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Inflammation in acquired hydrocephalus: pathogenic mechanisms and therapeutic targets

Nature Reviews Neurology volume 16, pages 285–296 (2020)Cite this article

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Abstract

Hydrocephalus is the most common neurosurgical disorder worldwide and is characterized by enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles resulting from failed CSF homeostasis. Since the 1840s, physicians have observed inflammation in the brain and the CSF spaces in both posthaemorrhagic hydrocephalus (PHH) and postinfectious hydrocephalus (PIH). Reparative inflammation is an important protective response that eliminates foreign organisms, damaged cells and physical irritants; however, inappropriately triggered or sustained inflammation can respectively initiate or propagate disease. Recent data have begun to uncover the molecular mechanisms by which inflammation — driven by Toll-like receptor 4-regulated cytokines, immune cells and signalling pathways — contributes to the pathogenesis of hydrocephalus. We propose that therapeutic approaches that target inflammatory mediators in both PHH and PIH could address the multiple drivers of disease, including choroid plexus CSF hypersecretion, ependymal denudation, and damage and scarring of intraventricular and parenchymal (glia–lymphatic) CSF pathways. Here, we review the evidence for a prominent role of inflammation in the pathogenic mechanism of PHH and PIH and highlight promising targets for therapeutic intervention. Focusing research efforts on inflammation could shift our view of hydrocephalus from that of a lifelong neurosurgical disorder to that of a preventable neuroinflammatory condition.

Key points

  • Hydrocephalus, that is, the enlargement of brain ventricles associated with failed cerebrospinal fluid (CSF) homeostasis, is the most common neurosurgical disorder and is treated mainly by neurosurgical CSF diversion procedures with high rates of morbidity and failure.

  • Posthaemorrhagic hydrocephalus and postinfectious hydrocephalus are the most common causes of hydrocephalus and are both characterized by inflammation in the brain tissue and CSF space.

  • Recent data have begun to uncover the molecular mechanisms by which inflammation, driven by activation of Toll-like receptor 4, contributes to the pathogenesis of hydrocephalus.

  • Pharmacotherapeutic approaches that target inflammation have the potential to address multiple drivers of posthaemorrhagic hydrocephalus and postinfectious hydrocephalus, including acute hypersecretion of CSF by the choroid plexus epithelium and scarring of CSF drainage pathways.

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Fig. 1: Classification and treatment of hydrocephalus.
Fig. 2: Proposed mechanism of CSF hypersecretion in PHH and PIH.
Fig. 3: Glymphatic CSF transport.
Fig. 4: Proposed inflammatory contributors to PHH and PIH.

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References

  1. Rekate, H. L. A contemporary definition and classification of hydrocephalus. Semin. Pediatr. Neurol. 16, 9–15 (2009).

    Article  PubMed  Google Scholar 

  2. Benveniste, H., Lee, H. & Volkow, N. D. The glymphatic pathway: waste removal from the CNS via cerebrospinal fluid transport. Neuroscientist 23, 454–465 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Brinker, T., Stopa, E., Morrison, J. & Klinge, P. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS 11, 10 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Furey, C. G. et al. De novo mutation in genes regulating neural stem cell fate in human congenital hydrocephalus. Neuron 99, 302–314.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kahle, K. T., Kulkarni, A. V., Limbrick, D. D. Jr. & Warf, B. C. Hydrocephalus in children. Lancet 387, 788–799 (2016).

    Article  PubMed  Google Scholar 

  6. Karimy, J. K. et al. Cerebrospinal fluid hypersecretion in pediatric hydrocephalus. Neurosurg. Focus 41, E10 (2016).

    Article  PubMed  Google Scholar 

  7. Karimy, J. K. et al. Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus. Nat. Med. 23, 997–1003 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Dewan, M. C. et al. Global hydrocephalus epidemiology and incidence: systematic review and meta-analysis. J. Neurosurg. 130, 1065–1079 (2018).

    Article  Google Scholar 

  9. Cherian, S., Whitelaw, A., Thoresen, M. & Love, S. The pathogenesis of neonatal post-hemorrhagic hydrocephalus. Brain Pathol. 14, 305–311 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Strahle, J. et al. Mechanisms of hydrocephalus after neonatal and adult intraventricular hemorrhage. Transl. Stroke Res. 3, 25–38 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Reddy, G. K., Bollam, P. & Caldito, G. Long-term outcomes of ventriculoperitoneal shunt surgery in patients with hydrocephalus. World Neurosurg. 81, 404–410 (2014).

    Article  PubMed  Google Scholar 

  12. Isaacs, A. M. et al. Age-specific global epidemiology of hydrocephalus: systematic review, metanalysis and global birth surveillance. PLOS ONE 13, e0204926 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Warf, B. C., Campbell, J. W. & Riddle, E. Initial experience with combined endoscopic third ventriculostomy and choroid plexus cauterization for post-hemorrhagic hydrocephalus of prematurity: the importance of prepontine cistern status and the predictive value of FIESTA MRI imaging. Childs Nerv. Syst. 27, 1063–1071 (2011).

    Article  PubMed  Google Scholar 

  14. Chen, Q. et al. Post-hemorrhagic hydrocephalus: recent advances and new therapeutic insights. J. Neurol. Sci. 375, 220–230 (2017).

    Article  PubMed  Google Scholar 

  15. Tsitouras, V. & Sgouros, S. Infantile posthemorrhagic hydrocephalus. Childs Nerv. Syst. 27, 1595–1608 (2011).

    Article  PubMed  Google Scholar 

  16. Murphy, B. P. et al. Posthaemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome. Arch. Dis. Child. Fetal Neonatal Ed. 87, F37–F41 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Warf, B. C. & East African Neurosurgical Research Collaboration. Pediatric hydrocephalus in East Africa: prevalence, causes, treatments, and strategies for the future. World Neurosurg. 73, 296–300 (2010).

    Article  PubMed  Google Scholar 

  18. Bir, S. C. et al. Epidemiology of adult-onset hydrocephalus: institutional experience with 2001 patients. Neurosurg. Focus 41, E5 (2016).

    Article  PubMed  Google Scholar 

  19. Chahlavi, A., El-Babaa, S. K. & Luciano, M. G. Adult-onset hydrocephalus. Neurosurg. Clin. North. Am. 12, 753–760 (2001).

