Influence of comorbidities in idiopathic normal pressure hydrocephalus — research and clinical care. A report of the ISHCSF task force on comorbidities in INPH
Fluids and Barriers of the CNS
Influence of comorbidities in idiopathic normal pressure hydrocephalus - research and clinical care. A report of the ISHCSF task force on comorbidities in INPH
Jan Malm 0 4
Neill R Graff-Radford 2
Masatsune Ishikawa 1
Bo Kristensen 8
Ville Leinonen 6 7
Etsuro Mori 5
Brian K Owler 10
Mats Tullberg 9
Michael A Williams 3
Norman R Relkin 11
0 Department of Clinical Neuroscience, Umea University , Umea 901 85 , Sweden
1 Normal Pressure Hydrocephalus Center, Otowa Hospital , Kyoto , Japan
2 Department of Neurology, Mayo Clinic Jacksonville , Jacksonville, Florida , USA
3 The Sandra and Malcolm Berman Brain & Spine Institute of Sinai Hospital , Baltimore , USA
4 Department of Clinical Neuroscience, Umea University , Umea 901 85 , Sweden
5 Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine , Sendai , Japan
6 Department of Neurosurgery, University of Eastern Finland , Kuopio , Finland
7 Department of Neurosurgery, KUH NeuroCenter, Kuopio University Hospital and Institute of Clinical Medicine , Kuopio , Finland
8 Department of Neurology, Aalborg University , Aalborg , Denmark
9 Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
10 Department of Surgery, University of Sydney , Sydney , Australia
11 Department of Neurology and Neuroscience, Weill Cornell Medical College , New York , USA
Idiopathic normal pressure hydrocephalus (INPH) is a syndrome of ventriculomegaly, gait impairment, cognitive decline and incontinence that occurs in an elderly population prone to many types of comorbidities. Identification of the comorbidities is thus an important part of the clinical management of INPH patients. In 2011, a task force was appointed by the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders (ISHCSF) with the objective to compile an evidence-based expert analysis of what we know and what we need to know regarding comorbidities in INPH. This article is the final report of the task force. The expert panel conducted a comprehensive review of the literature. After weighing the evidence, the various proposals were discussed and the final document was approved by all the task force members and represents a consensus of expert opinions. Recommendations regarding the following topics are given: I. Musculoskeletal conditions; II. Urinary problems; III. Vascular disease including risk factors, Binswanger disease, and white matter hyperintensities; IV. Mild cognitive impairment and Alzheimer disease including biopsies; V. Other dementias (frontotemporal dementia, Lewy body, Parkinson); VI. Psychiatric and behavioral disorders; VII. Brain imaging; VIII. How to investigate and quantify. The task force concluded that comorbidity can be an important predictor of prognosis and post-operative outcome in INPH. Reported differences in outcomes among various INPH cohorts may be partly explained by variation in the rate and types of comorbidities at different hydrocephalus centers. Identification of comorbidities should thus be a central part of the clinical management of INPH where a detailed history, physical examination, and targeted investigations are the basis for diagnosis and grading. Future INPH research should focus on the contribution of comorbidity to overall morbidity, mortality and long-term outcomes.
Hydrocephalus; Normal pressure; Comorbidity; Review; Guidelines; Task force
Background and objective
The International Society for Hydrocephalus and
Cerebrospinal Fluid Disorders (ISHCSF) has identified six
fields of interest for investigation by individual task
forces. The task forces have been charged with providing
evidence-based expert analysis of what we know now, and
what we need to know in the future, to improve the care of
INPH patients and move the field of adult hydrocephalus
research forward. This article discusses comorbidities in
Idiopathic Normal Pressure Hydrocephalus (INPH). For
the purposes of this review, comorbidity was defined as a
medical condition existing simultaneously but independent
of INPH or a medical condition in a patient that causes, is
caused by, or is otherwise related to INPH .
INPH is a complex syndrome of ventriculomegaly,
cognitive decline, gait impairment and incontinence that
occurs in an elderly population prone to many types of
comorbidities. Identification of comorbidities is an
important part of the clinical management of INPH
patients. For instance, comorbidities such as uncontrolled
hypertension and cardiac disease need to be addressed
before cerebrospinal fluid (CSF) shunt surgery is
performed, as part of the medical clearance for general
anesthesia. The presence of comorbidities can be a major
prognostic factor in the outcome of INPH treatment. For
example, shunt surgery in an INPH patient with multiple
strokes or co-existing Alzheimer disease is less likely to
yield a fully favorable long-term outcome than in persons
with INPH who lack these comorbidities. In an elderly
population, INPH may be one of many co-existing chronic
comorbid conditions, the management of which can
contribute to the patients overall health status. Identifying
and treating comorbid conditions in addition to INPH
serves the goal of maximizing overall health status, an
important goal in the care of the elderly.
Comorbidity is also important in hydrocephalus
research. In order to compare studies and different samples
of patients, the degree of comorbidity has to be quantified.
Large INPH studies often focus on outcome of CSF shunt
surgery [2-6] or report the usefulness of various kinds of
predictive tests for INPH such as CSF infusion tests ,
external lumbar drainage [3,5], intracranial pressure
monitoring , or MRI . However, none of these studies
have evaluated the contribution of comorbidity to the
reported results. Future INPH research should investigate
the contribution of comorbidity to overall morbidity,
mortality and long-term outcome in INPH.
The list of differential diagnoses in INPH is long and
complicated because of the comorbidities. This review
tries to explain how to recognize if INPH patients have
comorbid factors and should help in the management of
Search strategy and evidence review
The task force panel conducted an evidence-based
expert review of the literature. PubMed was searched for
peer-reviewed papers and reviews published in English
and including human subjects. The key search term
hydrocephalus was combined with the following words:
comorbidity, atherosclerosis, stroke, transient ischemic
attack, musculoskeletal, hip, knee, myelopathy, spinal
stenosis, urinary, incontinence, risk factors (including naming
of the most important vascular risk factors), Binswanger
disease, white matter, leukoaraiosis, MRI, Alzheimers
disease, biopsy, biomarker (and naming of the most
important CSF biomarkers), dementia, psychiatry, depression,
psychosis and atrophy.
