Journal of Clinical Neuroscience xxx (2018) xxx–xxx

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Journal of Clinical Neuroscience

journal homepage: www.elsevier.com/locate/jocn

Review article

Pathogenesis of idiopathic Normal Pressure Hydrocephalus: A review of

knowledge
Konstantin Bräutigam a,⇑, Antonis Vakis b, Christos Tsitsipanis b
a
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology,
Charitéplatz 1, 10117 Berlin, Germany
b
Department of Neurosurgery, University of Crete, Panepistimiou, 71500 Iraklio, Greece

a r t i c l e i n f o a b s t r a c t

Article history: Idiopathic Normal Pressure Hydrocephalus (iNPH) is a frequent neuropsychiatric entity. Clinically it is
Received 10 July 2018 characterised by Hakim’s triad: Dementia, gait disturbance and urinary incontinence. While its symp-
Accepted 29 October 2018 tomatology is typical, the etiology and thereby physiopathology of iNPH still remain enigmatic. This
Available online xxxx
review summarizes and synthesizes different etiologic conceptions and physiopathologic aspects of
iNPH. A research of literature via the PubMed/MEDLINE and the Cochrane database was conducted.
Keywords: Only English language articles clearly outlining a reasonable concept of physiopathology were included.
Normal pressure hydrocephalus
Most authors advocate that iNPH is a result of chronically altered cerebrospinal fluid (CSF) dynamics, i.e.
Idiopathic
Pathogenesis
deranged CSF production, kinetics and reabsorption. In addition, there are vascular, metabolo-
Physiopathology neurodegenerative and hereditary factors. Neuroinflammation does not seem to play a significant role
Literature review in the etiology of iNPH. All in all, iNPH seems to combine several pathogenetic factors leading to a
self-reinforcing vicious circle. The majority of studies hint at CSF disturbances on grounds of altered
hemodynamics.
Ó 2018 Elsevier Ltd. All rights reserved.

1. Introduction 2. Methods

Idiopathic Normal Pressure Hydrocephalus (iNPH) is a frequent
neuropsychiatric disorder. Its prevalence is estimated to be around
22 per 100 000 [1] and is higher in the elderly [2]. Normal Pressure
Hydrocephalus (NPH) shows a typical clinical triad (known as
‘‘Hakim’s triad” [3]) consisting of gait disturbance, dementia and
urinary incontinence [3–5] combined with ventriculomegaly.
Definitive therapy is ventricular shunting, mostly ventriculoperi-
toneal [6]. While primary NPH is considered as idiopathic,
secondary NPH is due to an underlying pathology, e.g. trauma or
hemorrhage. The exact etiology of iNPH is still controversial.
Vascular, biomechanical, hereditary, inflammatory and metabolic
factors are discussed. Ventriculomegaly in iNPH is contentious, as
it is a common phenomenon in the elderly in general. In addition,
reliable biological markers for iNPH are still missing [7]. Further-
more, iNPH coincides with Alzheimer’s Disease (AD) [6]. In this
review, we will synthesize current opinion on etiology and phys-
iopathology of iNPH.
2.1. Search strategy and selection criteria
We searched the US National Library of Medicine PubMed/
MEDLINE database and the Cochrane Database of Systematic
Reviews for the period from November 2007 to November 2017
using the Medical Subject Headings (MeSH) terms ‘‘Hydrocephalus,
Normal Pressure” and ‘‘Hydrocephalus, Normal Pressure/physiopa
thology” on November 19, 2017. Afterwards we reviewed the
retrieved articles’ titles and abstracts to identify articles clearly
dealing with the physiopathology of iNPH. We included articles
that fulfilled these criteria:

Articles supporting or describing a reasonable physiopathology
of iNPH

Original research articles

English language articles
The exclusion criteria were the following:

Articles confounding iNPH with Normal Pressure Hydro-

⇑ Corresponding author at: Department of Pathology, Charité Universitätsmedi- cephalus, i.e. not clearly referring to primary NPH
zin, Charitéplatz 1, 10117 Berlin, Germany.
Insufficient outline of a physiopathologic concept of iNPH
E-mail address: konstantin.braeutigam@charite.de (K. Bräutigam).

