The Differential Diagnosis and Treatment of Normal-Pressure Hydrocephalus N SUMMARY

Transcription

MEDICINE
CONTINUING MEDICAL EDUCATION
The Differential Diagnosis and Treatment
of Normal-Pressure Hydrocephalus
Michael Kiefer, Andreas Unterberg
SUMMARY
Background: Normal-pressure hydrocephalus (NPH) arises
in adulthood and is characterized by a typical combination
of clinical and radiological findings. The mean basal intracranial pressure is normal or mildly elevated. The typical
signs of the disease are gait impairment, urinary incontinence, and dementia. The difficulty of distinguishing NPH
from other neurodegenerative disorders is the likely reason why some 80% of cases remain unrecognized and
untreated. According to current evidence, the spontaneous
course of NPH ends, for the vast majority of patients, in
dependence on nursing care.
Methods: This review article is based on relevant publications retrieved by a selective search in Medline and on
national and international guidelines for the management
of NPH.
Results: Studies with a high evidence level are lacking;
thus, the current state of knowledge about NPH is derived
from studies of low or intermediate evidence levels, e.g.,
observational studies. Modern forms of treatment lead to
clinical improvement in 70% to 90% of treated patients.
The treatment of choice is the implantation of a ventriculoperitoneal shunt. The differential diagnosis is complicated
by the fact that three-quarters of patients with NPH severe
enough to require treatment also suffer from another neurodegenerative disorder. Therefore, the clinical findings
and imaging studies often do not suffice to establish the
indication for surgery. To do this, a further, semi-invasive
diagnostic procedure is recommended. Current risk/benefit analyses indicate that shunt operations improve outcome compared to the spontaneous course of the disease.
Conclusion: Normal pressure hydrocephalus should always
enter into the differential diagnosis of patients who present
with its characteristic manifestations. If the diagnosis of
NPH is confirmed, it should be treated at an early stage.
ormal-pressure hydrocephalus (NPH) was the
first treatable type of dementia ever described
and attracted much interest as soon as it became
known.
S. Hakim described the entity he called normalpressure hydrocephalus in 1963 (e1, e2). In the ensuing
years, an initially uncritical enthusiasm for cerebrospinal fluid (CSF) shunting was gradually dampened because of the underdeveloped shunt technology then
available, low clinical success rates, and frequent complications.
In the meantime, however, improved diagnostic and
therapeutic methods have raised clinical success rates
into the range of 70% to 90% (e3–e6), and risk-benefit
analyses have shown beyond any doubt that surgery for
NPH is far better than conservative treatment or the
natural course (e7). This statement applies particularly
to the idiopathic form of the entity (iNPH). Without
surgery, the clinical state of patients with untreated
iNPH generally worsens within a few months (e8), and
their life expectancy is lower than if they were operated
on (e7).
These facts make it all the more difficult to understand why, even today, only 10% to 20% of patients
with NPH get the appropriate specialized treatment
(e9–e11). We present an overview of the current state of
the diagnosis and treatment of NPH.
N
Methods
This article is based on a selective review of the literature, including current guidelines from Germany and
abroad (1–3), carefully selected review articles
published since 2001, and original articles retrieved by
a PubMed search. Levels of evidence were classified
by the scheme used in international guidelines (e12).
►Cite this as:
Kiefer M, Unterberg A: The differential diagnosis
and treatment of normal-pressure hydrocephalus.
Dtsch Arztebl Int 2012; 109(1–2): 15–26.
DOI: 10.3238/arztebl.2012.0015
Normal-pressure hydrocephalus
With modern diagnostic and therapeutic
techniques, the rate of clinical improvement
ranges from 70% to 90 %.
Klinik für Neurochirurgie des Universitätsklinikums des Saarlandes:
Prof. Dr. med. Kiefer
Neurochirurgische Klinik der Universität Heidelberg:
Prof. Dr. med. Unterberg
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2012; 109(1–2): 15–26
15
MEDICINE
There are no original publications providing level 1
evidence for the treatment of NPH. Therefore, this discussion is based on evidence of levels 2 and 3.
FIGURE 1
Alzheimer’s
disease?
Learning aims
Accumulation of
toxic proteins?
Reduced CSF turnover
Cerebral
hypoperfusion
Hydrocephalus
Autocompression
of brain tissue, mainly in
periventricular areas
Physical and anatomical
differences between
inner and outer brain
surfaces
Increased brain pulsation
Windkessel effect
of basal cerebral arteries
Cerebrovascular
disease
Reduced craniospinal
compliance
A current pathophysiological model of normal-pressure
hydrocephalus
According to the model, NPH results from low craniospinal compliance (intracranial reserve capacity) or low vascular compliance in
the vessels of the circle of Willis. The model further postulates that
the same causes can lessen cerebral blood flow and might also lead
to Alzheimer’s disease. It would thus account for the frequent simultaneous occurrence of NPH, Alzheimer’s disease, and cerebral hypoperfusion.
Definition
Normal-pressure hydrocephalus is characterized
by a combination of clinical and radiological findings arising in adulthood.
16
After reading this article, the reader should be able to
● know the typical clinical and radiological features
of normal-pressure hydrocephalus and how they
differ from those of other diseases in its differential diagnosis,
● know the current standards for the diagnosis and
treatment of NPH, and
● know that the mean clinical success rate of shunting is about 80%, and that treatment of NPH is indicated even in patients simultaneously suffering
from other conditions of a neurodegenerative
type.
Definition
Normal-pressure hydrocephalus is characterized by a
combination of clinical and radiological findings
arising in adulthood. The mean basal intracranial
pressure (ICP) is normal or only mildly elevated (upper
limit of normal in the supine adult: 15 mm Hg) (1,
e13–e17).