The chairman of the Comorbidity Task Force (JM) was
appointed by the ISHCSF and selected a group of
physicians and researchers with knowledge and experience in
this area. The task force was composed of neurosurgeons
and neurologists with international representation. Each
member was given responsibility for performing a
thorough literature search on identified subtopics and drafting
the relevant section of the consensus document. After
weighing the evidence, the various proposals were
discussed by all members of the task force by mail and in
web-based teleconferences. The final draft was reviewed by
external reviewers from this journal and approved by all
the task force members. The document thus represents
a consensus of expert opinions. The publication was
approved by the ISHCSF.
As there are no randomized clinical studies or
metaanalyses about comorbidity in INPH, an evidence-based
survey of current practice was the basis for the
recommendations given. Thus, the primary sources for the
recommendations are the expert consensus opinion, clinical
experience, case studies, or standard of care.
For each recommendation, the size and strength of
treatment effect was categorized as level I, IIa, IIb or III. If
level I, the treatment or procedure should be performed.
For level IIa the treatment or procedure is reasonable, for
IIb, treatment may be considered and for level III, the
treatment or procedure would have no effect or could be
dangerous for the patient. Those numbers do not
correspond to a level of evidence, but to a recommendation on a
consensus opinion of experts .
Comorbidities in INPH
Musculoskeletal problems are a common comorbidity in
INPH patients. The extent to which musculoskeletal
conditions contribute to disabilities in gait and balance
should be assessed routinely when examining patients
with suspected INPH. When significant co-existing
musculoskeletal conditions are confirmed, management
needs to be individualised to the patients condition.
Note that prognostic tests such as high volume tap test,
external lumbar drainage and infusion tests sometimes
yield false results if the CSF flow is altered because of a
severe spinal canal stenosis . Management may differ
considerably depending on whether symptoms are
primarily attributable to musculoskeletal comorbidities
versus INPH. In such cases, a multidisciplinary approach
may be required to optimise the management plan.
Conditions of the hip or knee Most patients with
INPH are elderly when diagnosed and may have a degree
of osteoarthritis of the hip and/or knee. Other
conditions such as gluteal enthesopathy, trochanteric bursitis
or gait abnormalities caused by inadequate joint mobility
are also common. The hallmark of all of these
conditions is pain. While they may limit tandem gait, or cause
unsteadiness and falls, they produce pain particularly
with weight bearing. Provocative testing may also elicit
pain but the diagnosis is usually confirmed through
investigations such as x-ray examination, SPECT bone
scan and more commonly MRI of the hip or knee.
Patients with INPH and painful hip or knee pathology
should have treatment tailored to their clinical picture.
The severity of pain will need to be balanced against the
severity of the symptoms attributable to INPH, as well
as the likelihood of response to shunting and candidacy
for long-term rehabilitation. For example, patients with
severe cognitive disturbance due to INPH may be unable
to participate in a rehabilitation program necessary for
successful outcome of hip or knee replacement surgery.
In cases where prognostic tests for shunt responsiveness
are positive and pain is not severe, treatment of INPH
should take priority. However, if hip or knee pain is
severe and cognitive impairment is mild, the hip or knee
should be given priority for management.
Hip and knee prostheses are commonplace in the
elderly. The presence of such prostheses is not usually a
contra-indication to investigation or treatment of INPH.
Patients with prostheses who have hip or knee pain,
particularly pain with weight bearing that interferes with gait,
should have their prostheses investigated to exclude
complications such as loosening or peri-prosthetic fractures.
Hip fractures, especially in women, are common in the
elderly. Recuperation time to maximal recovery after a hip
fracture regarding gait and balance is about 69 months
. Gait and balance are important for the diagnosis of
INPH and to evaluate outcome of surgery. It may
therefore be reasonable to postpone shunt surgery for INPH
for six months after a hip fracture if the patient is going to
be included in prospective research projects.
Cervical spondylotic myelopathy Cervical spondylotic
myelopathy is caused by degenerative changes in the
cervical spinal canal. In the elderly, this is the most
common cause of impaired function of the spinal cord. Like
INPH, it is typically painless and has an insidious onset.
Early symptoms tend to be weakness, sensory changes
and gait disturbance. Along with spastic gait, balance is
often adversely affected by cervical myelopathy.
Cervical myelopathy may progress rapidly, often
affecting upper limb function significantly as well as gait, and
represents a significant risk in some patients undergoing
surgery for other reasons. Endotracheal intubation with
neck extension, positioning with the head rotated for
shunt surgery and relative hypotension that often
accompanies general anaesthesia, all heighten the risk of
shunt surgery and may cause clinical deterioration in cases
of existing cervical canal stenosis and myelopathy .
Accordingly, when a diagnosis of myelopathy is confirmed
through MRI, priority is usually given to its treatment,
particularly when there is associated myelomalacia.
Lumbar canal stenosis Lumbar canal stenosis causes
neurogenic claudication. This is a limitation of walking
(or standing) for prolonged periods due to lower limb
pain. Many patients do not have pain but rather lower
limb paraesthesia or numbness. Sitting, usually for a
short period, provides relief from symptoms and the
patient can walk or stand again for a period of time. Except
in severe cases of lumbar canal stenosis, walking is not
affected in the initial stages as opposed to INPH where
initiation of gait is a predominant symptom.
Management of probable INPH should take priority over lumbar
canal stenosis. The decision should be based on clinical
symptoms rather than spinal radiological findings, which
tend to be a poor predictor of clinical symptoms .
The reason for giving management of INPH priority is
that lumbar canal stenosis will usually not limit gait
unless the patient is able to walk significant distances. An
exception to this scenario is the patient with lower limb
symptoms due to lumbar canal stenosis at rest that can
occur in severe cases and may indicate the rare but
possible progression to paraplegia.
