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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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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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