**3. Diagnostic considerations**

Many other illnesses can mimic iNPH and therefore have to be distinguished. Regarding in particular the motor disturbances, the most frequent disease in differential diagnosis is Parkinson's disease; start hesitation and freezing episodes can occur in iNPH similar to the gait 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 treated below.

directly cause the reduction in vascular compliance [23]; this could explain the association

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

CSF outflow resistance has been investigated in few studies, which reported an abnormal

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

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

Lastly, also neurodegeneration might play a role in iNPH development as suggested by the

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

Many other illnesses can mimic iNPH and therefore have to be distinguished. Regarding in particular the motor disturbances, the most frequent disease in differential diagnosis is Parkinson's disease; start hesitation and freezing episodes can occur in iNPH similar to the gait

high levels of tau protein in CSF of iNPH patients [32], as detailed below.

diagnosis is a great need, but must match the clinical accuracy.

between NPH and vascular disease.

48 Hydrocephalus: Water on the Brain

increased transvenular resistance.

this disease [29].

pharmacological management of iNPH.

**3. Diagnostic considerations**

outflow in animal models and subjects with in iNPH [26, 27].

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 have the iNPH syndrome because of multiple comorbidities.



**4. Management**

levodopa or dopamine agonists.

following criteria, as indicated by Schneck [38]:

• Absent or moderate white matter lesions on MRI.

• Presence of a clearly identified etiology.

Even though research in this field has advanced, iNPH still has to be considered a complex pathology whose diagnosis and management continue to present many problems. The main interest is represented by the fact that iNPH can be considered a potentially reversible dementia. Surgical diversion of CSF via a shunt remains the main treatment for this condition. This is based on the presumption that CSF diversion will reduce or normalize the transmantle

Clinical and Cognitive Features of Idiopathic Normal Pressure Hydrocephalus

http://dx.doi.org/10.5772/intechopen.73273

51

Ventriculo-peritoneal (VP) shunts are the most commonly used [35]; in Japan iNPH is treated mainly with lumboperitoneal (LP) shunts and in the last years also in Western Countries this procedure has began to be adopted. The data are still scarce, but LP shunts seem to have effectiveness rates similar to those of VP shunts. Despite greater rates of device-related complications, LP shunting can be recommended for the treatment of patients with iNPH because of their minimal invasiveness and lack of the lethal complications seen with VP shunts [36]. It must be stressed out that not all patients with iNPH are candidate for shunt surgery. The risk-to-benefit ratio has to be assessed individually. Prior to embarking upon surgical therapy, knowing which patients may benefit from surgery is necessary. All patients with suspected iNPH should undergo diagnostic CSF removal (either large-volume lumbar puncture and/or external lumbar drainage), which has both diagnostic and prognostic value. Detailed testing is performed before and after CSF drainage; improvement in motor symptoms after large-volume drainage supports the diagnosis of iNPH, while improvement does not rule out iNPH. Recently, a novel standardized paradigm with a simultaneous quantification of cognition and gait (dual task gait assessment and mental imagery of locomotion) before and 24 h after CSF tapping has been proposed [37], which can contribute to the identification of patients with iNPH from its mimics. The same authors underline the major limitation of this paradigm (i.e. an expansive and time-consuming evaluation), however it responds to the need of standardized evaluative parameters. Moreover, a levodopa challenge may be helpful to rule out idiopathic Parkinson disease; patients with iNPH have no significant response to

The best candidates for shunt surgery would show imaging evidence of ventriculomegaly, indicated by a frontal horn ratio exceeding 0.30 on imaging studies, with one or more of the

• Predominant gait difficulties with mild or absent cognitive impairment.

• Substantial improvement after CSF withdrawal (CSF tap test or lumbar drainage).

• Normal-sized or occluded sylvian fissures and cortical sulci on CT scan or MRI.

pressure, thereby stabilizing or improving symptoms [14].

**Table 1.** Differential diagnosis of idiopathic normal pressure hydrocephalus (iNPH). Taken from [1].

Initially is important to identify or exclude other disorders that should be treated before evaluating iNPH. Although iNPH is described as a symptom "triad," patients do not need to have all three symptoms. However, gait impairment is the symptom that affects nearly all patients as described by most published series and guidelines. A patient who has only dementia or incontinence should first be evaluated for other disorders. Patients with gait impairment and urinary symptoms but no cognitive impairment may need evaluation for spinal cord disorders. Although any of the primary iNPH symptoms may be the initial symptom, gait impairment is usually either the first or worst symptom.