Other pathologies including stroke There are several
other musculoskeletal pathologies that should be
considered in the assessment of patients with INPH. A
hemiplegic gait often indicates previous stroke. Peripheral
neuropathy, myopathy and polymyalgia rheumatica are
other pathologies that need to be considered in the
diagnosis. These are usually more easily assessed in cases
where cognitive impairment is mild and where the patient
is able to mobilise for some distance. Most difficulties
arise where the patient is bed-bound or has difficulty
describing other clinical symptoms, particularly pain.
Diagnosis must be guided by a history from family members
and careful clinical examination supplemented by other
In a recently-developed hemiplegia in which there is a
clear cause it would be unusual to shunt a patient for
INPH. However, other patients with more long-standing
deficits and newly-developed hydrocephalic symptoms
may benefit from shunting. Patients with deficits due to
polio would be another example, although in these cases
post-polio syndrome needs to be considered. In each of
these cases, treatment should be decided based on the
merits of the individual case.
1. If signs and symptoms of myelopathy are found in a
patient being investigated for INPH, a spinal MRI
should be performed (Class I).
2. If symptomatic and progressive, treatment of
cervical spondylotic myelopathy should usually take
priority over testing for INPH or shunt surgery
3. Patients who have coexisting INPH and lumbar canal stenosis should usually undergo shunt surgery. Exceptions are patients with pronounced
neurological symptoms due to stenosis, such as
paraplegia who should undergo back surgery first
4. A hip or knee prostheses is not a contra-indication
to investigation or treatment of INPH. Patients with
INPH and painful hip or knee pathology should have
treatment tailored to their clinical picture.
5. In the research setting, INPH patients with hip
fracture may need to recover for 69 months before
enrolling in INPH clinical studies in order to obtain
valid outcome assessments (Class IIb).
Urinary disturbances are common and distressing
problems in the elderly. In adults, the prevalence of urinary
tract symptoms has been reported to be 17% and it
increases with age . As urgency, frequency and
incontinence are cardinal features of INPH, it is important to
determine if the patients urinary symptoms are related
to hydrocephalus. However, urgency with or without
incontinence is not specific for INPH. The possibility of
co-existing types of incontinence or urinary problems
caused by other neurologic or non-neurologic disorders
should be taken into consideration.
The investigation of urinary problems in INPH should
include a detailed history targeting the most relevant
signs and symptoms. Patients should be asked about
urgency, frequency, nocturia, incontinence and any
accompanying neurological symptoms. When symptoms are
present, urinary tract infection and a large post void
residual urine should be excluded. Patients can be asked
to fill out a bladder diary for several days to provide
information about how often they urinate, the volume of
urine produced, and any episodes of incontinence.
Voiding more than 812 times in a 24 hour period is
usually considered compatible with a diagnosis of
overactive bladder (below), but the frequency is also
correlated to intake of fluids .
Frequency and urgency There are five major types of
urinary incontinence; (1) urge incontinence; (2) stress
incontinence; (3) mixed incontinence; (4) overflow
incontinence and (5) incontinence caused by other factors such as
decreased mobility, cognitive impairment or medications.
Urge incontinence is caused by a sudden, involuntary
bladder contraction and is also called detrusor
overactivity or simple overactive bladder. This condition is
defined as urinary urgency, often mixed with frequency
or nocturia, with or without incontinence . It could be
caused by many of the most important diseases that
coexists with INPH: different types of dementia, stroke, small
vessel disease and leukoaraiosis, Parkinsons disease,
multiple system atrophy and myelopathy . Also common
non-neurologic disorders such as prostatic hypertrophy,
tumor and cystitis could give similar symptoms.
Stress incontinence is when the bladder and urinary
sphincter cannot handle the increased compression
during exercise, coughing, or sneezing, resulting in loss of
urine. This kind of incontinence happens mostly to
women with pelvic-organ prolapse  but also in men
after prostate surgery.
Mixed incontinence is a combination of both stress
and urge incontinence, and is most common in older
women. Overflow incontinence, in which the bladder
becomes distended and cannot be fully emptied, is rarer
and is the result of bladder obstruction or injury. In
men, it can be the result of an enlarged prostate.
Increased age, impaired functional status, increased
duration of disease, diabetes and cholinesterase inhibitors
are associated with an increased frequency of urinary
incontinence . Functional incontinence is a condition
related to dementia and/or gait disturbance interfering
with independent toileting skills.
INPH and urinary incontinence The frequency of
urinary problems in INPH is reported to be between
55% to 79% [3,5,6,17]. Storage symptoms (93%) are more
common than voiding symptoms (71%) . In a
urodynamic study, it was reported that bladder capacity was
small and detrusor overactivity seen in 95% of INPH
patients; thus, detrusor overactivity is postulated to be the
basis for most urinary urgency/frequency and
incontinence in INPH. Improvement of bladder hyperactivity after
lumbar tap test in INPH patients has been reported .
Recent perfusion studies with single photon emission
tomography revealed that a hypoperfusion was present
in the right frontal area in INPH patients with moderate
or severe incontinence, compared to those with none or
mild incontinence .
1. Detrusor over activity with urgency is a common urinary problem in INPH.
2. A carefully-obtained history of symptoms is
important to the evaluation of urinary problems in
INPH. If possible, a bladder diary should be obtained
from the patient. Investigations should include tests
for urinary tract infection and increased post-void
residual urine (Class I).
3. In contrast to the gait disturbance and dementia, studies of urinary incontinence in INPH are scarce. Further studies are needed.
An association between INPH and cerebrovascular disease
is well supported. Neuropathological studies of the brain
of hydrocephalic patients show signs of cerebrovascular
disease such as sclerosis of the arterioli [21-23].
Hypertension and sometimes other vascular risk factors and a
previous history of cerebrovascular incidents are often found
in INPH patients [24-27]. Leukoaraiosis of the
periventricular and deep white matter is common [28,29]. The
cognitive deficits seen in NPH frequently involve
accentuated impairment of frontal systems, a pattern shared with
subcortical vascular cognitive impairment .