The cardinal symptoms of NPH are gait impairment,
dementia, and urinary incontinence. Imaging studies of
the brain reveal ventriculomegaly without any marked
degree of cortical atrophy (e15, e17, e18). In the
absence of a generally accepted classification (e19),
designations such as “communicating” or “malresorptive” hydrocephalus should be avoided, as these imply
pathophysiological mechanisms whose role in NPH is
not yet fully clear (e17, e18, e20).
Primary (idiopathic) normal-pressure hydrocephalus
(iNPH) is distinguished from secondary normalpressure hydrocephalus (sNPH) (e21), whose common
causes are subarachnoid hemorrhage (23%), meningitis
(4.5%), and traumatic brain injury (12.5%) (2). A common feature of iNPH and sNPH is that neither involves
any obstruction to the flow of CSF within the ventricular system of the brain (e17, e22).
The basal ICP must be initially elevated, at
least some of the time, for either iNPH or sNPH to
develop (e17, e23). The two entities carry a similar
prognosis (e6, e17, e24, e25). The only major clinical
difference between them is that sNPH affects
persons of all ages, while iNPH is a disease of the
elderly (e20).
Two types of NPH
Primary (idiopathic) normal-pressure hydrocephalus (iNPH) is distinguished from secondary
normal-pressure hydrocephalus (sNPH).
MEDICINE
The following discussion applies to NPH of either
type, unless it is explicitly stated that what is said
applies only to iNPH.
Epidemiology
In Germany today, one person in 80 is demented
(e26–e29). About 250 000 persons receive a new diagnosis of dementia in Germany each year (4).
Normal-pressure hydrocephalus is thought to account for about 6% of all cases of dementia (e11, e20,
e30, e31). A study of demented patients in nursing
homes revealed that 9% to 14% of them had findings
typical of NPH (e10).
The available epidemiological data are inconsistent,
partly because of the lack of uniform diagnostic criteria. The incidence of NPH is estimated at anywhere
from 0.2 to 5.5 new cases per 100 000 persons per year
(e9, e32) (5–7). Its prevalence is reported to be 0.003%
in persons under 65, and 0.2% to 2.9% for persons aged
65 or older (e9, e33, e34) (5–7). The prevalence of
NPH, like that of the neurodegenerative conditions,
rises markedly with age.
The differential diagnosis is complicated by the fact
that 75% of patients with iNPH also have cerebrovascular dementia or Alzheimer’s disease. Studies have
shown that 40% to 75% of patients with iNPH have
beta-amyloid or other typical histological findings of
Alzheimer’s disease, while 60% have signs of a cerebrovascular disease that could produce similar clinical
findings to those of iNPH (e18, e35, e36) (8). In such
patients, CSF shunting mainly improves gait, while
cognitive improvement is less common (9, e18).
Pathophysiology
Various pathophysiological models of NPH have been
proposed in the decades since its description. There is a
consensus that the imbalance of CSF production and resorption in NPH is not due to overproduction, and that
the resistance to CSF outflow (Rout) is often elevated
(e37, e38). Particularly in the early phase of the disease,
the intracranial reserve capacity appears to be low, as
reflected by such measures as the craniospinal compliance or the pressure-volume index (PVI). It remains
unclear, however, whether changes in compliance or
Rout are contributory causes or simply epiphenomena of
the condition. The frequent combination of NPH with
cerebrovascular disease and Alzheimer’s disease makes
it attractive to consider models in which these three entities are causally related (Figure 1) (1, 10); for
Pathophysiological models
The frequent combination of NPH with cerebrovascular disease and Alzheimer’s disease makes
it attractive to consider models in which these
three entities are causally related.
TABLE 1
Characteristics of gait impairment in NPH*1
Feature examined
Clinical finding
Step frequency in 10 m gait test
Number of steps >13; duration >10 sec.
Step breadth
Distance between toes >1 foot length
Step length
Distance from heel of front foot to toes of rear
foot <1 foot length
En bloc 360° turn
>4 to 6 steps
Bipedal gait
Correction of foot position in >25% of steps
*1
modified from (e17)
example, in one model, all three are caused by a loss of
the Windkessel effect in the skull base arteries. This
loss of elasticity may be either primary (e.g., due to
atherosclerosis) or secondary, a consequence of low
craniospinal compliance impeding the expansion of the
arteries at the skull base. The result in either case is that
higher compressive stress and greater shearing forces
develop in the brain parenchyma (11, 12). Tissue
damage and loss ensue mainly in the periventricular
areas because of the physical and physiological differences between superficial and deep (periventricular)
brain tissue (11, 12). This focal brain damage manifests
itself as ventriculomegaly without any need to model a
static pressure gradient from the inner to the outer CSF
spaces. A further consequence of loss of the Windkessel
effect is a lowering of cerebral blood flow, which explains the common simultaneous occurrence of iNPH
and cerebral hypoperfusion; the latter, in turn, lowers
CSF turnover. It has been hypothesized, but not yet
shown, that low CSF turnover impairs the clearance of
toxic metabolites and thereby contributes to the pathogenesis of Alzheimer’s disease.
Diagnosis and differential diagnosis
Clinical features
The clinical manifestations of NPH vary markedly; the
rapidity and extent of the deterioration differ from one
patient to another (e20). Impairments of gait and
balance are typically the first symptoms to be noticed
and may be very mild at the outset (e18). In the past,
NPH was only diagnosed and treated when all three
cardinal symptoms (the so-called “Hakim triad”) were
demonstrably present (e17); the current recommendation,
Clinical features
Impairments of gait and balance are typically the
first symptoms to be noticed and may be very
mild at the outset.
