**2. Imaging studies**

**1. Introduction**

44 Hydrocephalus: Water on the Brain

the disease progresses [1].

magnetic and shuffling gait).

The symptoms presented usually appear as:

spatial difficulties, decreased attention, apathy.

of gait disorders range from mild to the wheelchair.

described as "fronto-subcortical dysfunction".

minimum estimates according to the authors.

may have iNPH.

deficits. We will deal with this topic more in detail later on.

review [6] confirmed that this pathology is under-diagnosed.

Idiopathic normal pressure hydrocephalus (iNPH) was described for the first time in 1965 by Hakim and Adam as ventricular dilation accompanied by a progressive triad of a gait disturbance, "dementia" and incontinence. Usually gait and balance disorders appear early and are the most impressive symptoms, cognitive decline and incontinence generally appear later as

• Gait disturbances as apraxia or that are commonly seen in parkinsonism (bradykinetic,

• Dementia: executive dysfunction, psychomotor slowing, prominent memory loss, visuo-

The gait disturbance is typically the earliest feature noted and is considered to be the most responsive to treatment. The primary feature is thought to resemble an apraxia of gait or a "lower body parkinsonism". True weakness or ataxia is typically not observed. The severity

The urinary symptoms of NPH can present as urinary frequency, urgency, or incontinence. While incontinence can result from gait disturbance and dementia, in a study by Sakakibara and colleagues [2] 95% of patients had urodynamic parameters consistent with detrusor overactivity. The cognitive and behavioral disturbances accompanying iNPH have been commonly

However, this definition is reductive not encompassing the entire cognitive spectrum of iNPH

The incidence of iNPH is between 2 and 6% among people affected by any dementia condition; its occurrence is probably underestimated. Brean and Eide [3] reported a prevalence of 21.9/100,000 and an incidence of 5.5/100,000 in a Norwegian population, which are probably

A more recent epidemiological study [4] confirms this impression: the prevalence of probable iNPH has been reported to be 0.2% in subjects aged 70–79 years and 5.9% in those aged 80 years and older, respectively, without difference between men and women. Moreover, as the authors wrote: "the number of subjects with iNPH is probably much higher than the number of persons currently treated", and since the prevalence increases with increasing age they estimate approximately that 2 million persons in Europe and 700,000 in the United States

A high incidence was also reported by Iseki et al. [5] in a 10-year follow-up study of a population of 70 year olds from a rural Japanese community. A recent systematic epidemiological

• Urinary incontinence: urinary frequency, urgency, or frank incontinence.

In most cases of new onset of neurologic symptoms, a computerized tomography (CT) scan of the brain is initially obtained. Although magnetic resonance imaging (MRI) is more specific than CT in iNPH, a normal CT scan can exclude the diagnosis. As shown in **Figure 1** MRI findings in iNPH include the following:


A narrow CSF space at the high convexity/midline areas relative to Sylvian fissure size was recently shown to correlate with a diagnosis of probable or definite iNPH. This specific sign, called "Disproportionally enlarged Subarachnoid spaces Hydrocephalus" (DESH) [12] has been found the most sensitive to the ventricular shunting. To establish a diagnosis of NPH, an MRI or CT must show an Evans index of at least 0.3 [13]. In addition, to exclude hydrocephalus ex vacuo, one or more of the following must also be present:

The pathophysiology of iNPH is still not completely understood. iNPH differs from other causes of adult hydrocephalus, in which pathological changes alter the pressure of the cere-

Clinical and Cognitive Features of Idiopathic Normal Pressure Hydrocephalus

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47

The CSF space is a dynamic system, which constantly adapts its pressure to keep it constant. It responds to changes in CSF formation or reabsorption rates, arterial and venous flow, compliance of the intracranial structures and fluctuations in intracranial pressure (ICP). This process is essential for ensure the correct functioning of the brain. Indeed, the brain is enclosed in a fixed structure and any volume increase needs to be matched by a decrease to avoid changes

The volume of blood entering the brain varies with the cardiac cycle, being present a net intracranial inflow of blood during systole and a net outflow during diastole. Arterial supply to the brain is pulsatile while venous flow is not, and this mismatch generates transient rises in CSF pressure. The system compensates for this in two different ways. First, the blood vessels can smooth the arterial blood influx modulating their compliance. Second, the CSF flows through the cerebral aqueduct in response to pulsatile blood flow, thus maintaining intracranial pressure stable. When these processes are altered, compensatory strategies are applied. However, the compensatory mechanisms that keep the CSF pressure constant may also produce other