Risk factors A high burden of vascular risk factors
means that an individual will have an increased risk of
developing manifest end organ damage in the form of
stroke, white matter lesions, vascular dementia, ischemic
heart disease or claudication. All these are common in
the elderly and occur frequently as comorbidities in
patients with INPH.
It is presently unclear whether vascular risk factors are
an inherent part of the pathophysiology of INPH,
accelerate the progression of the disease, or occur
coincidently in INPH without affecting the hydrocephalus
itself. It is also uncertain whether INPH symptoms
improve if these risk factors are treated by lifestyle
modifications or by medical interventions. Despite these
uncertainties, it is important to assess and mitigate a
patients likelihood of developing risk factor-related
complications when INPH is diagnosed and whenever shunt
surgery is considered.
A few small casecontrol studies regarding INPH and
risk factors have been published [25,26,30]. The main
finding is that hypertension is more common in INPH
patients compared to matched controls with various
other neurological or neurosurgical diseases. These studies
are more than 20 years old and since then, the definition
of hypertension has changed and the systolic blood
pressure is today considered a much stronger risk factor than
the diastolic blood pressure . In the hydrocephalus
field, the arterial pulse pressure and the arterial pulsations
in the ICP curve have gained increasing interest. In
healthy individuals, arterial pulse pressure appears to
contribute to the expansion of the brain ventricles . The
amplitudes of cardiac-related ICP pulsations have been
suggested as a promising predictor of good outcome after
shunting patients with INPH [4,33].
Vascular risk factors other than hypertension may be
associated with INPH but have yet to be confirmed.
Several very large epidemiological studies have examined
the effects of vascular risk factors on long-term
prognosis in the elderly population. Among the most important
of these trials are the Interheart and Interstroke studies
that used casecontrol designs to investigate the
association between known and emerging risk factors for
ischemic heart disease and stroke . In the Interstroke
study involving 3000 patients and 3000 controls, 90% of
stroke was predicted by a combination of 10 risk factors
(history of hypertension, current smoking, waist-to-hip
ratio, diet risk score, regular physical activity, diabetes
mellitus, alcohol intake, psychosocial stress and
depression, cardiac causes and ratio of apolipoproteins B to A1)
. It is reasonable to hypothesise that in a similar way, a
risk factor profile is valid also in INPH, but additional
research will be needed to confirm or reject this hypothesis.
Thus, there is a need to verify if those new vascular
risk factors also implicate an increased risk for INPH as
well as to better characterize its association with
traditional risk factors such as hypertension. Future case
control and prospective cohort studies should not only
test for possible associations between risk factors and
INPH but also address the magnitude of risk factor
abnormality that promotes the association. For example, it
might be asked what degree of elevation in blood
pressure or pulse pressure constitutes a risk in the context
While a single risk factor can lead to a poor outcome,
multiple vascular risk factors can act synergistically and
worsen the prognosis to a greater extent than the simple
additive effects of the individual risk factors. To capture
this in future INPH studies, it would be valuable to
calculate a total or global cardiovascular risk score for each
patient. Various rating scales are available. One often
used is the SCORE chart, which estimates the risk of
dying a cardiovascular death within a decade  or the
Framingham vascular risk scores .
1. Hypertension is the best-documented risk factor associated with INPH.
2. Modifiable vascular risk factors in INPH patients
such as hypertension and hyperglycemia should be
identified and treated prior to shunt surgery (Class IIb).
3. It is currently unknown if remediation of modifiable vascular risk factors will increase survival in INPH or improve hydrocephalus symptoms (with or without a shunt).
4. Traditional risk factors and cardiovascular disease
should be identified in INPH patients, both in
research and clinical practise. For the estimation of
the global, or total, cardiovascular risk and its
impact on prognosis, standardized and validated
scales should be used (Class IIb).
5. Further studies are needed to better characterize the
vascular risk factor profile of INPH. Established and
emerging risk factors should be evaluated. It is
important that future studies include large number
of patients from different parts of the world with
adequate (preferable population-based) controls.
Binswanger disease Patients with vascular risk factors
and extensive MRI white matter hyperintensity changes
frequently present with symptoms and signs similar to
those seen in INPH patients. These patients often fulfil
the criteria for Binswanger Disease (BD) [37,38], a type
of vascular dementia characterised by progressive and
extensive subcortical ischemic vascular disease [38-40].
Ventricular enlargement is not a criterion of BD but is
frequently reported in the later stages of the disorder
. Hence, late stage BD can be difficult or even
impossible to distinguish from advanced stages of INPH.
Small vessel disease with periventricular white matter
changes has been proposed to be the cause of INPH in a
subgroup of patients with a less favourable prognosis
[27,41,42]. Several studies, however, indicate no negative
impact of vascular white matter changes on the effects
of shunt surgery [42,43]. Moreover, it has been reported
that patients fulfilling the criteria for BD with enlarged
ventricles, extensive vascular white matter changes and
symptoms compatible with INPH who had negative
responses to infusion and drain prognostic tests,
nevertheless showed improved motor and psychometric functions
after shunt surgery . In the aggregate, INPH and BD
can co-exist and may even be associated. Therefore, it is
important to consider shunt surgery also in patients
showing evidence of co-existing cerebrovascular disease (CVD).
The prognostic implications of cerebrovascular
disease in INPH There is currently no predictive test that
can reliably identify all INPH patients whose symptoms
will be shunt responsive. Infusion studies showing an
increased resistance to CSF outflow, or transient
symptomatic improvement after CSF drainage predicts a good
outcome after shunting [45,46]. However, a low
resistance to outflow or a negative CSF drainage test may
still be associated with improvement after shunting .
The value of these prognostic tests in the context of
comorbidities is unknown.