https://doi.org/10.1016/j.jocn.2018.10.147
0967-5868/Ó 2018 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Bräutigam K et al. Pathogenesis of idiopathic Normal Pressure Hydrocephalus: A review of knowledge. J Clin Neurosci
(2018), https://doi.org/10.1016/j.jocn.2018.10.147
2 K. Bräutigam et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx
2.2. Results
Our initial search identified more than 500 articles. After selec-
tion and search of the articles’ bibliographies, 29 full-text articles
satisfying our inclusion criteria remained (Fig. 1). 15 articles were
excluded based on their title, five based on their abstract (exclu-
sion criteria above). 5 additional articles were included after thor-
oughly inspecting the bibliography of the included articles. In
summary, this paper is based on a total of 34 articles.
3. Pathogenesis of iNPH
In the following, we present a synthesis of different etiologic
and physiopathologic approaches to idiopathic Normal Pressure
Hydrocephalus.
3.1. Abnormal cerebrospinal fluid dynamics
The most frequently encountered etiology of iNPH is related to
cerebrospinal fluid (CSF) dynamics and mainly mechanical
(Table 1). CSF pulsations are physiologic and mainly a result of car-
diac function, i.e. systole and diastole [8], respiration and brain
compliance. However, constrained (systolic) heart action, based
on several conditions, leads to altered cerebral perfusion and
disturbed CSF pulsation patterns. Chronic disturbance in CSF pulsa-
tions results in maladjusted CSF production and resorption. One of
the consequences is CSF diapedesis and thereby periventricular
oedema. Oedema interferes with regular brain homeostasis, has
mass effects and results in local ischemia. Local ischemia comes
along with dysfunctional metabolism and insufficient transport
of neurotoxic substances (Fig. 2). Mass effects by diapedesis and
Fig. 1. Flow diagram of the article selection process.
Please cite this article in press as: Bräutigam K et al. Pathogenesis of idiopathic Normal Pressure Hydrocephalus: A review of knowledge. J Clin Neurosci
(2018), https://doi.org/10.1016/j.jocn.2018.10.147
oedema are experimentally supported by observed increased
intracranial pressure (ICP) pulse amplitudes in iNPH [9,10]. The
intracranial volume gain decreases the compliance of the brain
[9] further compromising CSF production and absorption. More-
over, motor function in iNPH often improves after long-term exter-
nal lumbar drainage which might be explained by compression
relief of periventricular corticospinal tracts [11].
3.2. Vascular etiology
iNPH is associated with diabetes mellitus [12,13] which rises
suspicion for a vascular etiology [13,14] (Table 1). Moreover, arte-
rial hypertension is regarded as an independent risk factor [15] and
significantly more prevalent in patients with iNPH than in controls
[13]. Patients with iNPH are more prone to vascular risk factors,
e.g. dyslipidemia and obesity [13]. Chrysikopoulos assumes altered
arterial hemodynamics with a disturbed systole in the cerebral
ventricular system as a leading etiology, hence promoting intensi-
fied antihypertensive regimens in iNPH patients [8]. Reduced cere-
bral blood flow (CBF) in iNPH has been described, too [16,17].
Momjian et al. state that CBF is periventricularly decreased [17].
The assumption that the dilatation of lateral ventricles in iNPH is
result of an impaired CBF is debatable [17,18]. First of all, patients
with iNPH do not necessarily show evidence of ischemia [18] or
reduced CBF. Therefore, ischemia alone cannot sufficiently explain
iNPH. Bateman assumes no deep ischemia in iNPH, but rather
changes in superficial venous pressure [18]. Cortical veins are
thought to be functionally impaired which explains the irregular
CSF absorption [18]. Furthermore, the dilatation of the ventricles
itself might cause the impaired blood flow, not vice versa. Dilated
ventricles compress small vessels and generate parenchymal
oedema. Not only neuro- but also vasotoxic substances accumulate
more easily and affect autoregulation negatively [17]. Patients with
iNPH have significantly more white matter lesions than controls
[14] underlining microvascular disturbances in iNPH. Early inter-
vention against vascular risk factors could reduce the risk for the
development of iNPH [19].
3.3. Neurodegeneration and –inflammation in iNPH
Behaviour disorders and psychiatric abnormalities have been
described in iNPH [4]. Patients with iNPH can present themselves
with extensive memory loss and executional deficits. Coexistence
with Alzheimer’s Disease has been delineated [6]. In an autopsy
study AD was frequently confounded with iNPH [20]. Low CSF
Amyloid beta (Ab)-42 and high CSF phosphorylated tau (P-s) are
regarded as a specific CSF constellation of AD [21].
On the contrary, CSF P-s is described as being much lower in
iNPH [22]. Jingami et al. argue that this might be due to a dilution
effect related to the extensive CSF volume in iNPH [22]. Jingami
et al. argue that this might be due to a dilution effect related to
the extensive CSF volume in iNPH [22]. Leucine-rich alpha-2-
glycoprotein (LRG) is regarded as a useful CSF marker in iNPH
[23] but not a good parameter to differentiate iNPH from AD
[22]. Low CSF Ab-42 was associated with worse neurocognitive
function whereas CSF P-s showed no correlation with cognition
in iNPH. Lower CSF P-s was, however, associated with more severe
gait disturbance [24].
Functional studies of CSF flow reveal impaired CSF dynamics in
iNPH and AD [25]. It is not clear whether CSF disturbances promote
neurodegeneration in iNPH and thereby create symptoms sugges-
tive of AD. However, the typical amyloid cascade with cerebral
amyloid accumulation in AD seems not to be present in iNPH
[26]. The frequency of the APOE e4 allele, an important genetic risk
for AD, in patients with iNPH does not seem to be higher than in
the general population [27,28].
 K. Bräutigam et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx 3