    Article  CAS  Google Scholar 

  20. Cioca, A., Gheban, D., Perju-Dumbrava, D., Chiroban, O. & Mera, M. Sudden death from ruptured choroid plexus arteriovenous malformation. Am. J. Forensic Med. Pathol. 35, 100–102 (2014).

    Article  PubMed  Google Scholar 

  21. Muir, R. T., Wang, S. & Warf, B. C. Global surgery for pediatric hydrocephalus in the developing world: a review of the history, challenges, and future directions. Neurosurg. Focus 41, E11 (2016).

    Article  PubMed  Google Scholar 

  22. Aziz, I. A. Hydrocephalus in the Sudan. J. R. Coll. Surg. Edinb. 21, 222–224 (1976).

    CAS  PubMed  Google Scholar 

  23. Kamat, A. S., Gretschel, A., Vlok, A. J. & Solomons, R. CSF protein concentration associated with ventriculoperitoneal shunt obstruction in tuberculous meningitis. Int. J. Tuberculosis Lung Dis. 22, 788–792 (2018).

    Article  CAS  Google Scholar 

  24. Aranha, A., Choudhary, A., Bhaskar, S. & Gupta, L. N. A randomized study comparing endoscopic third ventriculostomy versus ventriculoperitoneal shunt in the management of hydrocephalus due to tuberculous meningitis. Asian J. Neurosurg. 13, 1140–1147 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Rajshekhar, V. Management of hydrocephalus in patients with tuberculous meningitis. Neurol. India 57, 368–374 (2009).

    Article  PubMed  Google Scholar 

  26. Li, K. et al. Clinical features, long-term clinical outcomes, and prognostic factors of tuberculous meningitis in West China: a multivariate analysis of 154 adults. Expert Rev. Anti Infect. Ther. 15, 629–635 (2017).

    Article  CAS  PubMed  Google Scholar 

  27. Lee, L. V. Neurotuberculosis among Filipino children: an 11 years experience at the Philippine children’s medical center. Brain Dev. 22, 469–474 (2000).

    Article  PubMed  Google Scholar 

  28. van der Linden, V. et al. Association of severe hydrocephalus with congenital Zika syndrome. JAMA Neurol. 76, 203–210 (2019).

    Article  PubMed  Google Scholar 

  29. Kulkarni, A. V. et al. Endoscopic treatment versus shunting for infant hydrocephalus in Uganda. N. Engl. J. Med. 377, 2456–2464 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Li, L. et al. Association of bacteria with hydrocephalus in Ugandan infants. J. Neurosurg. Pediatr. 7, 73–87 (2011).

    Article  PubMed  Google Scholar 

  31. Thigpen, M. C. et al. Bacterial meningitis in the United States, 1998-2007. N. Engl. J. Med. 364, 2016–2025 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Pyrgos, V., Seitz, A. E., Steiner, C. A., Prevots, D. R. & Williamson, P. R. Epidemiology of cryptococcal meningitis in the US: 1997–2009. PLOS ONE 8, e56269 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu, J. et al. Ventriculoperitoneal shunts in non-HIV cryptococcal meningitis. BMC Neurol. 18, 58 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Schiff, S. J., Ranjeva, S. L., Sauer, T. D. & Warf, B. C. Rainfall drives hydrocephalus in East Africa. J. Neurosurg. Pediatr. 10, 161–167 (2012).

    Article  PubMed  Google Scholar 

  35. Warf, B. C. Comparison of endoscopic third ventriculostomy alone and combined with choroid plexus cauterization in infants younger than 1 year of age: a prospective study in 550 African children. J. Neurosurg. 103, 475–481 (2005).

    PubMed  Google Scholar 

  36. Warf, B. C. Hydrocephalus in Uganda: the predominance of infectious origin and primary management with endoscopic third ventriculostomy. J. Neurosurg. 102, 1–15 (2005).

    Article  PubMed  Google Scholar 

  37. Stagno, V., Navarrete, E. A., Mirone, G. & Esposito, F. Management of hydrocephalus around the world. World Neurosurg. 79 (Suppl. 2), S23.e17–20 (2013).

    Article  Google Scholar 

  38. Kulkarni, A. V. First treatment in infants with hydrocephalus: the case for shunt. Neurosurgery 63 (Suppl. 1), 73–77 (2016).

    Article  PubMed  Google Scholar 

  39. Drake, J. M., Kulkarni, A. V. & Kestle, J. Endoscopic third ventriculostomy versus ventriculoperitoneal shunt in pediatric patients: a decision analysis. Childs Nerv. Syst. 25, 467–472 (2009).

    Article  PubMed  Google Scholar 

  40. Kulkarni, A. V. et al. Endoscopic third ventriculostomy in the treatment of childhood hydrocephalus. J. Pediatr. 155, 254–259.e1 (2009).

    Article  PubMed  Google Scholar 

  41. Limbrick, D. D. Jr., Baird, L. C., Klimo, P. Jr., Riva-Cambrin, J. & Flannery, A. M. Pediatric hydrocephalus: systematic review and evidence-based guidelines task force. Part 4: cerebrospinal fluid shunt or endoscopic third ventriculostomy for the treatment of hydrocephalus in children. J. Neurosurg. Pediatr. 14, 30–34 (2014).

    Article  PubMed  Google Scholar 

  42. Pindrik, J., Jallo, G. I. & Ahn, E. S. Complications and subsequent removal of retained shunt hardware after endoscopic third ventriculostomy: case series. J. Neurosurg. Pediatr. 11, 722–726 (2013).

    Article  PubMed  Google Scholar 

  43. Kulkarni, A. V. et al. Outcomes of CSF shunting in children: comparison of hydrocephalus clinical research network cohort with historical controls: clinical article. J. Neurosurg. Pediatr. 12, 334–338 (2013).

    Article  PubMed  Google Scholar 

  44. Kulkarni, A. V. et al. Endoscopic third ventriculostomy vs cerebrospinal fluid shunt in the treatment of hydrocephalus in children: a propensity score-adjusted analysis. Neurosurgery 67, 588–593 (2010).

    Article  PubMed  Google Scholar 

  45. Baird, L. C. First treatment in infants with hydrocephalus: the case for endoscopic third ventriculostomy/choroid plexus cauterization. Neurosurgery 63, 78–82 (2016).