Cerebrovascular disease can be associated with
irreversible brain damage. In order to elucidate the
prognostic importance of cerebrovascular disease comorbidity in
INPH, consensus criteria for characterisation of study
patients with co-existing CVD should be used, including
measures that describe the amount of cerebrovascular
pathology. Using MRI and volumetric segmentation of
periventricular and deep white matter hyperintensities,
structural changes associated with CVD can be
measured in research study populations. These structural
changes, however, have a limited predictive value and
cannot be used to select candidates for shunt surgery
[42-44,48]. The cerebrovascular disease process causes
metabolic changes in the brain of varying patterns that
are more pronounced than in normal ageing [49,50].
Metabolic impairment is also important in INPH,
probably reflecting a brain dysfunction that may be reversed
by shunting . MR diffusion weighted imaging (DWI),
perfusion weighted imaging (PWI) and diffusion tensor
imaging (DTI) are all promising techniques that can be
used to study functional and metabolic changes in the
white matter in order to identify imaging patterns
associated with favourable outcome after shunting.
The CSF is in connection with the white matter
extracellular fluid. Therefore, analysis of CSF biochemical
markers is appropriate to describe different
pathophysiological changes in this brain region. CSF biomarkers
associated with cerebrovascular disease show increased
levels in some INPH patients, but their predictive value
in relation to the outcome after shunting has yet to be
established. High preoperative CSF levels of the axonal
marker NFL, have been reported to correlate with a
favourable outcome after surgery in INPH . Reports
on the diagnostic value of CSF sulfatide in distinguishing
between INPH and BD are contradictory [53,54]. A
combined pattern of NFL, P-tau, and Abeta42 has been
reported to distinguish between the clinical diagnoses of
INPH and BD , a finding that needs to be confirmed.
Further studies are needed linking CSF biomarkers of
vascular disease to outcome of shunt surgery.
Future research studies should focus on elucidating
the importance of CVD comorbidity in INPH patients
including the possible prognostic value of CVD. It is
important that study inclusion criteria liberally allows
inclusion of patients with evidence of CVD, regardless of
severity, and that studies follow up outcome after shunting
in a standardised way. In order to find better predictive
tests, patients with different degrees of CVD burden and
different degrees of shunt outcome must be compared.
1. Among cerebrovascular disorders, BD is the most important for INPH differential diagnosis, since these disorders often show similar clinical and radiological signs.
2. Subcortical CVD frequently co-exists with INPH.
CVD patients often have vascular MR white matter
changes and may also present with focal
neurological signs or vascular cognitive impairment.
3. INPH patients with evidence of CVD may improve
significantly after shunting (Class IIa).
4. Better predictive tests that can select shunt candidates in patients with mixed INPH and BD are needed.
5. A consensus classification of coexisting INPH and
CVD is needed where both clinical and
neuroimaging measures such as MRI are included.
6. Future clinical studies should liberally include INPH
patients with co-existing cerebrovascular disease and
evaluate the shunt effect in this subgroup.
7. Future research should focus on assessing pathophysiological changes characteristic of INPH
and CVD using MR diffusion and perfusion imaging
as well as CSF biomarkers related to clinical measures
at baseline and changes after shunt surgery.
INPH and alzheimers disease
Alzheimers disease (AD) is the most common cause of
dementia and a common comorbidity with INPH.
Recently, guidelines defining AD were published
emphasizing history, neuropsychological testing and clinical
examination as the main base for diagnosis . To
increase the diagnostic accuracy, typical AD histological
features of -amyloid plaques and neurofibrillary tangles
can be confirmed either directly by a brain biopsy 
or indirectly by biomarkers such as the phosphorylated
tau/amyloid beta 142 ratio in CSF . Positron
emission tomography (PET) amyloid imaging and MR
volumetry are also promising methods to support AD
diagnosis, particularly for research studies.
Although AD itself is not usually associated with a gait
disturbance at presentation, gait disturbances are
common in the elderly population that is most prone to
develop AD. This fact, combined with the occurrence of
cognitive impairment and ventriculomegaly in both AD
and INPH, can make differential diagnosis of these two
INPH and AD can occur together in a mixed form,
INPH-AD . Although these disorders have
overlapping symptoms, a careful history and examination by a
skilled physician or neuropsychologist can assist in their
differential diagnosis as comorbid illnesses. Rapid
forgetting of newly acquired information related to hippocampal
dysfunction is the most common presenting symptom of
Alzheimers disease. Although memory may also be
affected in INPH, it is usually as a manifestation of frontal
executive disturbances that can often be improved by cues
or reminders. Various neuropsychological tests to
differentiate AD and INPH have been suggested [59,60].
Progressive disturbances of gait and balance are common
presenting symptoms of INPH, whereas comparable
degrees of motor impairment tend to occur only late in the
course of AD . Likewise, urinary frequency, urgency
and incontinence can occur in early stages of INPH but
tend to be late stage symptoms in AD.
The similarity between cognitive impairment in
vascular dementia and that seen in INPH patients is another
potential diagnostic confounder. Moreover, also AD and
vascular dementia can co-exist in a single patient.
Further research is needed to develop techniques to better
differentiate INPH from mixed INPH-AD. Future
clinical trials should endeavor to identify the frequency of
mixed INPH-AD in the study cohorts.
Brain biopsy AD-related neuropathological changes have
been found in biopsies from patients with amnestic mild
cognitive impairment (MCI) , i.e., a prodrome to AD
characterized by subtle memory problems occurring
without a significant decline in activities of daily living. It is
believed that the AD pathology in those patients develops
many years before onset of the manifest AD dementia
. However, typical AD features have also been found
at autopsy in elderly patients who did not develop
cognitive decline before their death [64,65].
In INPH patients, it is possible to obtain a small
cortical brain biopsy at the time of shunt placement or in
the course of carrying out invasive pre-operative
recording of intracranial pressure . Biopsies obtained in
this manner show typical AD histological findings in
2540% of INPH patients [67-70]. It is unclear whether
these findings correspond to manifest AD, a pre-stage of
AD or if they are random findings.
Studies have also attempted to correlate the degree of
AD findings at biopsy with outcome after shunt surgery.