Table 1
Selected studies on CSF-related and vascular factors in physiopathology of iNPH. CBF: cerebral blood flow, CSF: cerebrospinal fluid, CVR: cerebrovascular reactivity, ICP:
intracranial pressure.

Authors (year) Study Patients Main conclusion(s)

design/type
CSF related Lenfeldt et al. (2008) [11] Experimental 11 Improved motor function in iNPH after long-term external lumbar drainage
Eide et al. (2010) [9] Retrospective 214 Improvement after shunt surgery in iNPH is predicted by ICP variability
Qvarlander et al. (2013) [10] Experimental 51 Cardiac related ICP pulsations as a physiopathologic factor in iNPH
Vascular Krauss et al. (1996) [15] Case-control 65 Arterial hypertension strongly associated with iNPH
Momjian et al. (2004) [17] Experimental 12 White matter CBF reduced in iNPH
Chrysikopoulos (2009) [8] Expert opinion – Altered cerebral arterial hemodynamics and disturbed cerebral ventricular systole in iNPH
Chang et al. (2009) [16] Prospective 162 Reduced CBF and CVR in iNPH
Jaraj et al. (2016) [14] Retrospective 26 Arterial hypertension and diabetes involved in physiopathology of iNPH
Israelsson et al. (2017) [13] Case-control 176 Vascular risk factors in iNPH "

Fig. 2. ‘‘Vicious circle” of idiopathic Normal Pressure Hydrocephalus (iNPH): Visualisation of presumed etiologic and physiopathologic factors. Components of Hakim’s triad
in italics. CSF: Cerebrospinal fluid, ICP: Intracranial Pressure, O2: oxygen.

Neuroinflammatory markers have also been explored in iNPH
[26,29]. Pyykkö et al. describe different CSF cytokine patterns in
patients with iNPH (shunt responders and non-responders), AD
and mixed disease (i.e. iNPH and AD) [26]. Interleukin-6 and -8
seem to be frequently elevated in CSF of patients with iNPH
[26,29].
protective hormone promoting cell division. It is strongly released
after hypoxic brain injury [32]. Increased IGF-1 might be an
endogenous response to neuronal damage in iNPH [31].
4. Discussion