    Article  PubMed  Google Scholar 

  46. Kulkarni, A. V. et al. Endoscopic third ventriculostomy and choroid plexus cauterization in infants with hydrocephalus: a retrospective hydrocephalus clinical research network study. J. Neurosurg. Pediatr. 14, 224–229 (2014).

    Article  PubMed  Google Scholar 

  47. Marques, F. et al. The choroid plexus in health and in disease: dialogues into and out of the brain. Neurobiol. Dis. 107, 32–40 (2017).

    Article  PubMed  Google Scholar 

  48. Ghersi-Egea, J. F. et al. Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease. Acta Neuropathol. 135, 337–361 (2018).

    Article  CAS  PubMed  Google Scholar 

  49. Lauer, A. N., Tenenbaum, T., Schroten, H. & Schwerk, C. The diverse cellular responses of the choroid plexus during infection of the central nervous system. Am. J. Physiol. Cell Physiol. 314, C152–C165 (2018).

    Article  PubMed  CAS  Google Scholar 

  50. Damkier, H. H., Brown, P. D. & Praetorius, J. Cerebrospinal fluid secretion by the choroid plexus. Physiol. Rev. 93, 1847–1892 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. International PHVD Drug Trial Group. International randomised controlled trial of acetazolamide and furosemide in posthaemorrhagic ventricular dilatation in infancy. Lancet 352, 433–440 (1998).

    Article  Google Scholar 

  52. Whitelaw, A., Kennedy, C. R. & Brion, L. P. Diuretic therapy for newborn infants with posthemorrhagic ventricular dilatation. Cochrane Database Syst. Rev. 2, CD002270 (2001).

    Google Scholar 

  53. Libenson, M. H., Kaye, E. M., Rosman, N. P. & Gilmore, H. E. Acetazolamide and furosemide for posthemorrhagic hydrocephalus of the newborn. Pediatr. Neurol. 20, 185–191 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Teppema, L. J. & Dahan, A. Acetazolamide and breathing. Does a clinical dose alter peripheral and central CO2 sensitivity? Am. J. Respir. Crit. Care Med. 160, 1592–1597 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Erker, T. et al. The bumetanide prodrug BUM5, but not bumetanide, potentiates the antiseizure effect of phenobarbital in adult epileptic mice. Epilepsia 57, 698–705 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. Tollner, K. et al. A novel prodrug-based strategy to increase effects of bumetanide in epilepsy. Ann. Neurol. 75, 550–562 (2014).

    Article  PubMed  CAS  Google Scholar 

  57. Seelig, A., Gottschlich, R. & Devant, R. M. A method to determine the ability of drugs to diffuse through the blood-brain barrier. Proc. Natl Acad. Sci. USA 91, 68–72 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Larroche, J.-C. Post-haemorrhagic hydrocephalus in infancy. Anatomical study. Biol. Neonate 20, 287–299 (1972).

    Article  CAS  PubMed  Google Scholar 

  59. Omar, A. T. II, Bagnas, M. A. C., Del Rosario-Blasco, K. A. R., Diestro, J. D. B. & Khu, K. J. O. Shunt surgery for neurocutaneous melanosis with hydrocephalus: case report and review of the literature. World Neurosurg. 120, 583–589.e3 (2018).

    Article  PubMed  Google Scholar 

  60. Whitelaw, A. Intraventricular haemorrhage and posthaemorrhagic hydrocephalus: pathogenesis, prevention and future interventions. Semin. Neonatol. 6, 135–146 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Lategan, B., Chodirker, B. N. & Del Bigio, M. R. Fetal hydrocephalus caused by cryptic intraventricular hemorrhage. Brain Pathol. 20, 391–398 (2010).

    Article  PubMed  Google Scholar 

  62. Hill, A., Shackelford, G. D. & Volpe, J. J. A potential mechanism of pathogenesis for early posthemorrhagic hydrocephalus in the premature newborn. Pediatrics 73, 19–21 (1984).

    CAS  PubMed  Google Scholar 

  63. Milhorat, T. H., Hammock, M. K., Davis, D. A. & Fenstermacher, J. D. Choroid plexus papilloma. I. Proof of cerebrospinal fluid overproduction. Childs Brain 2, 273–289 (1976).

    CAS  PubMed  Google Scholar 

  64. Gram, M. et al. Extracellular hemoglobin–mediator of inflammation and cell death in the choroid plexus following preterm intraventricular hemorrhage. J. Neuroinflammation 11, 200 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Gram, M. et al. Hemoglobin induces inflammation after preterm intraventricular hemorrhage by methemoglobin formation. J. Neuroinflammation 10, 100 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Simard, P. F. et al. Inflammation of the choroid plexus and ependymal layer of the ventricle following intraventricular hemorrhage. Transl. Stroke Res. 2, 227–231 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Barichello, T. et al. Pathophysiology of neonatal acute bacterial meningitis. J. Med. Microbiol. 62, 1781–1789 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Bateman, G. A. & Brown, K. M. The measurement of CSF flow through the aqueduct in normal and hydrocephalic children: from where does it come, to where does it go? Childs Nerv. Syst. 28, 55–63 (2012).

    Article  PubMed  Google Scholar 

  69. Oi, S. & Di Rocco, C. Proposal of “evolution theory in cerebrospinal fluid dynamics” and minor pathway hydrocephalus in developing immature brain. Childs Nerv. Syst. 22, 662–669 (2006).

    Article  PubMed  Google Scholar 

  70. Oreskovic, D., Rados, M. & Klarica, M. Role of choroid plexus in cerebrospinal fluid hydrodynamics. Neuroscience 354, 69–87 (2017).

    Article  CAS  PubMed  Google Scholar 

  71. Miyajima, M. & Arai, H. Evaluation of the production and absorption of cerebrospinal fluid. Neurol. Med. Chir. 55, 647–656 (2015).

    Article  Google Scholar 

  72. Lohrberg, M. & Wilting, J. The lymphatic vascular system of the mouse head. Cell Tissue Res. 366, 667–677 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Olstad, E. W. et al. Ciliary beating compartmentalizes cerebrospinal fluid flow in the brain and regulates ventricular development. Curr. Biol. 29, 229–241.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gao, C. et al. Role of red blood cell lysis and iron in hydrocephalus after intraventricular hemorrhage. J. Cereb. Blood Flow Metab. 34, 1070–1075 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Polis, B., Polis, L. & Nowoslawska, E. Surgical treatment of post-inflammatory hydrocephalus. Analysis of 101 cases. Childs Nerv. Syst. 35, 237–243 (2019).