Patients with AD findings at biopsy can still improve
after shunting. The available information indicates that
the presence of AD pathology does not affect survival
after shunt placement, but is associated with a lesser
degree of improvement compared to INPH patients lacking
AD pathology [61,67,68,70-72]. More studies are needed
to clarify and confirm these relationships.
In summary, brain biopsies open a novel window to
the study of the pathobiology of INPH and its relation to
other neurodegenerative diseases like AD. Brain biopsy
is associated with a small risk of adverse events such as
infection, bleeding or epilepsy. As such, it should only
be performed in research protocols approved by an
ethical review board.
In AD, there is an accumulation of amyloid (A) in
the brain that can be reflected in alterations of the
amyloid content of ventricular CSF. CSF from INPH patients
is accessible via lumbar puncture or through a puncture
of the lateral ventricle. CSF biomarkers that can be used
in support of an AD diagnosis include total tau protein
(T-tau), hyperphosphorylated tau protein (P-tau) and
beta-amyloid protein (142) (A42). A typical AD
pattern consists of a decreased A42 and an increased
Tand P-tau  in the CSF. Limitations are the lack of
uniform reference values and the fact that T- tau is
increased in several brain disorders . Recently,
standards for biomarker collection for AD studies were
published that may also be applicable to future studies
of CSF biomarkers in INPH .
In two studies comparing CSF biomarkers in INPH
versus healthy controls, A42 concentrations were
reduced but T- and P-tau were normal in INPH subjects
. In direct comparison between INPH and AD, A42
was reduced in INPH but had varying results regarding
tau protein [76-78]. Increased  or normal [76,78] tau
levels were found in INPH. A positive correlation
between tau protein and the severity of dementia in INPH
has been reported . It has not been possible to use
CSF biomarkers to predict response to shunt surgery .
A major problem with these studies is that the number of
clinically diagnosed INPH-AD is unknown or not
mentioned, making comparison between studies difficult.
In a large study consisting of 182 patients with
presumed NPH, findings at brain biopsy correlated with the
concentration of A42 and tau in the CSF .
However, more studies are needed before it is possible to
make general recommendation on the use of CSF
biomarkers in the clinic to identify mixed cases of
INPHAD . The distinctive alterations in ventricular size
[83,84] and CSF dynamics associated with INPH have
been shown to alter the concentration gradients of
monoamine metabolites in CSF of hydrocephalus
patients [85,86] and could alter the concentrations of other
CSF biomarkers in unpredictable ways.
1. INPH and AD can co-exist. The frequency of
clinical manifest INPH-AD is unknown, but it may
be common. Patients with suspected INPH and
cognitive impairment should therefore be routinely
evaluated for possible AD by a clinician skilled
in the diagnosis of neurodegenerative disorders
2. Patients presenting with an isolated dementia
syndrome rarely have INPH. Those patients with a
gait disturbance in the absence of cognitive decline
rarely have AD. Better techniques are needed to
identify INPH-AD patients and to determine the
degree to which neurodegenerative changes versus
hydrocephalus-related pathology contributes to
disability in individual cases.
3. CSF and neuroradiological biomarkers for AD have
excellent potential as supplemental diagnostic,
prognostic and therapeutic indicators in the
assessment of INPH patients. However, further
studies are needed to better define sensitive and
specific imaging parameters and biomarker
alterations that are characteristic of INPH.
4. Small cortical brain biopsies are a promising
investigation tool in INPH research, particularly for
identifying mixed INPH-AD. The clinical value of
biopsies has to be validated and for now brain
biopsies should only be performed in the context of
research studies (Class IIb).
5. Patients with INPH-AD can improve following
shunt surgery. However, outcomes (particularly
cognitive) may be less satisfactory than in typical
Gait disturbances are a cardinal feature of INPH and
several neurodegenerative disorders. Disorders that can
pose challenges to the differential diagnosis of INPH
include Parkinsons disease (PD) and Parkinsonian
syndromes including dementia with Lewy bodies (DLB),
corticobasal syndrome (CBS), progressive supranuclear
palsy (PSP), multiple system atrophy (MSA) and a subset
of patients with frontotemporal dementia (FTD). These
neurodegenerative diseases tend to increase in incidence
with age, as does INPH. The size of the cerebral
ventricles also increase with age. Because of these overlapping
features it is not uncommon for persons with idiopathic
PD or secondary Parkinsonism to be suspected of having
hydrocephalus. This section will address each diseases and
ways of diagnosing the neurodegenerative comorbidities
in patients with suspected INPH.
Parkinsons disease The major triad of PD is tremor,
rigidity and akinesia. The best features for differentiating
PD from other Parkinsonian diseases is a careful history
and clinical evaluation revealing asymmetry of symptoms
and signs, resting tremor and response to levodopa .
Specifically, the evaluation should look for Parkinsonian
features affecting the face and arms more than or as much
as the legs, or are asymmetrical, or accompanied by
tremor or vertical eye movement abnormality, or in a
patient with disinhibited behavior. In INPH, lower body
Parkinsonism is characteristic.
Dementia with lewy bodies The published diagnostic
guidelines for DLB [88,89] include progressive dementia,
Parkinsonism, hallucinations, fluctuations in attention
and arousal, rapid eye movement (REM) sleep disorder,
neuroleptic sensitivity and low dopamine transporter
activity on SPECT or PET scan. While INPH patients have
gait difficulty and dementia, Parkinsonism affecting upper
body, visual hallucinations and REM sleep disorder will
help distinguish DLB from INPH.
Corticobasal syndrome Features of CBS include
asymmetrical apraxia, alien limb, cortical sensory loss,
asymmetric myoclonus, apraxia of speech and non-fluent
aphasia . Because patients with this syndrome may
have striatal involvement the ventricles may appear large
and the patients may have Parkinsonism but the
asymmetry of the cortical symptoms usually distinguishes this
syndrome from INPH.
