Basically, ventriculomegaly is indicated by Evan’s index or the frontal horn index, defined as the largest diameter of the frontal horns divided by the largest diameter of the brain at the level of the anterior commissure or at the level of the frontal horns: a value of this parameter above 0.3 or 0.4 is indicative of hydrocephalus. These indices are possibly the only findings obligatory for establishing the diagnosis of hydrocephalus, while all other imaging findings are optional [38], for example, large temporal horns, dilated third ventricle, enlarged perisylvian fissures, or both focal dilatation and obliteration of the cortical sulci (so-called periventricular edema, Fig. 34.2a), increased callosal angle, and aqueductal flow void (Fig. 34.2b).

Attention should be drawn to periventricular white matter lesions (PWMLs) and deep white matter lesions (DWMLs), as observed in T2-weighted MRI or in fluid-attenuated inversion-recovery sequences (Fig. 34.3). These have been clearly associated with cerebrovascular comorbidity and have been observed in a subgroup of patients with idiopathic NPH [45]. A negative correlation of DWMLs and PWMLs with the outcome in patients was found, although exclusion of an individual patient based on the finding of white matter lesions is not justified, as before shunting, there was no difference in either PWMLs or DWMLs between outcome groups in that study.

In a comparison of NPH and Binswanger’s disease, it was found that they share, for the major part, MRI changes with regard to white matter lesions, which the authors suggested indicate a common pathophysiological pattern [45]. Mechanisms are explained by an increased pulse pressure in periventricular and subcortical arteriosclerotic vessels, which may cause enlargement of ventricles in the absence of raised intracranial pressure in that subgroup of patients.

Although blood flow and metabolic studies have so far shown a variable correlation with the clinical outcome [35], those methods have been suggested to allow access to the brain disease in hydrocephalus, and studies are promising in this regard.

Using [¹⁵O]H₂O-positron emission tomography (PET), global cerebral blood flow and cerebrovascular reserve capacity before and after application of 1 g Diamox were quantified before, 1 week after, and 7 months after surgery in 70 patients with idiopathic NPH (Fig. 34.4) [17, 18]. Global blood flow was significantly lower in the “shunt responder.” The predictive accuracy increased to 88 % with the finding of a decreased blood flow, when compared to the accuracy score of 76 % obtained by a combination of dynamic CSF tests. Furthermore, the cerebrovascular reserve capacity was correlated with clinical changes after shunt placement: after 1 week, shunt responders showed considerable improvement (>30 %) in reserve capacity and nonresponders did not, suggesting that neurological improvement after shunting is related to early restoration of the hemodynamic reserve and to improved conditions in the chronic hypoxic environment of the hydrocephalic brain [17].

Using statistical parametric mapping (SPM 99, Wellcome Department of Cognitive Neurology, London, UK) in a series of idiopathic NPH, significant regional decreases in frontal, frontomedial, and temporomedial cortical areas were found, which positively correlated with the clinical impairment using a score based on a formal assessment of both gait and mental function (Fig. 34.5). These areas could have been attributed to the frontal association cortex, to the frontomesial and the supplementary motor cortex, and to the inner and outer limbic cortex after transformation into a standard stereotaxic space (Montreal Neurological Institute default template of SPM 99 for ¹⁵O regional cerebral blood flow studies). In addition, after shunting, clinical responders exhibited increases in regional blood flow in supplemental motor areas, while nonresponder did not.

Other PET studies using an anatomic region-of-interest analysis on coregistered magnetic resonance done in both secondary and idiopathic NPH demonstrated a reduction in cerebral blood flow in the basal ganglia and the thalamus. This was correlated with the level of function in patients, related to the motor disorder [36].

Disturbances in brain and neuronal metabolism have also been evidenced by ¹H- and ^31P-MRI spectroscopy investigations in NPH patients [8]: lactate peaks in the periventricular areas and reduced N-acetylaspartate/total creatine ratios in the cortex differed from those in controls and in other forms of dementia. Very recent studies in microdialysis have indicated a situation of postischemic recovery in patients with chronic hydrocephalus [1].