    Article  PubMed  Google Scholar 

  76. Raouf, A., Zidan, I. & Mohamed, E. Endoscopic third ventriculostomy for post-inflammatory hydrocephalus in pediatric patients: is it worth a try? Neurosurg. Rev. 38, 149–155; discussion 155 (2015).

    Article  PubMed  Google Scholar 

  77. [No authors listed]. Acute hydrocephalus, or water in the head, an inflammatory disease, and curable equally and by the same means with other diseases of inflammation. Br. Foreign Med. Rev. 11, 151–158 (1841).

  78. Davis, D. D. Acute Hydrocephalus, or Water in the Head: an Inflammatory Disease, and Curable Equally by the Same Means with Other Diseases of Inflammation (Taylor & Walton, 1840).

  79. [No authors listed]. Hydrocephalus reconsidered; and its relations to inflammation and irritation of the brain defined, with cases from hospital and private practice. Prov. Med. Surg. J. 15, 16–17 (1851).

  80. Sharma, S. et al. Cytokines do play a role in pathogenesis of tuberculous meningitis: a prospective study from a tertiary care center in India. J. Neurol. Sci. 379, 131–136 (2017).

    Article  CAS  PubMed  Google Scholar 

  81. Chaudhry, S. R. et al. Elevated systemic IL-6 levels in patients with aneurysmal subarachnoid hemorrhage is an unspecific marker for post-SAH complications. Int. J. Mol. Sci. 18, E2580 (2017).

    Article  PubMed  CAS  Google Scholar 

  82. Kitazawa, K. & Tada, T. Elevation of transforming growth factor-β1 level in cerebrospinal fluid of patients with communicating hydrocephalus after subarachnoid hemorrhage. Stroke 25, 1400–1404 (1994).

    Article  CAS  PubMed  Google Scholar 

  83. Whitelaw, A., Christie, S. & Pople, I. Transforming growth factor- β1: a possible signal molecule for posthemorrhagic hydrocephalus? Pediatr. Res. 46, 576–580 (1999).

    Article  CAS  PubMed  Google Scholar 

  84. Mlakar, J. et al. Zika virus associated with microcephaly. N. Engl. J. Med. 374, 951–958 (2016).

    Article  CAS  PubMed  Google Scholar 

  85. Ulfig, N., Bohl, J., Neudorfer, F. & Rezaie, P. Brain macrophages and microglia in human fetal hydrocephalus. Brain Dev. 26, 307–315 (2004).

    Article  PubMed  Google Scholar 

  86. Thwaites, G. E. et al. Serial MRI to determine the effect of dexamethasone on the cerebral pathology of tuberculous meningitis: an observational study. Lancet Neurol. 6, 230–236 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Schurkamper, M., Medele, R., Zausinger, S., Schmid-Elsaesser, R. & Steiger, H. J. Dexamethasone in the treatment of subarachnoid hemorrhage revisited: a comparative analysis of the effect of the total dose on complications and outcome. J. Clin. Neurosci. 11, 20–24 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Gutierrez-Murgas, Y. M., Skar, G., Ramirez, D., Beaver, M. & Snowden, J. N. IL-10 plays an important role in the control of inflammation but not in the bacterial burden in S. epidermidis CNS catheter infection. J. Neuroinflammation 13, 271 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Hausler, M. et al. Murine gammaherpesvirus-68 infection of mice: a new model for human cerebral Epstein-Barr virus infection. Ann. Neurol. 57, 600–603 (2005).

    Article  PubMed  Google Scholar 

  90. Zhu, W. et al. Mouse models of intracerebral hemorrhage in ventricle, cortex, and hippocampus by injections of autologous blood or collagenase. PLOS ONE 9, e97423 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Harada, T., Takamoto, M., Jin, D. H., Tada, T. & Sugane, K. Young C3H mice infected with Toxoplasma gondii are a novel experimental model of communicating hydrocephalus. Neurol. Res. 29, 615–621 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Guo, J. et al. Minocycline-induced attenuation of iron overload and brain injury after experimental germinal matrix hemorrhage. Brain Res. 1594, 115–124 (2015).

    Article  CAS  PubMed  Google Scholar 

  93. Sansing, L. H. et al. Toll-like receptor 4 contributes to poor outcome after intracerebral hemorrhage. Ann. Neurol. 70, 646–656 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wang, Y. C. et al. Toll-like receptor 4 antagonist attenuates intracerebral hemorrhage-induced brain injury. Stroke 44, 2545–2552 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Lattke, M., Magnutzki, A., Walther, P., Wirth, T. & Baumann, B. Nuclear factor κB activation impairs ependymal ciliogenesis and links neuroinflammation to hydrocephalus formation. J. Neurosci. 32, 11511–11523 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Galbreath, E., Kim, S. J., Park, K., Brenner, M. & Messing, A. Overexpression of TGF-β1 in the central nervous system of transgenic mice results in hydrocephalus. J. Neuropathol. Exp. Neurol. 54, 339–349 (1995).

    Article  CAS  PubMed  Google Scholar 

  97. Tada, T., Kanaji, M. & Kobayashi, S. Induction of communicating hydrocephalus in mice by intrathecal injection of human recombinant transforming growth factor-β1. J. Neuroimmunol. 50, 153–158 (1994).

    Article  CAS  PubMed  Google Scholar 

  98. Lindvall-Axelsson, M., Hedner, P. & Owman, C. Corticosteroid action on choroid plexus: reduction in Na+-K+-ATPase activity, choline transport capacity, and rate of CSF formation. Exp. Brain Res. 77, 605–610 (1989).

    Article  CAS  PubMed  Google Scholar 

  99. Weiss, M. H. & Nulsen, F. E. The effect of glucocorticoids on CSF flow in dogs. J. Neurosurg. 32, 452–458 (1970).

    Article  CAS  PubMed  Google Scholar 

  100. Sato, O., Hara, M., Asai, T., Tsugane, R. & Kageyama, N. The effect of dexamethasone phosphate on the production rate of cerebrospinal fluid in the spinal subarachnoid space of dogs. J. Neurosurg. 39, 480–484 (1973).