3.4. Hereditary factors In iNPH functional studies partially contradict themselves. On

There are hints that iNPH might be hereditary. McGirr and Cusi-
mano discovered familial aggregation in iNPH [12]. Patients with
iNPH (n = 20) have relatives with symptoms similar to those of
iNPH in almost ten percent of the cases. Huovinen et al. reported
in their study that around sixteen percent of iNPH patients
(n = 375) have relatives with shunt-operated or possible iNPH
[28]. Nevertheless, so far no specific genetic risk factors were
identified.
3.5. Brain metabolism in iNPH
iNPH has implications on brain metabolism. Miyamoto et al.
showed significantly reduced oxygen metabolism and reduced
blood flow in the basal ganglia of patients with iNPH using positron
emission tomography (PET) (n = 19) [30]. Cerebral hypometabo-
lism has a negative impact on cerebral hemodynamics [16]. Pitu-
itary anomalies in iNPH are subject of discussion, too. High
serum Insulin-like Growth Factor-1 (IGF-1), terminus of the
growth hormone axis has been described in iNPH compared to con-
trols by Yang et al. (n = 104) [31]. IGF-1 is considered to be a brain-
the one hand there is postulation of disturbed CSF flow in iNPH
[33], on the other hand exactly the opposite. Cisternography, as
one example, cannot securely confirm impaired CSF flow [34]. In
addition, ventricular wall movement disorders do not seem to be
a physiopathologic component of iNPH (n = 3) [33] and do not
explain CSF diapedesis sufficiently. Heterogeneous clinical out-
comes after ventriculoperitoneal shunting in patients with sus-
pected iNPH also question CSF dynamics as sole cause of iNPH. A
combination of physiopathologic factors seems reasonable (Fig. 2).
iNPH certainly implies vascular anomalies. However, authors
are divided over the specific vascular compartment. While some
argue for arterial malfunction [8], others rather suspect (cortical)
venous dysfunction [18]. Both theories do not necessarily contra-
dict each other and, there is agreement on vascular anomalies in
iNPH.
Local cerebral hypometabolism is rather the consequence of
dilated lateral ventricles and not their cause. Periventricular hypo-
metabolism has been experimentally confirmed [30] and con-
tributes to disease progression. Moreover, reduced oxygenation
of the basal ganglia, important component of voluntary motor con-
trol, might contribute to gait disturbance [30]. The mentioned

Please cite this article in press as: Bräutigam K et al. Pathogenesis of idiopathic Normal Pressure Hydrocephalus: A review of knowledge. J Clin Neurosci
(2018), https://doi.org/10.1016/j.jocn.2018.10.147
4 K. Bräutigam et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx
accumulation of toxic substances does not only reduce brain
perfusion but might also generate neurodegeneration. Neurode-
generation contributes to demential symptoms. iNPH is often
confounded with AD and vice versa [20]. However, AD is a singular
entity with a distinct physiopathology and specific CSF pattern.
CSF and plasma interleukin levels in iNPH [26,29] are inconsis-
tent and therefore currently of minor relevance in iNPH. An infec-
tious background of iNPH has not been thoroughly investigated so
far. Hereditary factors in iNPH are inconclusive, too. While iNPH
seems to cluster in families [12,28], specific genes have not yet
been identified.
4.1. Study limitations
This literature review is a synthesis of current knowledge and
an approach to merge etiologic and physiopathologic conceptions
on iNPH. iNPH implies a multitude of theories (Table 1), sometimes
supported by only weak evidence, which makes a systematic anal-
ysis difficult. Here, several of the included studies had only low
amounts of patients (exemplarily [25, 30, 33]). This led partially
to statistical insignificance and thereby to vague conclusions. The
physiopathology of iNPH resembles a mosaic pattern of different
aspects which considerably hinders the attempt to rigorously com-
pare studies. As etiology is not clear, physiopathology can only
remain vague, too.
5. Conclusion
This systematic review offers different insights into current
knowledge on pathogenesis of iNPH. iNPH is not an idiopathic con-
dition, instead it combines several coherent etiologic factors
(Fig. 2). It seems to be the result of a cascade of deregulated pro-
cesses which chronically lead to macroscopic pathology in form
of dilated ventricles and white matter lesions. iNPH is not a merely
mechanical problem but rather a vicious, self-reinforcing circle. It
is a chronic disease, not an acute pathology, which might also
explain the heterogeneous response to CSF shunting. Cerebral
dyshomeostasis, hypometabolism and neurotoxicity offer an
explanation to the pathognomonic triad of Hakim. Nevertheless,
iNPH remains challenging.
Funding
None.
Conflict of interest
None.
Acknowledgement
This work was in part presented at the 44th Annual Panhellenic
Congress of Medicine, Athens, May 9, 2018.
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