17
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TABLE 2
Differential-diagnostic criteria:
Similarities and differences of NPH and other neurodegenerative disorders
Disease
Common features with NPH Features that are atypical of NPH
Cortical dementias
Alzheimer’s
disease
dementia without gait
impairment is very rare
Frontotemporal
dementia
No gait disturbance until dementia is
at least moderately severe; focal
cortical deficits
Personality change, psychiatric
abnormalities: disinhibition, impulsiveness, irritability, emotional lability;
aphasia; no motor disturbance;
incontinence very rare
Subcortical dementias
Lewy-body
dementia
Gait impairment
and dementia
Parkinson’s
disease and
vascular
parkinsonism
Hypokinetic gait, tremor
(40%) in NPH
Progressive
supranuclear
palsy
Frontal brain signs,
impaired executive function,
gait disturbance
Visual hallucinations, delusions,
markedly fluctuating cognitive
function
Rest tremor, unilateral onset; speed
of movement can be increased with
the aid of external stimuli (this is not
(unilateral symptoms in NPH the case in NPH).
always indicate some type of The patient cannot simulate walking
comorbidity [e.g., cerebroand bicycle-riding while supine; no
vascular disease, Alzheimer’s broad-based gait with externally
disease])
rotated feet; mildly reduced step
height, markedly reduced arm swing,
markedly stooped posture,
autonomic dysfunction
Corticobasal
degeneration
Pseudobulbar palsy,
supranuclear upward gaze paresis
Rigor, asymmetrical symptoms, alienlimb phenomenon, apraxia, supranuclear upward gaze paresis, cortical
sensory deficits, severe loss of
postural control
AIDSdementia
complex
Psychomotor slowing,
impairment of memory and
concentration, gait impairment due to HIV myelopathy
Positive HIV serology
Age-related
depression
Pseudodementia, neuropsychological test findings very
similar to those seen in NPH
Depressive thought content because
of frequently comorbid vascular
dementia, sometimes other features
as well
Mixed dementias
Vascular
dementia
Thought disorder, impaired
executive function
Asymmetrical (sometimes transient)
symptoms, possibly correlated with
lesions seen in imaging studies
however, is that NPH can be diagnosed and treated in
the presence of only two cardinal symptoms (1–3), or
even just one (e17, e18). This change in attitude
resulted from the recognition that the prognosis
worsens the longer NPH remains untreated (e39), with
the complete Hakim triad always representing an
advanced stage of the disease (e17). At present, 60%
of NPH patients are demented at the time of shunting,
and 50% are incontinent (e18).
Gait impairment
Impairments of gait and balance are the most common
and, usually, the earliest symptoms of iNPH. They are
also the most likely to improve after CSF shunting,
with a probability of more than 85% (e15–e18).
Patients may initially complain of dizziness, difficulty
walking on a slope or stairs, and difficulty getting up
from or sitting down on a chair.
As the disease progresses, the patient’s gait deteriorates markedly, becoming broad-based, slow,
short-stepped, and glue-footed (a gait disturbance of
the abasia-astasia type) (2) (Table 1). Typical features
of gait in NPH, of major importance for the differential diagnosis, are the following:
● Externally rotated posture of the feet
● Particular difficulty turning on the body’s long
axis
● Absence of apraxia.
In the late stage of NPH, the motor deficit is often
worsened by the concomitant cognitive deficits, perhaps so severely that the patient is unable to walk at all.
Dysequilibrium in NPH is typically worse with the
eyes closed, but patients need to stand on a broad base
even when their eyes are open. The upper body is
usually mildly stooped, but retropulsion can also be
seen, either spontaneously or on provocation. Motor
abnormalities in the upper limbs are mild or absent and
generally restricted to bradykinesia.
Cognitive deficits/dementia
The cognitive deficits of iNPH are mainly due to subcortical frontal dysfunction. They affect executive
functions first; thus, even early in the course of the
disease, patients may have difficulty carrying out their
everyday activities (e16–e18), while specific psychometric tests may still yield normal results. Later on,
further deficits arise, at least two of which must be
present for the diagnosis of a cognitive deficit/dementia to be made (13, e16–e18):
Gait impairment
Patients may initially complain of dizziness, difficulty walking on a
slope or stairs, and difficulty getting up from or sitting down on a
chair.
Differential diagnostic criteria
• Externally rotated posture of the feet
• Difficulty turning on the body’s long axis
• Absence of apraxia
18
Photographs: Neuroradiology Dept., Universitätsklinikum des Saarlandes
MEDICINE
Figure 2: Cranial CT of a patient with normal-pressure hydrocephalus before and after CSF shunting (upper and lower rows, respectively).
Yellow arrows:There is hardly any change of ventricular size after shunting. The change may be very small or not noticeable at all at first glance.
Blue arrows: After shunting, the CSF spaces over the convexity near the vertex are wider; this is the sole reliable sign of adequate CSF drainage through the shunt.
Red arrows: The tip of the ventricular catheter lies in the right frontal horn.
●
●
●
Psychomotor slowing
Impaired attention and concentration
Slowing and reduced precision of fine motor performance
● Short-term memory impairment (new information
can be taken in, but not repeated)
● In the late stage: apathy, reduced drive, indifference, bradyphrenia, reduced speech production
(rarely, akinetic mutism).
Aside from reactive depression (without depressive
thought content) (e16–e18), patients with NPH
generally do not have any psychiatric abnormalities.
Thus, changes of mood, personality, and behavior steer
the differential diagnosis toward a neurodegenerative
disorder of another type. An objective examination
should be performed with the aid of specific psychometric
tests for the assessment of subcortical frontal lobe deficits.
Some suitable tests of this type are (e40, e41):
● the grooved pegboard test
● the Stroop test
● the digit span test
● the trail-making A/B test
● the Rey auditory-verbal learning test
On the other hand, the Mini-Mental Status Test and
the DEMTEC Test are unsuitable, as they were
developed for cortical dementias (13, 14).
Early CSF shunting can still improve the cognitive
deficits in as many as 80% of patients with iNPH, but
improvement is less likely if the patient simultaneously
has vascular or Alzheimer’s dementia.