    Article  CAS  PubMed  Google Scholar 

  101. Steffensen, A. B. et al. Cotransporter-mediated water transport underlying cerebrospinal fluid formation. Nat. Commun. 9, 2167 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Keep, R. F. & Jones, H. C. A morphometric study on the development of the lateral ventricle choroid plexus, choroid plexus capillaries and ventricular ependyma in the rat. Brain Res. Dev. Brain Res. 56, 47–53 (1990).

    Article  CAS  PubMed  Google Scholar 

  103. Praetorius, J. Water and solute secretion by the choroid plexus. Pflug. Arch. 454, 1–18 (2007).

    Article  CAS  Google Scholar 

  104. Praetorius, J. & Damkier, H. H. Transport across the choroid plexus epithelium. Am. J. Physiol. Cell Physiol. 312, C673–C686 (2017).

    Article  PubMed  Google Scholar 

  105. Medzhitov, R. TLR-mediated innate immune recognition. Semin. Immunol. 19, 1–2 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Coorens, M. et al. Cathelicidins inhibit Escherichia coli-induced TLR2 and TLR4 activation in a viability-dependent manner. J. Immunol. 199, 1418–1428 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Skipor, J., Szczepkowska, A., Kowalewska, M., Herman, A. P. & Lisiewski, P. Profile of toll-like receptor mRNA expression in the choroid plexus in adult ewes. Acta Vet. Hung. 63, 69–78 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Rivest, S. Molecular insights on the cerebral innate immune system. Brain Behav. Immun. 17, 13–19 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Miyake, K. Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin. Immunol. 19, 3–10 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Fang, H. et al. Toll-like receptor 4 (TLR4) is essential for Hsp70-like protein 1 (HSP70L1) to activate dendritic cells and induce Th1 response. J. Biol. Chem. 286, 30393–30400 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tsan, M. F. & Gao, B. Endogenous ligands of Toll-like receptors. J. Leukoc. Biol. 76, 514–519 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Chen, S., Luo, J., Reis, C., Manaenko, A. & Zhang, J. Hydrocephalus after subarachnoid hemorrhage: pathophysiology, diagnosis, and treatment. Biomed. Res. Int. 2017, 8584753 (2017).

    PubMed  PubMed Central  Google Scholar 

  113. Okamoto, T. et al. Matrix metalloproteinases in infants with posthemorrhagic hydrocephalus. Early Hum. Dev. 84, 137–139 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Ehrchen, J. M., Sunderkotter, C., Foell, D., Vogl, T. & Roth, J. The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J. Leukoc. Biol. 86, 557–566 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Yang, B., Zhou, Z., Li, X. & Niu, J. The effect of lysophosphatidic acid on Toll-like receptor 4 expression and the nuclear factor-κB signaling pathway in THP-1 cells. Mol. Cell Biochem. 422, 41–49 (2016).

    Article  CAS  PubMed  Google Scholar 

  116. Kwon, M. S. et al. Methemoglobin is an endogenous toll-like receptor 4 ligand-relevance to subarachnoid hemorrhage. Int. J. Mol. Sci. 16, 5028–5046 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Demeestere, D., Libert, C. & Vandenbroucke, R. E. Clinical implications of leukocyte infiltration at the choroid plexus in (neuro)inflammatory disorders. Drug Discov. Today 20, 928–941 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. Kleine, T. O. & Benes, L. Immune surveillance of the human central nervous system (CNS): different migration pathways of immune cells through the blood-brain barrier and blood-cerebrospinal fluid barrier in healthy persons. Cytometry A 69, 147–151 (2006).

    Article  PubMed  Google Scholar 

  119. Wang, Y. C. et al. Toll-like receptor 2/4 heterodimer mediates inflammatory injury in intracerebral hemorrhage. Ann. Neurol. 75, 876–889 (2014).

    Article  CAS  PubMed  Google Scholar 

  120. Cox, K. H., Cox, M. E., Woo-Rasberry, V. & Hasty, D. L. Pathways involved in the synergistic activation of macrophages by lipoteichoic acid and hemoglobin. PLOS ONE 7, e47333 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Berkes, J., Viswanathan, V. K., Savkovic, S. D. & Hecht, G. Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion transport, and inflammation. Gut 52, 439–451 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wilson, R. et al. Upper respiratory tract viral infection and mucociliary clearance. Eur. J. Respir. Dis. 70, 272–279 (1987).

    CAS  PubMed  Google Scholar 

  123. Doyle, W. J. et al. Nasal and otologic effects of experimental influenza A virus infection. Ann. Otol. Rhinol. Laryngol. 103, 59–69 (1994).

    Article  CAS  PubMed  Google Scholar 

  124. Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Nowarski, R., Jackson, R. & Flavell, R. A. The stromal intervention: regulation of immunity and inflammation at the epithelial-mesenchymal barrier. Cell 168, 362–375 (2017).

    Article  CAS  PubMed  Google Scholar 

  126. Karimy, J. K. et al. A novel method to study cerebrospinal fluid dynamics in rats. J. Neurosci. Methods 241, 78–84 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Piechotta, K., Garbarini, N., England, R. & Delpire, E. Characterization of the interaction of the stress kinase SPAK with the Na+-K+-2Cl– cotransporter in the nervous system: evidence for a scaffolding role of the kinase. J. Biol. Chem. 278, 52848–52856 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. Shekarabi, M. et al. WNK kinase signaling in ion homeostasis and human disease. Cell Metab. 25, 285–299 (2017).

    Article  CAS  PubMed  Google Scholar 

  129. Yan, Y. & Merlin, D. Ste20-related proline/alanine-rich kinase: a novel regulator of intestinal inflammation. World J. Gastroenterol. 14, 6115–6121 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Yan, Y. et al. Nuclear factor-κB is a critical mediator of Ste20-like proline-/alanine-rich kinase regulation in intestinal inflammation. Am. J. Pathol. 173, 1013–1028 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Thiagarajah, J. R., Donowitz, M. & Verkman, A. S. Secretory diarrhoea: mechanisms and emerging therapies. Nat. Rev. Gastroenterol. Hepatol. 12, 446–457 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Lin, T. J. et al. SPAK plays a pathogenic role in IgA nephropathy through the activation of NF-κB/MAPKs signaling pathway. Free Radic. Biol. Med. 99, 214–224 (2016).