Progressive supranuclear palsy Patients with PSP 
have voluntary vertical gaze impairment, axial rigidity,
early falls, difficulty swallowing, speech impairment. In
the early stages movement disorder specialists may have
difficulty distinguishing PSP from PD but over time the
diagnosis becomes more obvious. It is important to
evaluate eye movements in possible INPH patients.
Further, speech and swallowing difficulty are not features of
the early stages of INPH.
Multiple system atrophy MSA can present with a
cerebellar or a Parkinsonian form . The latter is more
common. Autonomic dysfunction such a postural
intolerance, bladder or bowel dysfunction, impotence and
sweating dysfunction are frequently present. As many as
half the patients may suffer REM sleep disorder. The
subset with cerebellar degeneration has ataxia. Other features
include inspiratory stridor and dysarthria. The cerebellar
dysfunction and autonomic features and speech changes
should help distinguish INPH from this disease.
Frontotemporal dementia Patients with FTD are
classified into behavioral variant (bv) , non-fluent
progressive aphasia (nfpa) and semantic dementia (sd) subtypes
. The bvFTD patients have features of behavioral
disinhibition, apathy, loss of empathy, perseveration,
hyperorality and a neuropsychology profile showing
executive dysfunction with relatively preserved memory
and visuospatial dysfunction. The nfpaFTD patients have
progressive impairment in word finding and other
aspects of expressive language. sdFTD patients lose the
meaning of words and other aspects of semantic
knowledge. Because FTD patients frequently have Parkinsonism
and may have caudate atrophy, that makes the frontal
horns of the ventricles appear enlarged, they may be
thought to have a component of INPH. However, language
and behavioral disturbances in INPH are generally milder
and less evidently progressive than in FTD, and these
differences can be useful in distinguishing among these
Psychiatric and behavioral disorders
Cognitive symptoms and neuropsychological dysfunction
are common in patients with INPH. Disturbances in
executive and memory function usually dominate and
impaired wakefulness may be present, but a range of other
less typical symptoms have been reported, such as
anxiety, emotional instability and motivational blunting,
depression, impatience and psychosis [24,41,95-100], some
of which have been shown to improve after shunting.
However, little is known about the frequency of
psychiatric symptoms in INPH or the frequency of co-existing
psychiatric or behavioral disorder. Using
neuropsychological testing, INPH patients can be distinguished from
healthy individuals . No such testing is available for
differentiating between INPH and psychiatric or behavioral
disorders and there are no biomarkers available. As a
consequence, it may be difficult to differentiate between
psychiatric features of INPH and symptoms caused by other
psychiatric disorders. A premorbid history of psychiatric
illness such as depression or psychosis may be helpful.
In the work-up of patients, it is essential to search for
and evaluate the typical cognitive symptoms of the
INPH disorder using neuropsychological testing as well
as assessing the typical motor and urinary symptoms. If
a psychiatric or behavioral disorder is suspected, the
patient should usually be referred to a psychiatrist. A
psychiatric disorder should primarily be suspected in
patients presenting with psychosis. Depression with mental
slowness, apathy or anxiety may mimic hydrocephalic
symptoms and underlying depression is important to
rule out or treat. Patients with suspicion of INPH
presenting with major depressive symptoms should
therefore be carefully evaluated using an appropriate
evaluation instrument and given a trial of antidepressant
medication for a period of time before the final decision
to perform shunt surgery is taken. This approach is
taken to rule out depressive symptoms mimicking INPH
and to allow proper assessment of cognitive symptoms
and improvement after shunting. At the same time,
depression, anxiety, psychosis and other behavioral
symptoms may be masked by apathy and cognitive deficits
caused by INPH and such symptoms may therefore be
aggravated after successful shunting. Doses of
antidepressant and other psychoactive medications should
be monitored closely in INPH patients and adjusted
appropriately after shunt surgery.
1. Very little is known about frequency of depression
and other psychiatric and behavioural disorders in
INPH but a wide range of symptoms have been
described in these patients. Population based
casecontrol and cohort studies are needed as well
as studies of biomarkers and neuropsychological
2. In the clinical work-up, effort should be put on
identifying and measuring cognitive and
neuropsychological dysfunction characteristic of
INPH (Class I).
3. A comorbidity of psychiatric or behavioural disorder
should not exclude a patient from shunt surgery but
objective and balanced information of expected
effect of shunting is essential (Class IIa). Depression,
anxiety or psychosis in INPH are optimally treated
before surgery (Class I).
4. A primary depressive disorder should be ruled out in
suspected INPH patients presenting with major
depression symptoms. Severity of depression should
usually be assessed using a depression rating scale
and patients should be treated with antidepressant
drugs before a probable diagnosis of INPH can be
made (Class IIa).
Brain imaging Structural brain imaging by computed
tomography (CT) and magnetic resonance imaging
(MRI) is essential for screening and clinical diagnosis of
INPH. CT is convenient, fast and inexpensive, and very
well suited to reveal ventriculomegaly. However, MRI
has become the first choice in the preoperative
investigation of INPH as it is essential for the differential
diagnosis of disorders, such as BD or AD. While an enlarged
ventricular system is a prerequisite, certain imaging signs
favour INPH, however none have proved sensitive
enough, including flattening of the cortical sulci,
widened temporal horns, an enlarged third ventricle, callosal
angle 90 degrees and an increased aqueductal flow.
Although ventricular dilatation is a hallmark of
hydrocephalus, it is also a sign of cortical atrophy. A primary
aim is to differentiate between ventricular dilatation
caused by a CSF dynamic disturbance and dilatation
caused by a primary cerebral atrophy, which can be
difficult, especially in mixed cases. Coronal sections are
particularly useful in evaluating the high cerebral convexity
and medial temporal lobe including the hippocampus. It
has been observed that in patients with INPH, the
subarachnoid space in the Sylvian fissures is dilated (or at
least not narrowed) while at the same time those over
the high cerebral convexity and medial surface are
narrowed . This disproportionately enlarged
subarachnoid space hydrocephalus (DESH)  has been
reported to differentiate INPH from brain atrophy in
Alzheimers disease, results that need to be confirmed.