Most common deficits leading to the diagnosis
of cognitive impairment/dementia:
• Psychomotor slowing
• Impaired attention and concentration
• Fine motor slowing and imprecision
• Short-term memory impairment
Suitable neuropsychological tests:
Grooved pegboard test, Stroop test,
digit span test, trail-making A/B test,
Rey auditory-verbal learning test
19
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Figure 3: Coronal head CT (left) and MRI (right) at the level of the posterior commissure: on the left image, the CSF spaces over the convexity
near the vertex are narrowed (“tight convexity,” red circle), as are the medial cisterns (red circle)—these are typical findings of NPH. On the
right image, however, the CSF spaces over the convexity near the vertex (red arrow) and the medial cisterns (green arrow) are widened, a
finding consistent with brain atrophy. The blue lines in both images indicate the callosal angle: an angle less than 90° is typical of NPH (left
image), while an angle greater than 90° is typical of brain atrophy (right image). The blue arrows indicate periventricular signal alterations.
Their unilateral occurrence (right image) suggests that they are probably due to vascular encephalopathy. The abnormalities seen on the left
image may well represent transependymal CSF diapedesis due to NPH
Incontinence
Disturbances of bladder function in NPH result from
detrusor hyperactivity owing to the partial or total absence of central inhibitory control. Patients initially
suffer from increased urinary frequency (e42–e44);
later developments are urge incontinence and, finally,
permanent urinary incontinence. Fecal incontinence is
rare in NPH (2) and should arouse suspicion of another
type of neurodegenerative disease. If present in a patient with NPH, it implies severe frontal subcortical
dysfunction.
CSF shunting can improve bladder dysfunction in as
many as 80% of iNPH patients if performed early, but
in no more than 50% to 60% if performed in an
advanced stage of the disease (e15, e20, e45).
Differential diagnosis
Many elderly people suffer from combined motor and
cognitive dysfunction (and sometimes from incontinence as well). Moreover, three-quarters of patients
with (i)NPH simultaneously have vascular or
Alzheimer’s dementia. Thus, the differential diagnosis
Incontinence
Disturbances of bladder function in NPH result
from detrusor hyperactivity owing to the partial or
total absence of central inhibitory control.
20
of NPH can be quite difficult. Findings that make the
diagnosis of NPH less likely include the following:
● Intracranial pressure above 25 cm H2O (this rules
out iNPH, by definition)
● Age under 40 (iNPH unlikely)
● Asymmetrical or transient symptoms
● Cortical deficits, e.g., aphasia, apraxia, or paresis
● Progressive dementia without gait disturbance
(even if the ventricles are enlarged)
● Lack of progression of symptoms (a controversial
point, as authors differ on the period of time in
which symptoms should be seen to progress).
The differential diagnosis of gait disturbances
includes peripheral neuropathy, spinal canal stenosis,
disorders of the inner ear, chronic alcoholism, and
deficiencies of vitamin B6 and B12 (2, e17, e18). The
differential diagnosis of cognitive deficits includes
various types of dementing disease (Table 2). It is often
not possible to distinguish NPH from other causes of
subcortical dementia by the clinical and radiological
findings alone, so that further, invasive tests are needed
(e17, e18, e20, e45).
Findings that make NPH less likely:
• Asymmetrical findings
• Cortical deficits, e.g., aphasia, apraxia, paresis
• Progressive dementia without gait disturbance
• Lack of progression of symptoms
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Imaging studies and other noninvasive
diagnostic techniques
Either computerized tomography (CT) or magnetic resonance imaging (MRI) of the brain is necessary—yet,
alone, never sufficient—to establish the diagnosis of
NPH.
Typical findings of NPH include disproportionate
widening of the ventricles in comparison to the cerebral
sulci (inner vs. outer CSF spaces; see Figure 2) (1). A
coronal section at the level of the posterior commissure
reveals a narrow subarachnoid space surrounding the
outer surface of the brain (a “tight convexity”) and narrow medial cisterns (Figures 3 and 4) (e46–e48). The
third ventricle is usually enlarged as well, while the
fourth ventricle may or may not be enlarged (eFigure 1)
(11). Thus, a fourth ventricle of normal size in the presence of enlarged lateral and third ventricles need not
indicate aqueductal stenosis and is a finding consistent
with NPH (11). Changes in the signal characteristics of
periventricular tissue must be interpreted with caution
(eFigure 2): subcortical vascular encephalopathy
(SVE) may cause changes quite similar to those seen in
NPH as a result of transependymal CSF diapedesis.
Yet, the presence of SVE still does not rule out concurrent NPH that might improve with treatment (e49–e52).
It would be a serious error in such cases to ascribe all
symptoms to SVE alone, thereby depriving the patient
of the chance of therapeutic benefit from CSF shunting
(e50, e51).
Further imaging modalities to assess cerebral blood
flow and metabolism or of CSF dynamics (PET,
SPECT, scintigraphy, CSF biomarkers, and newer
functional MRI techniques) so far play no role in
routine clinical evaluation (1–3).
Invasive diagnostic testing
The clinical and radiological findings, taken together,
have only limited prognostic value (e12). Particularly
in patients with iNPH, further testing is needed to raise
the prognostic accuracy above 80% (1–3):
● Spinal tap test: lumbar puncture with the removal
of 30 to 70 mL of CSF. This can be repeated on
two or three consecutive days.
● Continuous spinal drainage of 150 to 200 mL of
CSF per day for 2 to 7 days (1–2).
We consider such tests to be positive if the number
of steps taken in a 10 m gait test, and the time needed to
walk 10 m, are reduced by at least 20%, and/or psychometric tests show an improvement of at least 10%.
Imaging studies
Either cranial computerized tomography (CT) or
magnetic resonance imaging (MRI) of the brain is
necessary—yet, alone, never sufficient—to
establish the diagnosis of NPH.
●
Alternatively, certain features of CSF dynamics
(Rout, compliance) can be measured with infusion
tests (Figure 5) (15, 16).