    Article  CAS  PubMed  Google Scholar 

  133. Lan, C. C. et al. Inhibition of Na-K-Cl cotransporter isoform 1 reduces lung injury induced by ischemia-reperfusion. J. Thorac. Cardiovasc. Surg. 153, 206–215 (2017).

    Article  CAS  PubMed  Google Scholar 

  134. Yan, Y., Nguyen, H., Dalmasso, G., Sitaraman, S. V. & Merlin, D. Cloning and characterization of a new intestinal inflammation-associated colonic epithelial Ste20-related protein kinase isoform. Biochim. Biophys. Acta 1769, 106–116 (2007).

    Article  CAS  PubMed  Google Scholar 

  135. Polek, T. C., Talpaz, M. & Spivak-Kroizman, T. The TNF receptor, RELT, binds SPAK and uses it to mediate p38 and JNK activation. Biochem. Biophys. Res. Commun. 343, 125–134 (2006).

    Article  CAS  PubMed  Google Scholar 

  136. Alessi, D. R. et al. The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters. Sci. Signal. 7, re3 (2014).

    Article  PubMed  CAS  Google Scholar 

  137. Thastrup, J. O. et al. SPAK/OSR1 regulate NKCC1 and WNK activity: analysis of WNK isoform interactions and activation by T-loop trans-autophosphorylation. Biochem. J. 441, 325–337 (2012).

    Article  CAS  PubMed  Google Scholar 

  138. de Los, H. P. et al. The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl– co-transporters. Biochem. J. 458, 559–573 (2014).

    Article  CAS  Google Scholar 

  139. Lee, D., Lee, S. A., Shin, D. M. & Hong, J. H. Chloride influx of anion exchanger 2 was modulated by calcium-dependent spinophilin in submandibular glands. Front. Physiol. 9, 889 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Li, Q. et al. Targeting germinal matrix hemorrhage-induced overexpression of sodium-coupled bicarbonate exchanger reduces posthemorrhagic hydrocephalus formation in neonatal rats. J. Am. Heart Assoc. 7, e007192 (2018).

    PubMed  PubMed Central  Google Scholar 

  141. Kim, K. S. Mechanisms of microbial traversal of the blood-brain barrier. Nat. Rev. Microbiol. 6, 625–634 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Koedel, U., Klein, M. & Pfister, H.-W. New understandings on the pathophysiology of bacterial meningitis. Curr. Opin. Infect. Dis. 23, 217–223 (2010).

    Article  CAS  PubMed  Google Scholar 

  143. Deopujari, C. E., Padayachy, L., Azmi, A., Figaji, A. & Samantray, S. K. Neuroendoscopy for post-infective hydrocephalus in children. Childs Nerv. Syst. 34, 1905–1914 (2018).

    Article  PubMed  Google Scholar 

  144. Sellner, J., Tauber, M. G. & Leib, S. L. Pathogenesis and pathophysiology of bacterial CNS infections. Handb. Clin. Neurol. 96, 1–16 (2010).

    Article  PubMed  Google Scholar 

  145. Malley, R. et al. Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc. Natl Acad. Sci. USA 100, 1966–1971 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Lahrtz, F., Piali, L., Spanaus, K. S., Seebach, J. & Fontana, A. Chemokines and chemotaxis of leukocytes in infectious meningitis. J. Neuroimmunol. 85, 33–43 (1998).

    Article  CAS  PubMed  Google Scholar 

  147. Krebs, V. L., Okay, T. S., Okay, Y. & Vaz, F. A. Tumor necrosis factor-alpha, interleukin-1beta and interleukin-6 in the cerebrospinal fluid of newborn with meningitis. Arq. Neuropsiquiatr. 63, 7–13 (2005).

    Article  PubMed  Google Scholar 

  148. van Furth, A. M., Roord, J. J. & van Furth, R. Roles of proinflammatory and anti-inflammatory cytokines in pathophysiology of bacterial meningitis and effect of adjunctive therapy. Infect. Immun. 64, 4883–4890 (1996).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Grandgirard, D. & Leib, S. L. Meningitis in neonates: bench to bedside. Clin. Perinatol. 37, 655–676 (2010).

    Article  PubMed  Google Scholar 

  150. Dessing, M. C. et al. Role played by Toll-like receptors 2 and 4 in lipoteichoic acid-induced lung inflammation and coagulation. J. Infect. Dis. 197, 245–252 (2008).

    Article  CAS  PubMed  Google Scholar 

  151. Flo, T. H. et al. Human toll-like receptor 2 mediates monocyte activation by Listeria monocytogenes, but not by group B streptococci or lipopolysaccharide. J. Immunol. 164, 2064–2069 (2000).

    Article  CAS  PubMed  Google Scholar 

  152. Janot, L. et al. CD14 works with toll-like receptor 2 to contribute to recognition and control of Listeria monocytogenes infection. J. Infect. Dis. 198, 115–124 (2008).

    Article  CAS  PubMed  Google Scholar 

  153. Seki, E. et al. Critical roles of myeloid differentiation factor 88-dependent proinflammatory cytokine release in early phase clearance of Listeria monocytogenes in mice. J. Immunol. 169, 3863–3868 (2002).

    Article  CAS  PubMed  Google Scholar 

  154. Mook-Kanamori, B. B., Geldhoff, M., van der Poll, T. & van de Beek, D. Pathogenesis and pathophysiology of pneumococcal meningitis. Clin. Microbiol. Rev. 24, 557–591 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Hayashi, F. et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099–1103 (2001).

    Article  CAS  PubMed  Google Scholar 

  156. Mottahedin, A., Joakim, Ek,C., Truve, K., Hagberg, H. & Mallard, C. Choroid plexus transcriptome and ultrastructure analysis reveals a TLR2-specific chemotaxis signature and cytoskeleton remodeling in leukocyte trafficking. Brain Behav. Immun. 79, 216–227 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Jimenez, A. J., Dominguez-Pinos, M. D., Guerra, M. M., Fernandez-Llebrez, P. & Perez-Figares, J. M. Structure and function of the ependymal barrier and diseases associated with ependyma disruption. Tissue Barriers 2, e28426 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Guerra, M. M. et al. Cell junction pathology of neural stem cells is associated with ventricular zone disruption, hydrocephalus, and abnormal neurogenesis. J. Neuropathol. Exp. Neurol. 74, 653–671 (2015).

