Exploring mechanisms of ventricular enlargement in idiopathic normal pressure hydrocephalus: a role of cerebrospinal fluid dynamics and motile cilia

Abstract

Idiopathic normal pressure hydrocephalus (iNPH) is considered an age-dependent chronic communicating hydrocephalus associated with cerebrospinal fluid (CSF) malabsorption; however, the aetiology of ventricular enlargement in iNPH has not yet been elucidated. There is accumulating evidence that support the hypothesis that various alterations in CSF dynamics contribute to ventricle dilatation in iNPH. This review focuses on CSF dynamics associated with ventriculomegaly and summarises the current literature based on three potential aetiology factors: genetic, environmental and hydrodynamic. The majority of gene mutations that cause communicating hydrocephalus were associated with an abnormal structure or dysfunction of motile cilia on the ventricular ependymal cells. Aging, alcohol consumption, sleep apnoea, diabetes and hypertension are candidates for the risk of developing iNPH, although there is no prospective cohort study to investigate the risk factors for iNPH. Alcohol intake may be associated with the dysfunction of ependymal cilia and sustained high CSF sugar concentration due to uncontrolled diabetes increases the fluid viscosity which in turn increases the shear stress on the ventricular wall surface. Sleep apnoea, diabetes and hypertension are known to be associated with the impairment of CSF and interstitial fluid exchange. Oscillatory shear stress to the ventricle wall surfaces is considerably increased by reciprocating bidirectional CSF movements in iNPH. Increased oscillatory shear stress impedes normal cilia beating, leading to motile cilia shedding from the ependymal cells. At the lack of ciliary protection, the ventricular wall is directly exposed to increased oscillatory shear stress. Additionally, increased oscillatory shear stress may be involved in activating the flow-mediated dilation signalling of the ventricular wall. In conclusion, as the CSF stroke volume at the cerebral aqueduct increases, the oscillatory shear stress increases, promoting motor cilia shedding and loss of ependymal cell coverage. These are considered to be the leading causes of ventricular enlargement in iNPH.

Molecular Mechanisms and Risk Factors for the Pathogenesis of Hydrocephalus

“…Challenging to traditional CSF physiology, increasing investigations raise the new concept of CSF dynamics that, rather than choroid plexus, CSF production also comes from the interstitial fluid efflux, and the major CSF outflow pathway may go through the lymphatic drainages rather than dural venous sinuses through arachnoid villi ( Louveau et al, 2016 ; Da Mesquita et al, 2018 ; Louveau et al, 2018 ; Mestre et al, 2018 ; Ringstad and Eide, 2020 ; Yamada et al, 2021 ). The CSF outflow through lymphatic drainages mainly goes through the subarachnoid spaces to the meningeal lymphatics and cervical lymphatics via the cribriform plate and nasal lymphatics ( Proulx, 2021 ).…”

“…Based on the new CSF dynamic concept, the pathogenic mechanisms of iNPH or communicating hydrocephalus that correlate with the alterations in motile cilia and cerebrospinal fluid dynamics have been extensively investigated, and the related mutant genes have also been reported ( Table 2 ). The mutant genes related to motile cilium dysfunction on ependymal cells, and consequent hydrocephalus development may include Ccdc39 , Celsr2 , Celsr3 , Cetn2 , Dvl , Foxj1 , Hydin , Mdnah5 , Pkd1 , Tg737 , Daple , Dnah14 , Cfap43 , Cwh43 , Eml1 , Fmn2 , Tmem67 , and Zcchc8 ( Law et al, 2014 ; Shaheen et al, 2017 ; Kundishora et al, 2021 ; McKnight et al, 2021 ; Yamada et al, 2021 ). For example, Foxj1 mutation results in ciliopathy and hydrocephalus due to dysfunction of motile cilia ( Abdi et al, 2018 ; Wallmeier et al, 2019 ).…”

“…With regard to the environment and acquired elements, alcohol consumption, diabetes, hypertension, inflammation, aging, and sleep apnea are remarkable risk factors for iNPH development ( Sakata-Haga et al, 2004 ; Kahle et al, 2016 ; Omran et al, 2017 ; Holth et al, 2019 ; Ghaffari-Rafi et al, 2020 ; Zhang et al, 2020 ; Yamada et al, 2021 ). Alcohol consumption demonstrated a correlation with iNPH development possibly due to ethanol-induced decrease in beating frequency of motile cilia and consequent dysfunction on the ependymal cells of ventricles ( Omran et al, 2017 ; Ghaffari-Rafi et al, 2020 ).…”

Reconsidering Ventriculoperitoneal Shunt Surgery and Postoperative Shunt Valve Pressure Adjustment: Our Approaches Learned From Past Challenges and Failures

“…The finding of ventricular enlargement on CT or MRI is essential for the diagnosis of iNPH. Although the etiology of ventricular enlargement in iNPH has not yet been elucidated, the total amount of intracranial CSF volume increases due to CSF malabsorption ( 41 ). The historically used Evans index >0.3 is defined as the maximum width of both frontal horns of the lateral ventricles divided by the maximum intracranial width on the same slice on CT or MRI.…”

Sustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus

“…Recently, a more severe PCD phenotype in humans was reported, known as 'reduced generation of multiple motile cilia' (RGMC) involving mutations in the multicilin gene which is linked to a high incidence of hydrocephalus and choroid plexus hyperplasia [26,27]. Notably, studies have shown that the CSF stroke volume and the oscillatory shear stress in the cerebral aqueduct increase in normal pressure hydrocephalus (NPH) which impede normal cilia beating [28][29][30]. Furthermore, a study using dynamic contrast enhanced MRI (DCE-MRI) with CSF administration of a Gd-based tracer showed that glymphatic clearance was reduced in human patients with NPH [31,32] suggesting a potential link between impaired glymphatic clearance, cilia dysfunction and hydrocephalus.…”