In Germany, unlike the rest of continental Europe,
the United Kingdom, and the United States, the
measurement of CSF dynamics has not yet become established in all centers. It is nonetheless recommended
in the current guidelines of the German Neurological
Society (Deutsche Gesellschaft für Neurologie), just as
it is in the foreign guidelines (1, 2). Risk-benefit
analyses have shown all three techniques to be of
equivalent value (e12); thus, each center should use the
one with which it has the most experience (2). Further
testing with the other techniques is indicated only if the
findings are inconclusive.
Other invasive tests
Long-term ICP measurement for 24 to 72 hours is performed in no more than a few centers. Special pressure
waves and brain pulse amplitudes are measured (16,
e53). Such techniques are not recommended for routine
use, both because their predictive value has not yet
been sufficiently documented and because they require
specialized equipment and expertise (16).
Treatment
No prospective, double blind, randomized, controlled
clinical trials of the treatment of NPH have been performed to date. It is hard to collate the findings of the
available observational studies and draw conclusions
from them, because, even today, the clinical findings
before and after treatment are assessed with a wide
variety of measures, and the potential complications are
not uniformly defined. It is harder still to compare
current results with historical data, because the assessment of clinical outcomes and complications was even
less well-defined in the past. Thus, if we speak of
“clinical improvement” and complications in what
follows, then only while remaining aware of the
heterogeneity of these entities. Nevertheless, despite all
of the difficulties in evaluating the data, the authors’ experience and their overall impression of the literature
point to a marked improvement in clinical outcomes
along with a reduction of complications in the past ten
years. There is certainly no longer any justification for
therapeutic nihilism.
The standard treatment of NPH is the implantation
of a ventriculoperitoneal (VP) shunt. Ventriculo-atrial
(VA) shunts were implanted in the past but have fallen
Invasive diagnostic testing
Particularly in patients with iNPH, invasive testing
is needed to increase the prognostic accuracy to
80% or more.
21
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Figure 4: Typical cranial CT of a patient with iNPH. The CSF spaces near the vertex are narrow (blue arrows); the few wide sulci that are seen on the cerebral convexity (gray arrows)
are all in the vicinity large, superficial arteries. Widening of the insular cisterns (red arrow) is
a good indicator of iNPH that will respond to treatment
out of use, except in rare cases, because of their more
frequent long-term complications (1, 2, 17). In the
English-speaking countries, lumboperitoneal (LP)
shunts are also implanted to treat NPH (1). For the great
majority of patients with NPH, endoscopic third
ventriculostomy (ETV) is not a suitable therapeutic option (18, e54); it is one only for those with a locally
confined, infratentorial, extraventricular obstruction to
CSF flow (e55–e57). Such an obstruction is typically
characterized by a protrusion of the lamina terminalis
and the floor of the third ventricle into the adjacent
basal cisterns (e54), which can be seen on close inspection of the MR images. Carbonic anhydrase inhibitors
Long-term ICP measurement
Long-term ICP measurement is not recommended
for routine use, both because its predictive value
has not yet been sufficiently documented and
because it requires specialized equipment and
expertise.
22
and serial lumbar punctures are not advisable as alternative treatments (e58), except for a limited time in
medically inoperable patients.
The current guidelines favor the use of adjustable
shunt valves in the treatment of iNPH (1–3, 20). The
option of adjusting the valves' opening pressure noninvasively enables fine tuning of the ventricular drainage,
potentially obviating the need for reoperation
(e59–e61). Unlike their earlier counterparts, adjustable
valves of the most recent generation cannot be unintentionally reset when subjected to magnetic fields of up to
3 T (20). It remains to be seen, however, whether they
are as robust as simple differential-pressure valves.
The main advance of the past two decades has been
the introduction of gravity-controlled valves (G
valves). A low valve opening pressure when the patient
is lying down is an important factor in therapeutic
success, particularly in iNPH (21, e37, e38, e63). Such
a low pressure would, however, be associated with a
high risk of overdrainage in a mobile patient if a G
valve were not implanted (21, e37, e38, e64), and this
problem is still not fully solved by the use of an adjustable valve (e64). G valves enable a low valve opening
pressure when the patient is lying down without elevating the risk of overdrainage (e64). Their opening
pressure is mainly controlled by gravity: they present a
lower resistance to CSF flow when horizontal than
when vertical. Thus, when the patient changes position,
the outflow resistance in the valve changes in tandem
with the hydrostatic pressure gradient of CSF. As
shown in the SWASONA study, G valves lower the risk
of overdrainage by 90% without impairing the efficacy
of treatment (e37, e64). They may, therefore, be particularly suitable for use in mobile patients with iNPH.
On the other hand, in bedbound NPH patients, the
hydrostatic CSF pressure gradient hardly ever changes,
and a simple and robust differential-pressure valve may
well be the better choice (e62). Patients with secondary
NPH of known cause and recent onset are also often
well served with a simple differential-pressure valve.
Clinical outcome
It is currently reported that 70% to 90% of patients with
NPH (including iNPH) obtain a lasting clinical benefit
from shunting compared to their preoperative state,
with follow-up intervals ranging from one to seven
years (e59, e61, e64, e66–e69). This is a marked improvement over the therapeutic outcomes seen in the
past (e44, e65).
The standard treatment of NPH
The standard treatment of NPH is the implantation
of a ventriculoperitoneal (VP) shunt.
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Today, one can even see an improvement in all three
domains of the Hakim triad, compared to the patients’
preoperative state, in more than 80% of patients after
seven years of follow-up (e70, e71). In some patients,
however, the initial improvements of cognitive function
and bladder control subside again over the next few
years (e68). This secondary deterioration is presumed
to reflect the progression of concomitant neurodegenerative disease (e6, e65, e72).