    Article  PubMed  Google Scholar 

  159. Yung, Y. C. et al. Lysophosphatidic acid signaling may initiate fetal hydrocephalus. Sci. Transl Med. 3, 99ra87 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Bayatti, N. et al. A molecular neuroanatomical study of the developing human neocortex from 8 to 17 postconceptional weeks revealing the early differentiation of the subplate and subventricular zone. Cereb. Cortex 18, 1536–1548 (2008).

    Article  PubMed  Google Scholar 

  161. Rodriguez, E. M. et al. A cell junction pathology of neural stem cells leads to abnormal neurogenesis and hydrocephalus. Biol. Res. 45, 231–242 (2012).

    Article  PubMed  CAS  Google Scholar 

  162. McAllister, J. P. et al. Ventricular zone disruption in human neonates with intraventricular hemorrhage. J. Neuropathol. Exp. Neurol. 76, 358–375 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Castaneyra-Ruiz, L. et al. Blood exposure causes ventricular zone disruption and glial activation in vitro. J. Neuropathol. Exp. Neurol. 77, 803–813 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Liu, S. F., Ye, X. & Malik, A. B. Inhibition of NF-κB activation by pyrrolidine dithiocarbamate prevents in vivo expression of proinflammatory genes. Circulation 100, 1330–1337 (1999).

    Article  CAS  PubMed  Google Scholar 

  165. Hu, Y. et al. Melatonin protects against blood-brain barrier damage by inhibiting the TLR4/ NF-κB signaling pathway after LPS treatment in neonatal rats. Oncotarget 8, 31638–31654 (2017).

    PubMed  PubMed Central  Google Scholar 

  166. Robinson, S. et al. Extended combined neonatal treatment with erythropoietin plus melatonin prevents posthemorrhagic hydrocephalus of prematurity in rats. Front. Cell Neurosci. 12, 322 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Rice, T. W. et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit. Care Med. 38, 1685–1694 (2010).

    Article  CAS  PubMed  Google Scholar 

  168. Allette, Y. M. et al. Decoy peptide targeted to Toll-IL-1R domain inhibits LPS and TLR4-active metabolite morphine-3 glucuronide sensitization of sensory neurons. Sci. Rep. 7, 3741 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Jung, K. et al. Toll-like receptor 4 decoy, TOY, attenuates gram-negative bacterial sepsis. PLOS ONE 4, e7403 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Lemonnier, E. et al. A randomised controlled trial of bumetanide in the treatment of autism in children. Transl. Psychiatry 2, e202 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Lemonnier, E. & Ben-Ari, Y. The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects. Acta Paediatr. 99, 1885–1888 (2010).

    Article  PubMed  Google Scholar 

  172. Lemonnier, E. et al. Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Transl. Psychiatry 7, e1056 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Pressler, R. M. et al. Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial. Lancet Neurol. 14, 469–477 (2015).

    Article  CAS  PubMed  Google Scholar 

  174. Sveinsdottir, S. et al. Altered expression of aquaporin 1 and 5 in the choroid plexus following preterm intraventricular hemorrhage. Developmental Neurosci. 36, 542–551 (2014).

    Article  CAS  Google Scholar 

  175. Gharagozloo, M. et al. NLR-Dependent regulation of inflammation in multiple sclerosis. Front. Immunol. 8, 2012 (2017).

    Article  PubMed  CAS  Google Scholar 

  176. White, C. S., Lawrence, C. B., Brough, D. & Rivers-Auty, J. Inflammasomes as therapeutic targets for Alzheimer’s disease. Brain Pathol. 27, 223–234 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Ringstad, G., Vatnehol, S. A. S. & Eide, P. K. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain 140, 2691–2705 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Ringstad, G. et al. Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight 3, 121537 (2018).

    Article  PubMed  Google Scholar 

  179. Nedergaard, M. Neuroscience. Garbage truck of the brain. Science 340, 1529–1530 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Ding, Y. et al. Astrogliosis inhibition attenuates hydrocephalus by increasing cerebrospinal fluid reabsorption through the glymphatic system after germinal matrix hemorrhage. Exp. Neurol. 320, 113003 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Plog, B. A. & Nedergaard, M. The glymphatic system in central nervous system health and disease: past, present, and future. Annu. Rev. Pathol. 13, 379–394 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Jin, B. J., Smith, A. J. & Verkman, A. S. Spatial model of convective solute transport in brain extracellular space does not support a “glymphatic” mechanism. J. Gen. Physiol. 148, 489–501 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Smith, A. J., Yao, X., Dix, J. A., Jin, B. J. & Verkman, A. S. Test of the ‘glymphatic’ hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma. eLife 6, e27679 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Smith, A. J. & Verkman, A. S. The “glymphatic” mechanism for solute clearance in Alzheimer’s disease: game changer or unproven speculation? FASEB J. 32, 543–551 (2018).

    Article  CAS  PubMed  Google Scholar 

  185. Iliff, J. & Simon, M. CrossTalk proposal: the glymphatic system supports convective exchange of cerebrospinal fluid and brain interstitial fluid that is mediated by perivascular aquaporin-4. J. Physiol. 597, 4417–4419 (2019).

    Article  CAS  PubMed  Google Scholar 

  186. Smith, A. J. & Verkman, A. S. Rebuttal from Alex J. Smith and Alan S. Verkman. J. Physiol. 597, 4427–4428 (2019).

    Article  CAS  PubMed  Google Scholar 

  187. Simon, M. & Iliff, J. Rebuttal from Matthew Simon and Jeffrey Iliff. J. Physiol. 597, 4425–4426 (2019).

    Article  CAS  PubMed  Google Scholar 

  188. Eming, S. A., Hammerschmidt, M., Krieg, T. & Roers, A. Interrelation of immunity and tissue repair or regeneration. Semin. Cell Dev. Biol. 20, 517–527 (2009).

    Article  CAS  PubMed  Google Scholar 

  189. Klingberg, F., Hinz, B. & White, E. S. The myofibroblast matrix: implications for tissue repair and fibrosis. J. Pathol. 229, 298–309 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Sarnat, H. B. Ependymal reactions to injury. A review. J. Neuropathol. Exp. Neurol. 54, 1–15 (1995).

