK. blood flow and oxygenation. Elife 8, e47324 space directly from the ventricles, as in ven- 2Department of Anesthesiology, Yale School of (2019). Medicine, New Haven, CT, USA. 10. Evans, P. G. et al. Non-invasive MRI of blood– tricular obstruction, although this route is 3Section for Translational Neuroscience, Faculty of cerebrospinal fluid barrier function. Nat. Commun. 11, 2081 (2020). unlikely to be a major contributor to physio- Health and Medical Sciences, University logical interstitial fluid. Fluid also enters the of Copenhagen, Copenhagen, Denmark. Acknowledgements brain from CSF via the perivascular spaces 4Division of Glia Disease and Therapeutics, Center for The authors acknowledge the Fondation Leducq Transatlantic Translational Neuromedicine, University of Rochester Network of Excellence for the Study of Perivascular Spaces in as part of the glymphatic flushing system, as Small Vessel Disease (grant reference 16 CVD 05). 1 Medical School, Rochester, NY, USA. explained in our Review . Therefore, it is 5 Department of Physiology and Neuroscience, Keck Competing interests possible that some fluid has passed through School of Medicine, University of Southern California, The authors declare support from academic grants but have several intracranial compartments before Los Angeles, CA, USA. no other competing interests.
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