FIGURE 5
Clinical suspicion of iNPH
Clinical:
at least 2 of 3
cardinal
symptoms
no
Complications
Modern materials (22, 23) and valve designs (9) have
lowered the rate of shunt-related complications (failure
3%, over/underdrainage or subdural hematoma 3% to
4%, infection <1%); as a result, their overall long-term
prevalence is less than 20% (21, 22, e60, e64, e67,
e73). Thus, the mean complication rates of 35% to 40%
reported in the past (24, e44) have been halved.
Complications unrelated to shunting, such as epileptic
seizures and intracerebral hemorrhage, occurred in 6%
to 14% of patients in the past (19, e44) but are now encountered in less than 5% (e60, e64, e67, e73). It was
pointed out years ago already that shunt complications,
when they occur, only rarely leave lasting damage or
impair the therapeutic outcome (19). There have been
no perioperative deaths at all in the more recent clinical
series (19, e15–e18, e53, e60, e64, e67). Overall, it is
now clear that CSF shunting to treat NPH carries a perioperative severe morbidity of less than 5% and a mortality of less than 1‰; these are safe estimates, assuming that not all of the complications that actually
occurred were captured in the published studies (9).
The most convincing argument in favor of surgery
comes from a risk-benefit analysis performed with the
aid of a Monte Carlo simulation model (e7, e8), which
led to the conclusion that shunt implantation yields far
better results than conservative management (e7).
Follow-up management after shunting
Two to three postoperative follow-up visits are advisable in the first year after shunting (e74), as this is when
complications tend to arise (24). Patients with an uncomplicated course can be followed up thereafter at
longer intervals (1 to 3 years). Patients who have had
shunt failures and infections in the past should be
followed up more often, as they are more likely to have
further complications (e74).
Aside from the physical examinations performed in
routine clinical follow-up, cerebral imaging should be
Local obstruction to CSF flow
Such obstructions are typically characterized by
protrusion of the lamina terminalis and the floor
of the third ventricle into the adjacent basal
cisterns.
yes
Imaging:
typical
appearance
of NPH
yes
no
Tests of
CSF dynamics
Observe
no
Drainage protocol:
1. Lumbar puncture
(ca. 50 mL)
2. Lumbar drainage
(ca. 200 mL/day
over 72 hours)
Improvement*
>20 – 30%
Rout > 13 mm Hg/mL/min
PVI <30 mL
yes
1
yes
Shunt
no
Diagnostic flowchart. If NPH is suspected on clinical and radiological grounds, diagnostic
accuracy can be secured with invasive testing (CSF drainage or measurement of CSF dynamic variables such as compliance and resistance to outflow). Such tests are often needed
for adequate confirmation of the indication for shunting, particularly in patients with iNPH.
*1
In the 10 m gait test, at least 20% improvement; in psychometric tests, at least 10%
improvement.
PVI, pressure-volume index; Rout, resistance to outflow
performed at some point during the first year after
shunting and a few weeks after any resetting of the
opening pressure of adjustable valves. No more
imaging studies need be performed after that, except in
case of clinical worsening or as indicated by the patient’s individual risk profile. Patients with VA shunts
should have regular testing of their C-reactive protein
concentration (17, 25) (particularly in the first year
after surgery) and of their D-dimers for the early detection of subclinical chronic septicemia and/or thromboembolism. D-dimer monitoring obviates the need for
transesophageal echocardiography. There is no need at
all for routine “shunt pumping”: This practice should
be abandoned, as the large positive and negative
Clinical outcome
70% to 90% of patients with iNPH experience
clinical improvement after CSF shunting.
23
MEDICINE
pressure changes that it creates can destroy the shunt
valve or lead to partial aspiration of the choroid plexus
into the ventricular catheter, with occlusion of the latter.
A very important point for postoperative imaging is the
following: In the past, a marked reduction of ventriculomegaly was considered to be a sign of adequate
drainage. After G valves were introduced, it became
clear that such a dramatic narrowing of the ventricles is
unnecessary for therapeutic success (e66) and is, rather,
an expression of (latent) overdrainage (2, 9, 20). When
a G valve is used, the ventricles may become only a
little bit narrower despite therapeutically adequate
drainage. The only reliable sign of adequate drainage in
a CT or MR image is a freer subarachnoid space in the
vicinity of the vertex-near cisterns, compared to the
preoperative image (Figure 2).
Overview and perspective
In the past two decades, innovative valve techniques
have led to marked improvements in CSF shunt
therapy. Coming electronic and mechatronic innovations in shunt technology may bring about further
improvement.
The authors’ research teams are currently working
on an ICP telemetry project (eFigure 4). We have been
performing telemetric shunt checks for the last two
years; in future, they may become part of routine
clinical practice.
Conflict of interest statement
Prof. Unterberg states that he has no conflict of interest.
Prof. Kiefer has received honoraria and/or financial support for consulting activities and for the preparation and scientific direction of continuing education
meetings, as well as reimbursement of travel costs and participation fees for
scientific conferences, with the approval of each of these outside activities by
his main employer (Universitätsklinikum des Saarlandes), from the following
firms: Aesculap AG (Tuttlingen, Germany), a subsidiary of B. Braun AG (Melsungen, Germany); Miethke KG & Co KG (Potsdam, Germany); Raumedic AG
(Helmbrechts, Germany); and Codman AG (Norderstedt, Germany), a subsidiary
of Johnson & Johnson (New Brunswick, USA). He has also purchased a small
number of newly developed products at reduced prices from some of the
above-named companies for a short time only, by agreement between his
main employer and the companies, in order to test these products personally
in his routine clinical work. He has received honoraria, reimbursement of expenses, and some reimbursement of travel fees from Codman AG, Aesculap
AG, and ASKLEPIOS-proresearch (Hamburg) for the performance of investigator-initiated clinical studies, after approval by his main employer.