    Article  CAS  PubMed  Google Scholar 

  191. Fukumizu, M., Takashima, S. & Becker, L. E. Neonatal posthemorrhagic hydrocephalus: neuropathologic and immunohistochemical studies. Pediatric Neurol. 13, 230–234 (1995).

    Article  CAS  Google Scholar 

  192. Marlin, A. E., Wald, A., Hochwald, G. M. & Malhan, C. Kaolin-induced hydrocephalus impairs CSF secretion by the choroid plexus. Neurology 28, 945–949 (1978).

    Article  CAS  PubMed  Google Scholar 

  193. Silverberg, G. D. et al. Downregulation of cerebrospinal fluid production in patients with chronic hydrocephalus. J. Neurosurg. 97, 1271–1275 (2002).

    Article  PubMed  Google Scholar 

  194. Kosteljanetz, M. Cerebrospinal fluid production in subarachnoid haemorrhage. Br. J. Neurosurg. 2, 161–167 (1988).

    Article  CAS  PubMed  Google Scholar 

  195. Mestre, H. et al. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat. Commun. 9, 4878 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  196. Wagshul, M. E., Eide, P. K. & Madsen, J. R. The pulsating brain: a review of experimental and clinical studies of intracranial pulsatility. Fluids Barriers CNS 8, 5 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Hladky, S. B. & Barrand, M. A. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluids Barriers CNS 11, 26 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Shibukawa, S. et al. Time-spatial labeling inversion pulse (Time-SLIP) with pencil beam pulse: a selective labeling technique for observing cerebrospinal fluid flow dynamics. Magn. Reson. Med. Sci. 17, 259–264 (2018).

    Article  PubMed  Google Scholar 

  199. Yamada, S. et al. Visualization of cerebrospinal fluid movement with spin labeling at MR imaging: preliminary results in normal and pathophysiologic conditions. Radiology 249, 644–652 (2008).

    Article  PubMed  Google Scholar 

  200. Hoffmann, A. et al. MRI of iron oxide nanoparticles and myeloperoxidase activity links inflammation to brain edema in experimental cerebral malaria. Radiology 290, 359–367 (2019).

    Article  PubMed  Google Scholar 

  201. Millward, J. M. et al. Application of europium-doped very small iron oxide nanoparticles to visualize neuroinflammation with MRI and fluorescence microscopy. Neuroscience 403, 136–144 (2017).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

K.T.K. is supported by NIH grants NRCDP K12-228168, 1RO1NS109358 and R01 NS111029-01A1; the Hydrocephalus Association; the Rudy Schulte Research Institute; and the Simons Foundation. J.K.K. is supported by the Howard Hughes Medical Institute. M.N. is supported by NIH 1R01NS100366 and RF1 AG057575-01. P.Q.D. is supported by NIH Medical Scientist Training Program Grant T32GM007205. B.C.W. is supported by NIH grants 1R01HD096693 and 7R01HD085853 and NIH Director’s Pioneer Award 5DP1HD086071. S.J.S. is supported by NIH Director’s Pioneer Award, NIH Director’s Transformative Award 1R01AI145057, and NIH grants 1R01HD096693 and 7R01HD085853. D.D.L. is supported by NIH Director’s Pioneer Award 5DP1HD086071, the Patient-Centered Outcomes Research Institute (PCORI 1503–29700), the Hydrocephalus Association, and the Rudy Schulte Research Institute. D.D.L. also receives research support through Microbot Medical, Inc. J.M.S. is supported by grants from the Department of Veterans Affairs (I01BX002889), the Department of Defense (SCI170199), the National Heart, Lung and Blood Institute (R01HL082517), and the National Institute of Neurological Disorders and Stroke (R01NS060801, R01NS102589, R01NS105633). The content of this report is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Review criteria

We searched PubMed for articles in all year ranges with multiple combinations of search terms, including “post-haemorrhagic hydrocephalus”, “post-infectious hydrocephalus”, “worldwide”, “epidemiology”, “ETV/CPC”, “VP Shunt”, “NKCC1”, “SPAK”, “Toll-like receptors”, “inflammation”, “obstruction”, “impaired reabsorption”, “CSF hypersecretion”, “cerebrospinal fluid”. There were no language exclusions and articles chosen were based on relevance to topics covered in this Review.

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Author notes

  1. These authors contributed equally to this work: Jason K. Karimy, Benjamin C. Reeves, Eyiyemisi Damisah.

Authors and Affiliations

  1. Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA

    Jason K. Karimy, Benjamin C. Reeves, Eyiyemisi Damisah, Phan Q. Duy, Prince Antwi, Wyatt David & Kevin Wang

  2. Departments of Neurosurgery, Engineering Science & Mechanics, and Physics; Center for Neural Engineering, The Pennsylvania State University, University Park, PA, USA

    Steven J. Schiff

  3. Departments of Neurosurgery and Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA

    David D. Limbrick Jr.

  4. Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, USA

    Seth L. Alper

  5. Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Benjamin C. Warf 

  6. Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY, USA

    Maiken Nedergaard

  7. Center for Translational Neuromedicine, Faculty of Medical and Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Maiken Nedergaard

  8. Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA

    J. Marc Simard

  9. Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology and Yale-Rockefeller NIH Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT, USA

    Kristopher T. Kahle

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All authors researched the data for the article, discussed the content of the article, wrote the text, and reviewed and edited the manuscript before submission.

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Supplementary information

Glossary

Bulk flow model

Model of cerebrospinal fluid flow, in which cerebrospinal fluid moves from the choroid plexus through the cerebral ventricles and cisterns to the subarachnoid space, where reabsorption through the arachnoid granulations occurs.

Neurohumoural mechanisms

Mechanisms involving the sympathetic nervous system and hormonal signalling.

Periventricular heterotopia

Bilateral nodules of grey matter that line the lateral ventricles and consist of neurons that failed to migrate during fetal development.

Time-spatial labelling inversion pulse imaging

A non-contrast MRI technique that uses cerebrospinal fluid as a tracer.

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Karimy, J.K., Reeves, B.C., Damisah, E. et al. Inflammation in acquired hydrocephalus: pathogenic mechanisms and therapeutic targets. Nat Rev Neurol 16, 285–296 (2020). https://doi.org/10.1038/s41582-020-0321-y

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