In iNPH, the compliance of the system is reduced, especially in the vessel of the superior sagittal sinus [15, 16]. This lack of arterial compliance is initially countered by increased pulsatile CSF flow through the aqueduct, but as the amplitude of arterial pulsatility increases, the blood flow in systole induces large ICP pulsations, determining the 'water hammer' effect. These exaggerated pulsations cause venous damage in the periventricular region and displace the brain toward the skull [17], thus determining the development of the hydrocephalus. Indeed, hydrocephalus occurs as a result of enlarging ventricles at the expense of a reduced subarachnoid space. This is secondary to increasing pressure within the ventricles directed toward the subarachnoid space, namely as increase of the transmantle pressure (i.e., the pressure gradi-

This pressure gradient also explains why, although there is increased intraventricular pressure, the measured opening pressure during a lumbar puncture is within normal limits. It also

It is still unclear what triggers the initial reduction in arterial compliance. Deep white matter ischaemia surrounding arterioles may explain the loss of autoregulation [18].When the arterioles are obstructed, venous collapse ensues, followed by impaired CSF drainage and

Evidence points also to an altered cerebral blood flow (CBF), which may favor such perivasal ischemia. It has been described a strong association between impaired CBF and iNPH. Patients with iNPH are more likely to have concomitant cerebrovascular disease [19]. MRI shows increased white matter changes (WMCs) [20] and this is further supported by neuropathological studies showing microvascular alterations [21, 22]. Age-related vascular changes can

brospinal fluid (CSF), but it is also related to alterations of the CSF dynamicity [14].

of the intracranial pressure and consequential functional abnormalities.

ent between the ventricles and the subarachnoid space) [17].

implies that 'normal pressure' in NPH is somewhat of a misnomer [14].

pathological alteration [14].

ventricular enlargement [18].


**Figure 1.** A: Axial FLAIR shows periventricular white matter changes, ventricles dilatation in both frontal and occipital horns, Evan's index >0.30 B: Axial FLAIR at upper level shows global sulcal thinning and focal sulcal dilatation C coronal T2 shows acute callosal angle and disproportionally enlarged subarachnoidal spaces hydrocephalus (DESH) D sagittal T1 shows callosal bulging and mild aqueduct enlargement.

The pathophysiology of iNPH is still not completely understood. iNPH differs from other causes of adult hydrocephalus, in which pathological changes alter the pressure of the cerebrospinal fluid (CSF), but it is also related to alterations of the CSF dynamicity [14].

MRI or CT must show an Evans index of at least 0.3 [13]. In addition, to exclude hydrocepha-

**Figure 1.** A: Axial FLAIR shows periventricular white matter changes, ventricles dilatation in both frontal and occipital horns, Evan's index >0.30 B: Axial FLAIR at upper level shows global sulcal thinning and focal sulcal dilatation C coronal T2 shows acute callosal angle and disproportionally enlarged subarachnoidal spaces hydrocephalus (DESH) D sagittal

T1 shows callosal bulging and mild aqueduct enlargement.

lus ex vacuo, one or more of the following must also be present:

• acute callosal angle

46 Hydrocephalus: Water on the Brain

• Pathophysiology

• hyperdynamic aqueduct.

• disproportionally enlarged subarachnoid spaces hydrocephalus (DESH)

The CSF space is a dynamic system, which constantly adapts its pressure to keep it constant. It responds to changes in CSF formation or reabsorption rates, arterial and venous flow, compliance of the intracranial structures and fluctuations in intracranial pressure (ICP). This process is essential for ensure the correct functioning of the brain. Indeed, the brain is enclosed in a fixed structure and any volume increase needs to be matched by a decrease to avoid changes of the intracranial pressure and consequential functional abnormalities.

The volume of blood entering the brain varies with the cardiac cycle, being present a net intracranial inflow of blood during systole and a net outflow during diastole. Arterial supply to the brain is pulsatile while venous flow is not, and this mismatch generates transient rises in CSF pressure. The system compensates for this in two different ways. First, the blood vessels can smooth the arterial blood influx modulating their compliance. Second, the CSF flows through the cerebral aqueduct in response to pulsatile blood flow, thus maintaining intracranial pressure stable. When these processes are altered, compensatory strategies are applied. However, the compensatory mechanisms that keep the CSF pressure constant may also produce other pathological alteration [14].

In iNPH, the compliance of the system is reduced, especially in the vessel of the superior sagittal sinus [15, 16]. This lack of arterial compliance is initially countered by increased pulsatile CSF flow through the aqueduct, but as the amplitude of arterial pulsatility increases, the blood flow in systole induces large ICP pulsations, determining the 'water hammer' effect. These exaggerated pulsations cause venous damage in the periventricular region and displace the brain toward the skull [17], thus determining the development of the hydrocephalus. Indeed, hydrocephalus occurs as a result of enlarging ventricles at the expense of a reduced subarachnoid space. This is secondary to increasing pressure within the ventricles directed toward the subarachnoid space, namely as increase of the transmantle pressure (i.e., the pressure gradient between the ventricles and the subarachnoid space) [17].