The University of the Saarland and, indirectly, Prof. Kiefer are the recipients of
a grant in the sum of ca. €490 000 from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF)
for a research project within the framework of the BMBF’s initiative to promote
research in microsystems technology (No. 16SV3745). This research project is
being carried out in collaboration with another academic division of the RWTH
Aachen and two industrial partners (Raumedic AG, RECO Medizintechnik
[Pirna, Germany]), working as a consortium of independent partners.
Manuscript submitted on 14 June 2011, revised version accepted on 18
November 2011.
Translated from the original German by Ethan Taub, M.D.
REFERENCES
1. Relkin N, Marmarou A, Klinge P, Bergsneider M, Black PM: Diagnosing idiopathic normal-pressure hydrocephalus. Neurosurgery 2005;
57: 4–16.
2. Deutsche Gesellschaft für Neurologie: Leitlinie Normaldruckhydrocephalus. www.dgn.org/images/stories/dgn/leitlinien/
LL2008/ll08kap_017.pdf.
3. Ishikawa M, Hashimoto M, Kuwana N, et al.: Guidelines for
management of idiopathic normal pressure hydrocephalus. Neurol
Med Chir (Tokyo) 2008; 48(Suppl): S1–23.
4. Ziegler U, Doblhammer G: Prevalence and incidence of dementia
in Germany—a study based on data from the public sick funds in
2002. Gesundheitswesen 2009; 71: 281–90.
5. Brean A, Fredo HL, Sollid S, Muller T, Sundstrom T, Eide PK:
Five-year incidence of surgery for idiopathic normal pressure hydrocephalus in Norway. Acta Neurol Scand 2009; 120: 314–6.
6. Tanaka N, Yamaguchi S, Ishikawa H, Ishii H, Meguro K: Prevalence
of possible idiopathic normal-pressure hydrocephalus in Japan: the
Osaki-Tajiri project. Neuroepidemiology 2009; 32: 171–5.
7. Krauss JK, Halve B: Normal pressure hydrocephalus: survey
on contemporary diagnostic algorithms and therapeutic decisionmaking in clinical practice. Acta Neurochir 2004; 146: 379–88.
8. Bech-Azeddine R, Hogh P, Juhler M, Gjerris F, Waldemar G: Idiopathic normal-pressure hydrocephalus: clinical comorbidity correlated with cerebral biopsy findings and outcome of cerebrospinal
fluid shunting. J Neurol Neurosurg Psychiatry 2007; 78: 157–61.
9. Kiefer M, Eymann R: Gravitational shunt complications after
a five-year follow-up. Acta Neurochir (Supp) 2010; 106: 107–12.
10. Silverberg GD: Normal pressure hydrocephalus (NPH):
ischaemia, CSF stagnation or both. Brain 2004; 127: 947–8.
11. Greitz D: Radiological assessment of hydrocephalus:
new theories and implications for therapy. Neurosurg Rev 2004;
27: 145–65.
12. Bateman GA: Vascular compliance in normal pressure hydrocephalus.
AJNR Am J Neuroradiol 2000; 21: 1574–85.
13. Hellstrom P, Edsbagge M, Blomsterwall E, et al.: Neuropsychological
effects of shunt treatment in idiopathic normal pressure hydrocephalus. Neurosurgery 2008; 63: 527–35.
14. Vanneste JA: Diagnosis and management of normal-pressure hydrocephalus. J Neurol 2000; 247: 5–14.
15. Kiefer M, Eymann R: Clinical proof of the importance of compliance
for hydrocephalus pathophysiology. Acta Neurochir Suppl 2010;
106: 69–73.
16. Weerakkody RA, Czosnyka M, Schuhmann MU, et al.: Clinical
assessment of cerebrospinal fluid dynamics in hydrocephalus.
Guide to interpretation based on observational study. Acta Neurol
Scand 2011; doi: 10.1111/j.1600–0404.2010.01467.x.
17. Kiefer M, Eymann R: Huge thrombosis as a consequence of VAshunts. Acta Neurochir Suppl 2010; 106: 95–9.
Further management
Two to three postoperative follow-up visits are
advisable in the first year after shunting, as this
is when complications tend to arise. Patients
with an uncomplicated course can be followed
up thereafter at longer intervals (1 to 3 years).
24
18. Cage TA, Auguste KI, Wrensch M, Wu YW, Gupta N: Self-reported functional outcome after surgical intervention in patients with idiopathic
normal pressure hydrocephalus. J Clin Neurosci 2011; 18: 649–54.
19. Bergsneider M, Black PM, Klinge P, Marmarou A, Relkin N: Surgical
management of idiopathic normal-pressure hydrocephalus.
Neurosurgery 2005; 57: 29–39.
20. Lavinio A, Harding S, Van Der Boogaard F, et al.: Magnetic field interactions in adjustable hydrocephalus shunts. J Neurosurg Pediatr
2008; 2: 222–8.
MEDICINE
21. Meier U, Kiefer M, Neumann U, Lemcke J: On the optimal opening
pressure of hydrostatic valves in cases of idiopathic normal-pressure
hydrocephalus: a prospective randomized study with 123 patients.
Acta Neurochir Suppl 2006; 96: 358–63.
22. Eymann R, Chehab S, Strowitzki M, Steudel WI, Kiefer M: Clinical
and economic consequences of antibiotic-impregnated cerebrospinal fluid shunt catheters. J Neurosurg Pediatr 2008; 1: 444–50.
23. Richards HK, Seeley HM, Pickard JD: Efficacy of antibiotic-impregnated shunt catheters in reducing shunt infection: data from the
United Kingdom Shunt Registry. J Neurosurg Pediatr 2009; 4:
389–93.
24. Drake JM, Sainte-Rose C: The shunt book. Cambridge (Mass, USA)
Blackwell Science; 1995.
25. Schuhmann MU, Ostrowski KR, Draper EJ, et al.: The value of
C-reactive protein in the management of shunt infections. J
Neurosurg 2005; 103: 223–30.
