Review: Rethinking the Cilia Hypothesis of Hydrocephalus
Key findings
- This review discusses why the loss of cilia-generated cerebrospinal fluid (CSF) flow is unlikely to be an important mechanism of intraventricular CSF overaccumulation in hydrocephalus
- Neuroembryology and physiology data don't support a role for ependymal cilia as the primary propeller of CSF across the ventricles in humans, and associations between loss of cilia-generated CSF flow and hydrocephalus are inconsistent in animal models
- Ciliary gene mutations are associated with hydrocephalus in mouse models, but in humans, it's rare for hydrocephalus to develop solely from motile cilia abnormalities, implying other factors are involved
- Human genomic studies suggest certain cases of hydrocephalus linked to ciliary gene mutations arise not just from the loss of cilia-generated CSF flow but also deficient cortical neurogenesis, such that brain parenchyma can't contain the fluid
- Rethinking the cilia hypothesis could inform the development of new treatment strategies beyond the current standard practice of neurosurgical CSF diversion, such as gene therapy or pharmacological approaches intended to optimize brain development
For decades, neurosurgery for hydrocephalus has been directed almost exclusively toward diverting cerebrospinal fluid (CSF) and reducing ventricle size. Yet even when these strategies are technically successful, neurocognitive impairments may persist, and the cortical mantle may not re-expand in children with hydrocephalus.
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Those outcomes suggest that either irreversible damage from neural tissue compression has already occurred by the time of shunting or that CSF overaccumulation is not the primary disease mechanism. Even so, recent hydrocephalus literature has bolstered the notion of impaired CSF circulation by proposing that dysfunction of motile cilia leads to CSF overaccumulation.
Researchers at Massachusetts General Hospital recently reviewed in Neurobiology of Disease why the loss of cilia-generated CSF flow is unlikely to be the sole cause of hydrocephalus, especially in human patients. The authors include neurosurgeon William Butler, MD, of the Department of Neurosurgery, Mass General Cancer Center and Mass General for Children, Kristopher T. Kahle, MD, PhD, a neurosurgeon in the Department of Neurosurgery and director of Pediatric Neurosurgery, and colleagues.
Evidence Against the Cilia Hypothesis
After explaining the standard model of hydrocephalus and the cilia hypothesis, the authors discuss potential links between ependymal motile cilia, CSF movement, neural development, and the pathophysiology of hydrocephalus.
Cilia-generated flow is not a major mechanism for fluid dynamics before birth—Primary cilia on ventricular neural stem cells are immotile and can't generate fluid flow. Motile cilia emanate from ependymal cells, a glial cell that lines the ventricles of the brain and the central spinal cord. Ependymal cell maturation and development of motile cilia along the ventricle wall aren't completed until after birth, so motile cilia are unlikely to be a major contributor to CSF movement for much of gestation and perhaps even the early neonatal period.
The link between loss of cilia-generated CSF flow and hydrocephalus in animal models is inconsistent—Associations between ventricular dilation and ciliary dysfunction are frequently reported in the mouse literature, but numerous genetic mouse models of hydrocephalus don't exhibit ependymal cilia defects. In addition, some mouse and zebrafish models don't exhibit ventricular dilation and hydrocephalus despite ependymal ciliary dysfunction. Perturbed cilia-generated CSF flow must not be the sole determinant of hydrocephalus in these animals.
Cilia-generated CSF flow is not a major contributor to CSF dynamics—Multiple human studies have failed to support a major role for cilia in driving CSF across different ventricular compartments. Intraventricular CSF flow is bidirectional and pulsatile in accordance with the heartbeat, suggesting the heart is the mechanical driver of CSF movement.
Motile ciliopathies infrequently cause hydrocephalus in humans—In contrast to mouse models, motile ciliopathies don't often cause hydrocephalus in humans. Instead, gene mutations affecting motile cilia function affect not only ependymal cilia but also motile cilia found in organ systems besides the brain. This causes a clinical syndrome of recurrent respiratory infections and situs inversus, symptoms that don't typically accompany human hydrocephalus.
Human genetics suggests altered neurodevelopment in hydrocephalus—Recent genomic studies in humans suggest hydrocephalus has a neurodevelopmental component—genetic defects in brain structure and integrity may alter the biomechanical stability of the brain parenchyma and thus facilitate secondary enlargement of ventricles from a "floppy" cortical mantle that's unable to resist the pressure exerted by CSF.
Potential New Treatments
A rethinking of the cilia hypothesis could inform the development of new treatment strategies beyond the current standard practice of neurosurgical CSF diversion, such as gene therapy or pharmacological approaches intended to optimize brain development.
Ependymal cilia are hypothesized to be involved in the pathogenesis of other neuropsychiatric conditions, including schizophrenia, in which ventricular dilation is a neuroradiographic feature. Thus, a better understanding of cilia biology in the context of brain function and homeostasis might improve care for neurodevelopmental disorders besides hydrocephalus.
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