This pressure gradient also explains why, although there is increased intraventricular pressure, the measured opening pressure during a lumbar puncture is within normal limits. It also implies that 'normal pressure' in NPH is somewhat of a misnomer [14].

It is still unclear what triggers the initial reduction in arterial compliance. Deep white matter ischaemia surrounding arterioles may explain the loss of autoregulation [18].When the arterioles are obstructed, venous collapse ensues, followed by impaired CSF drainage and ventricular enlargement [18].

Evidence points also to an altered cerebral blood flow (CBF), which may favor such perivasal ischemia. It has been described a strong association between impaired CBF and iNPH. Patients with iNPH are more likely to have concomitant cerebrovascular disease [19]. MRI shows increased white matter changes (WMCs) [20] and this is further supported by neuropathological studies showing microvascular alterations [21, 22]. Age-related vascular changes can directly cause the reduction in vascular compliance [23]; this could explain the association between NPH and vascular disease.

in Parkinson disease, however rest tremor and usually unilateral symptoms onset typical of Parkinson's disease are less commonly observed in iNPH. Furthermore, in iNPH the response to the therapy with levodopa is usually scarce. The differential diagnosis can be particularly challenging in case of vascular dementia with small vessels disease or atypical parkinsonisms, Progressive supranuclear palsy in particular [34]. The differential diagnosis with AD will be

Clinical and Cognitive Features of Idiopathic Normal Pressure Hydrocephalus

In their paper Williams, Relkin [1] report a precise analysis of differential diagnosis. Each of the primary symptoms of iNPH has in fact multiple potential etiologies (**Table 1**). It is quite uncommon to see patients affected by only iNPH because most of them have other conditions contributing to their symptoms. On the other hand, patients without iNPH may appear to

iNPH, with or without comorbidities X X X Parkinsonism X X X Lewy body dementia X X X Corticobasal degeneration X X X Progressive supranuclear palsy X X X Multiple system atrophy X X X Vascular dementia X X X Neurosyphilis X X X Medication side effects X X X Multifactorial—any combination of diagnoses, with or without iNPH X X X

iNPH, with or without comorbidities X X X

Cervical stenosis and myelopathy X X Lumbosacral stenosis X X Peripheral neuropathy X X

Vitamin B12 deficiency X X

iNPH X

**Gait Dementia Incontinence**

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49

X X X

have the iNPH syndrome because of multiple comorbidities.

treated below.

Disorders that may have all 3 symptoms

Disorders that may have 2 symptoms Multifactorial—any combination of diagnoses, with or without iNPH

Disorders that may have only one symptom

Alternatively, it has been proposed that increased transvenular resistance in the territory of the superior sagittal sinus can act as trigger in iNPH. Indeed, it might be that the majority of CSF resorption occurs through the brain parenchyma and not at the level of the arachnoid villi or arachnoid granulations [17, 24, 25]. In this view, CSF resorption would be affected with increased transvenular resistance.

CSF outflow resistance has been investigated in few studies, which reported an abnormal outflow in animal models and subjects with in iNPH [26, 27].

More recently, the new concept of glymphatic system has been introduced [28, 29]. The glymphatic system is a macroscopic waste clearance system which utilizes a unique system of perivascular tunnels formed by astroglial cells to promote the elimination of soluble proteins and metabolites from the central nervous system. It also facilitates brain-wide distribution of several compounds including glucose, lipids, amino acids, growth factors and neuromodulators; interestingly it functions mainly during sleep. The glymphatic system has been proposed to be instrumental in normal aging and brain pathology; in particular altered glymphatic function in iNPH could possibly be a mechanism behind the high comorbidity between iNPH and Alzheimer's disease [30]. A reduced glymphatic clearance has been found in a MRI study in iNPH and interpreted as instrumental for the development of dementia in this disease [29].

Further data suggest that aquaporin-4 channels can be implicated in the pathophysiology of iNPH [31]. Aquaporin-4 channels are transmembrane proteins that facilitate water transport in the brain and play roles in fluid secretion, cell migration, brain edema, metabolism, and many aspects of cell homeostasis; a modulation of their activity could be a potential target for pharmacological management of iNPH.

Lastly, also neurodegeneration might play a role in iNPH development as suggested by the high levels of tau protein in CSF of iNPH patients [32], as detailed below.

In conclusion, there is still a debate on the different theories of iNPH pathogenesis, even if it must be stressed that these theories may not be mutually exclusive [33]. Besides the possible mechanisms, it should be stressed out that many (although not all) of the clinical symptoms are reversible if patients are early recognized and correctly treated. The fostering of an early diagnosis is a great need, but must match the clinical accuracy.