Corresponding author
Prof. Dr. med. Michael Kiefer
Klinik für Neurochirurgie
Universitätsklinikum des Saarlandes
Kirrberger Str.
66421 Homburg, Germany
@
For eReferences please refer to:
www.aerzteblatt-international.de/ref0112
eFigures:
www.aerzteblatt-international.de/12m0015
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MEDICINE
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Only one answer is possible per question. Please select the answer that is most appropriate.
Question 1
Question 6
What are the cardinal symptoms of idiopathic normalpressure hydrocephalus (iNPH)?
a) Apathy, tremor, and rigidity
b) Reduced muscle tone, urinary and fecal retention, and
dementia
c) Gait impairment, incontinence, and dementia
d) Gait impairment, tremor, and akinesia
e) Difficulty initiating gait, affect incontinence, organic brain
syndrome
According to epidemiological studies, how common is iNPH?
a) In the elderly, its incidence is 6%, and its prevalence has been
estimated with figures ranging from 12% to 18%.
b) It accounts for about 6% of all cases of dementia, and its prevalence among the elderly has been estimated with figures ranging
from 0.2% to 2.9%.
c) Its incidence is 0.3% and its prevalence is 0.8% (average figures
for all age groups).
d) Its prevalence among the elderly is about 6%.
e) Its prevalence among persons under age 65 is between 0.2%
and 2.9%.
Question 2
What changes on imaging studies (computerized tomography [CT], magnetic resonance imaging [MRI]) are
the most characteristic of normal-pressure hydrocephalus (NPH)?
a) Disproportional width of inner and outer CSF spaces
b) Marked atrophy of the frontal lobes
c) Lack of periventricular signal changes or hypodensities
d) Enlargement of both inner and outer CSF spaces
e) Enlargement of inner CSF spaces, narrowing of outer CSF
spaces on the skull base solely
Question 7
What is the standard treatment of NPH?
a) Ventriculoperitoneal shunting
b) Diuretics
c) Endoscopic third ventriculostomy
d) Serial lumbar punctures
e) Lumboperitoneal shunting
Question 3
Question 8
What constellation of changes in imaging studies (CT,
MRI) definitively establishes the diagnosis of NPH?
a) Narrow cisterns near the vertex and a callosal angle <90°
b) Enlarged insular cisterns and inner CSF spaces
c) Enlarged insular cisterns and narrow cisterns near the
vertex
d) A callosal angle <90° and enlarged inner CSF spaces
e) There is no such constellation of changes
What was the conclusion of risk-benefit analysis of the treatment of NPH that employed a Monte Carlo simulation model?
a) Shunting is markedly superior to conservative management.
b) Drug treatment markedly lowers basal intracranial pressure (ICP)
and improves the quality of life.
c) Shunting lowers the quality of life.
d) There has been an increase in perioperative mortality.
e) The overdrainage rate has gone down by about 20%.
Question 4
What ancillary tests are often needed to confirm the
indication for CSF shunting, especially in patients with
iNPH?
a) An infusion test or a scintigraphic study of the CSF spaces
b) Glucose-PET and diffusion-weighted MRI
c) MR spectroscopy and a spinal tap test or continuous lumbar CSF drainage
d) A spinal tap test, continuous lumbar CSF drainage, or an
infusion test
e) Specific psychometric testing after an infusion test
Question 5
What percentage of patients with iNPH also have vascular dementia or Alzheimer’s disease?
a) 15%
b) 30%
c) 45%
d) 60%
e) 75%
26
Question 9
Which of the following statements about the clinical course of
NPH after shunting is correct?
a) Shunting has no effect on life expectancy.
b) Shunting generally has no effect on the course of the disease.
c) Rapid progression and clinical deterioration are the rule.
d) Shunting generally shortens life expectancy.
e) In patients with NPH who have no other comorbid conditions,
shunting can arrest the progression of the disease.
Question 10
As a rule, what type of follow-up should patients have in the
first year after CSF shunting?
a) Monthly cranial CT or MRI
b) Two to three clinical follow-ups and imaging study.
c) Bimonthly imaging studies.
d) Mini-Mental Status Tests every three months.
e) Biannual DEMTEC tests.
MEDICINE
Photograph: Neuroradiology Dept., Universitätsklinikum des Saarlandes
eFigure 1: In this sagittal T2-weighted MR image of a patient
with NPH, the flow-void phenomenon (blue arrows) reflects increased pendular flow of CSF in the cerebral aqueduct due to
untreated hydrocephalus. Its presence supports the diagnosis,
but its absence would not imply that no treatment is needed.
The corpus callosum is typically thinned (red arrows). The disproportion between the third and fourth ventricles does not
conclusively distinguish NPH from aqueductal stenosis.
eFigure 2: Typical signal abnormalities (arrows) in which the extent of periventricular hypodensity is too great to be due to transependymal
CSF seepage alone. Signal abnormalities extending this far out into the white matter must be presumed to be due mainly to microvascular
changes.
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2012; 109(1–2) | Kiefer, Unterberg: eFigures
I
Photograph: Neuroradiology Dept., Universitätsklinikum des Saarlandes
MEDICINE
eFigure 3: This lateral skull film shows both a conventional differential-pressure valve (black arrow) and a gravitycontrolled valve (white arrow). One can also see an ICP telemetry probe that has been implanted into the brain (blue
arrow) for long-term ICP measurement, enabling optimal setting of the opening pressure of the adjustable G valve.
II
Deutsches Ärzteblatt International | Dtsch Arztebl Int 2012; 109(1–2) | Kiefer, Unterberg: eFigures
MEDICINE
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Deutsches Ärzteblatt International | Dtsch Arztebl Int 2012; 109(1–2) | Kiefer, Unterberg: eReferences

The Differential Diagnosis and Treatment of Normal-Pressure Hydrocephalus N SUMMARY

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