In addition, hippocampal atrophy  and widening of
the parahippocampal sulci  are usually milder in
INPH compared with AD. Importantly, there are INPH
patients displaying a few large convexity sulci (focally
dilated, entrapped or transport sulci) [103,104]
which should not be mistaken for cortical atrophy.
Moreover, population-based studies indicate that some
of the elderly present with MRI features consistent with
DESH without any neurological symptoms .
In frontotemporal dementia (FTD), the frontal cortical
atrophy is typically marked, which together with reduced
frontotemporal cerebral blood flow and metabolism
makes it possible to differentiate FTD from INPH.
Periventricular and deep white matter changes (leukoariosis)
are seen more often and more severely in patients with
INPH than in healthy elderly individuals; however, they
are not requisite signs for INPH and rather suggest
comorbid chronic cerebral ischemia .
Periventricular and deep white matter changes are
discussed in section 2.3.4. New imaging techniques
represent a promising development, such as diffusion or
perfusion weighted MR imaging, MR spectroscopy or cerebral
blood flow or metabolism measurement. These techniques
may be used to characterise pathophysiologically different
types of white matter changes but have so far not proven
able to reliably identify reversible changes typical for
INPH or to predict outcome after shunting [107-109].
More studies using contemporary techniques are needed
where inclusion of patients with vascular changes must be
Cerebral microbleeds are probably a marker of cerebral
microangiopathy . The microbleeds are best
visualized on T2* gradient echo or susceptibility-weighted MR
imaging and are reported in patients with vascular
dementia but also in healthy elderly. Cerebral microbleeds may
play a role in the pathophysiology of INPH and CVD but
have so far not been studied in patients with INPH.
1. MRI of the brain is essential for the evaluation of
comorbidity in INPH (Class I). For patients who
cannot have an MRI, CT scanning with axial, sagittal
and coronal views is recommended.
2. Coronal MRI is useful for the evaluation of the
morphological changes of the brain characteristic of
INPH and other degenerative dementias. The sign of
tight high-convexity and midline subarachnoid
spaces (i.e., DESH) can be helpful in differentiating
INPH from brain atrophy in AD. Hippocampal
atrophy and widening of the parahippocampal sulci
are suggestive of comorbid AD.
3. The role of white matter hyperintensities in INPH is unclear. Patients with extensive white matter lesions may improve following surgery, but the relation
Table 1 Investigations that may be performed to verify
comorbidity in INPH
MRI brain (T1, T2, FLAIR, T2*,
Lumbar or cervical spinal stenosis?
Atrophy? White matter lesions?
Brain volumes? Cerebral blood flow?
X-ray or MRI of hip or knee
Type of urinary problems?
Burden of cerebrovascular
disease risk factors?
Alzheimers disease. Only in research and
if approved by internal review board
Dementia with Lewy bodies?
Quantification of co-morbidity
Malm et al. Fluids and Barriers of the CNS 2013, 10:22
between its severity and the magnitude of shunt
effect is unclear.
4. Cerebral microbleeds have not been studied in INPH.
How to investigate and quantify comorbidity
The overall type and degree of comorbidity in INPH
should always be assessed. A comorbidity index created
only for INPH would probably have advantages. Such a
scale consisting of vascular risk factors, peripheral
vascular disease, cerebrovascular disease, heart disease etc.
has been suggested . However, it has not been
validated and is not yet established. While waiting for a
dedicated INPH index, a universal scale could be helpful in
clinic and research. Two of the most promising
comorbidity scales that have been validated in the elderly are the
Modified Cumulative illness rating scale (CIRS-G) 
and the Charlson comorbidity index (CMI) [113-118].
These scales have not been created specifically for INPH,
meaning that diseases are weighed and scored irrespective
of the impact the individual disease has on the prognosis
of INPH. However, they probably represent the best index
to be used until a dedicated INPH scale has been accepted
by the hydrocephalus community.
A cornerstone in the work-up of INPH patients is a
detailed history and a thorough physical examination of
clinical symptoms. By performing a careful examination,
clinical symptoms typical for important potential
comorbidities will usually be discovered, such as Parkinsons
disease and related disorders, Alzheimers or other
dementia types, or other neurologic or musculoskeletal disorders.
Several auxiliary investigation methods are at hand for
differential diagnostics and for quantification of co-morbidity
in the single patient, the most important being displayed
in Table 1.
Comorbidity is an important factor in the prognosis and
post-operative outcome of shunt surgery for INPH.
Differences between INPH cohorts sampled at different
hydrocephalus centers may be partly explained by
variations in comorbidity across those centers. Identification
of comorbidities should thus be a central part of the
clinical management of INPH where a detailed history,
physical examination, and targeted investigations are the
basis for diagnosis and grading. Future INPH research
should focus on the contribution of comorbidity to
overall morbidity, mortality and long-term outcome.
Investigators should also consider broader inclusion criteria
in order to include rather than exclude patients with
comorbidities so results can be more reliably
extrapolated to the general population. We hope that this
review will inspire investigators to create new hypotheses
that will improve our understanding of comorbidity in
JM has a patent interest in Likvor AB but no ownership, board function or
funding. NG-R is on the Scientific Advisory Board and is consultant for
Codman. MI, BTK, VL, EM, BO, MT and NR have no competing interests. MW
is the associate editor for Ethics for Continuum, and president of the
International Society for Hydrocephalus and CSF Disorders 20122014. He
holds the following patents relating to shunt surgery: United States Patent
6,585,677, Canadian Patent 2,356,032, United States Patent 6,932,787 B2,
Continuation of US Patent 6,585,677, International Patent WO 2006/060181
A1. He receives research support relating to hydrocephalus and shunt
obstruction from NeuroDx Development, Trevose, PA (NCT01323764), from
National Space Biomedical Research Institute, Project Numbers SMST02802
and CA02801 and has 5% interest in Mensana Therapeutics.
Authors contributed equally in the process of creating recommendations
and the manuscript. All authors read and approved the final manuscript.
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