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Rethink the Classical View of Cerebrospinal Fluid

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Rethink the Classical View of Cerebrospinal Fluid CORRESPONDENCE 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 app roach, 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 Dynamic oxygen-enhanced accurately indicate that the occurrence of CSF largely been replaced by shunt or endoscopic MRI of cerebrospinal fluid.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 590 | SEPTEMBER 2021 | VOLUME 17 www.nature.com/nrneurol 0123456789();: CORRESPONDENCE 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. Peri vascular 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
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