In the light of these observations, the CSF contents of neuronal metabolites and peptides, neurotransmitters, and products reflecting neuronal degeneration (tau, A-beta, neurofilament, and sulfatide) have emphasized the potential advantage of investigating neuronal and brain metabolism and have shown to be effective diagnostic and prognostic markers in adult hydrocephalus [42].

Whether an increased R _out and/or B-wave is linked to the pathophysiology of chronic hydrocephalus has been discussed. Early investigations have shown an association between an elevated R _out and a reduced compliance with CSF malabsorption [41]. These parameters have since been associated with chronic hydrocephalus and, it has been suggested, are important diagnostic tools [7].

Biopsy specimens taken at the time of shunt surgery in patients diagnosed with NPH did not show any correlation between an increased R _out and arachnoids fibrosis, although arachnoid fibrosis was previously supposed to be the morphological correlate causing CSF malabsorption [2]. There is no normative data on any of these physiological parameters, regardless of the methodology used to estimate R _out and/or intracranial compliance; this questions the significance of R _out for diagnosing chronic hydrocephalus. It is meanwhile acknowledged that R _out naturally increases with age in otherwise healthy individuals [11]. As such, in the subgroup of chronic hydrocephalus of the elderly, much higher cutoff values are likely to be indicative of the disease [5].

In the aforementioned cortical biopsy studies, a high incidence of amyloid plaques and neurofibrillary tangles has been observed in patients with idiopathic NPH [2]; 30–50 % of patients have Alzheimer’s disease on cortical biopsy [16]. It has therefore been suggested that the two diseases may have some common pathophysiology (e.g., diminished clearance of extracellular amyloid-beta peptides, Aβ, and hyperphosphorylated tau proteins, hpTau, from the brain interstitial fluid) [39]. Altered CSF dynamics and decreased expression of Aβ transport proteins at the capillary endothelium may be causal.

These findings were corroborated by an experimental study of kaolin-induced hydrocephalus in aged rats: Aß[1–42] and Aß[1–40] accumulation was evident at 6 and 10 weeks post-hydrocephalus induction [22]. Kaolin-induced blockage of CSF circulation in the basal subarachnoidal space results in hydrocephalus (Fig. 34.6a) and increased resistance to CSF absorption. In the later stages, intracranial pressure normalizes; however, resistance remains above normal values [9]. Increasing amyloid burden at CSF absorption sites, in vessel walls and perivascular spaces, and within the parenchyma was observed (Fig. 34.6b). Low-density lipoprotein-receptor-related protein 1 (LRP-1), the primary capillary endothelial receptor for transport of Aβ out of the brain interstitial fluid, also showed reduced expression [22]. The findings suggest that the age-related impairment of the CSF circulation decreases the clearance or washout of potentially toxic products of brain metabolism from the brain interstitial fluid (e.g., beta amyloid), leading to Alzheimer’s disease pathology in chronic hydrocephalus of the elderly.

Other experimental studies have furthermore supported the role for chronic ischemia causing neuronal injury in vulnerable brain regions and adaptive vascular and neuronal processes [21, 27], playing a more important role in the disease than ventricular enlargement and CSF dynamic parameters.

Experimental studies have contributed to many of the clinical–pathological aspects of chronic hydrocephalus. They allow, however, a more structured insight into the biomechanical as well as the biochemical mechanisms. As a consequence, they have opened the field for adjunct neuroprotective strategies [12].

Since very recently, a proportion of patients in a large idiopathic NPH cohort with large head circumference (HC) have been identified, who presumably have congenital hydrocephalus that has not become clinically apparent until late in life. It is clear that our traditional classification scheme in adult-type hydrocephalus is no longer valid [47].

Practically speaking, decision making for shunt surgery results in a variety of different strategies: a strict investigator considers shunting only in patients presenting with the complete triad, marked ventriculomegaly, and other supportive clinical and imaging findings. A liberal investigator shunts nearly everybody, even in the presence of an incomplete triad, comorbid conditions, and/or unexpected clinical and radiological findings. The first investigator may miss an occasionally treatable patient and the second may perform many useless and risky surgical interventions. Neither of the strategies will eventually help to improve the quality of our treatment of NPH but rather may increase the risk of an upcoming “therapeutic nihilism.”