Normal-pressure hydrocephalus

Pathogenesis and pathophysiology
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By Peter Hedera MD and Robert P Friedland MD

Hydrocephalus in normal-pressure hydrocephalus is a consequence of the disequilibrium between production and absorption of CSF. It is thought that, in the majority of cases, ventricular enlargement results from an obstruction of the CSF flow around the brain convexities and insufficient absorption through the arachnoid granulations and arachnoid villi of the superior sagittal sinus. Subarachnoid hemorrhage, meningitis, head injuries, and elevated levels of CSF protein all cause scarring and fibrosis in the subarachnoid space. Deficiency of the arachnoid granulations and obstruction of the pacchionian villi due to meningioma of the superior sagittal sinus are other examples of this mechanism. This subtype of normal-pressure hydrocephalus is often referred to as communicating hydrocephalus. Communication between the ventricles and subarachnoid space is unobstructed; however, the communication between the subarachnoid space and arachnoid granulations is not intact. Other lesions (intracranial tumors, cerebellar hematomas, nontumorous stenosis of the aqueduct of Sylvius, arachnoid cysts) can result in normal-pressure hydrocephalus due to obstruction of CSF circulation within the ventricular system. This subtype of normal-pressure hydrocephalus is sometimes called noncommunicating.

A relatively large proportion of normal-pressure hydrocephalus patients do not have an identifiable cause of hydrocephalus. The preponderance of evidence in these cases points to reduced absorption of CSF. Patients with normal-pressure hydrocephalus (both idiopathic and secondary) have increased resistance to outflow (ROUT) of CSF (ROUT, mmHg/mL per minute), suggestive of an impediment of CSF absorption (Kosteljanetz 1986). This has been corroborated by pathological studies showing fibrotic changes of the leptomeninges and pacchionian villi (Bech et al 1997).

Normal opening pressure of CSF and abnormally high outflow resistance indicate that normal pressure is an endpoint of previously elevated intracranial pressure (Kosteljanetz 1986). Indeed, intracranial pressure is not always normal, and long-term monitoring has shown transient elevation of intracranial pressure. Thus, elevation of intracranial pressure causes enlargement of ventricles, and a new balance is reached with normal (ie, nonelevated) pressure but higher force, affecting a bigger ventricular surface according to Pascal's law of pressure in fluids (Hakim and Adams 1965). Reduced compliance of the brain, further enhanced by degenerative changes of the periventricular white matter, may also contribute to abnormal distensibility of the ventricles. Increased CSF pulse amplitude is another possible explanation for the development of hydrocephalus despite normal intracranial pressure (Foltz and Aine 1980). It is interesting in this regard that hypertension, with a potential to contribute to higher pulse amplitude, is positively associated with normal-pressure hydrocephalus (Graff-Radford and Godersky 1987).

The development of the clinical symptoms of normal-pressure hydrocephalus is multifactorial. Motor fibers innervating the legs and sphincters project through the vicinity of the frontal horns of the lateral ventricles. The frontal horns of the lateral ventricles are often disproportionally expanded. Stretching of these fibers is thought to be responsible for gait and urinary symptoms. Volumetric changes after CSF removal are most pronounced in the periventricular region of the lateral ventricles and in the frontal and temporal lobes (Singer et al 2012). Corticospinal tract fibers show signs of axonal degeneration, which can be clinically assessed by diffusion tensor imaging (Hattori et al 2011; Jurcoane at al 2014).

Early urinary involvement is characteristic of the loss of voluntary supraspinal control with bladder hyperactivity and detrusor instability, which is manifested as urinary urgency. Late frank incontinence also has a frontal component with indifference and lack of concern. Many symptoms of cognitive decline can also be accounted for by compression of the frontal white matter (deficits in attention, initiation, and other executive functions).

Compromised microcirculation due to increased intraparenchymal pressure is another putative factor in the pathogenesis of dementia and the apractic features of gait. Studies of regional cerebral blood flow in normal-pressure hydrocephalus have shown regional reduction of blood flow in the periventricular white matter with gradual improvement toward the cortical regions. Induction of increased intracranial pressure further reduced cerebral blood flow in the subcortical regions (Momjian et al 2004).

Impaired vascular autoregulation with reduced cerebrovascular reactivity, suggesting a limited capacity to compensate for transitional increases of intracranial pressure, is also a feature of normal-pressure hydrocephalus (Chang et al 2009). Clinical changes do not tightly correlate with regional cerebral blood flow changes; the degree of clinical improvement has been disproportionally higher than changes of regional cerebral blood flow. This suggests that additional factors (such as demyelinization and decreased clearance of various macromolecules) may play roles in the pathogenesis of dementia in normal-pressure hydrocephalus (Silveberg et al 2002; Tullberg et al 2002).

Results of quantitative studies of the brain metabolism are more consistent. Jagust and colleagues found global reduction of glucose metabolism using PET; patients with normal-pressure hydrocephalus had a different pattern compared to patients with Alzheimer disease (Jagust et al 1985). The decrease of glucose uptake in normal-pressure hydrocephalus is lower than expected for the degree of dementia and suggests widespread cortical and subcortical dysfunction. The relationship between symptoms of normal-pressure hydrocephalus and alterations of blood flow and cerebral metabolism is not firmly established. Clinical motor symptoms may be caused by blood flow abnormalities in the supplementary motor cortex, causing reversible suppression of frontal periventricular corticobasal ganglia-thalamocortical pathways. This area showed improved blood flow after a prolonged lumbar drainage, suggesting that motor function recovery in normal-pressure hydrocephalus patients after CSF removal is related to enhanced activity in medial parts of frontal motor areas that are important for motor planning (Lenfeldt et al 2008).

Impaired corticospinal excitability, assessed by transcranial magnetic stimulation, can result in disinhibition of the motor cortex and, thus, plays a key role in mediating the effects of frontal lobe dysfunction on motor performance in patients with normal-pressure hydrocephalus (Chistyakov et al 2012). These abnormalities likely reflect a disturbed connectivity of the frontal motor networks rather than a direct lesion of the primary motor cortex or corticospinal tract, and shunting can normalize transcranial magnetic stimulation responses

Ischemia of deep white matter may not be a mandatory precondition for the development of normal-pressure hydrocephalus because not every patient with normal-pressure hydrocephalus has abnormal blood flow studies; however, secondary microcirculation changes may be caused by stretching of periventricular white matter due to ventriculomegaly. MR imaging studies with flow quantification measuring the total blood inflow, sagittal and straight sinus outflow, aqueduct stroke volume, and arteriovenous delay did not detect any abnormalities in the periventricular regions, and the main changes showed alterations in superficial venous compliance and a reduction in the blood flow returning via the sagittal sinus (Bateman 2008). The overall load of the white matter changes also negatively correlated with the gait improvement after shunting, further supporting the notion that white matter lesions contribute to the irreversibility of symptoms in normal-pressure hydrocephalus but not to the pathophysiological mechanisms that lead to them (Bugalho and Alves 2007).

Abnormalities of jugular venous system draining the blood from the brain can contribute to abnormal absorption of CSF. Incompetent jugular valves may allow the transmission of the high venous pressures to the subarachnoid space. This hypothesis is supported by the findings of retrograde jugular flow during Valsalva maneuver in 95% patients with normal pressure hydrocephalus, and this finding is rare in apparently normal controls (Kuriyama et al 2008). This test can be also used for the diagnosis of normal pressure hydrocephalus, even though its specificity and sensitivity have not been established in a larger cohort of patients.

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited