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Brain drain A bottom-up approach to normal pressure hydrocephalus.

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Brain Drain: A Bottom-Up Approach to
Normal Pressure Hydrocephalus
lthough a treatment for idiopathic normal pressure
hydrocephalus (iNPH) was described by Adams
et al1,2 in 1965, it has remained an elusive progressive disorder of the brain, with characteristic changes in gait, cognitive functioning, and urinary incontinence. The prevalence of iNPH is estimated at 0.1% among individuals
aged 60 years, but doubles in frequency with each decade
of life thereafter.3 Although there are no recent data, in
2000 the costs for treating iNPH were approximately $1
billion.4 Although some patients benefit from removal of
cerebrospinal fluid (CSF) by ventriculoperitoneal shunting
(VPS),5 and possibly endoscopic third ventriculostomy,6
the pathogenesis, natural history, treatment determinants,
and degree of overlap with other dementias remain an
enigma. Unfortunately, there is still no consensus on how
best to evaluate patients with suspected iNPH prior to surgery, despite numerous algorithms employed around the
world.7 Furthermore, none of these can completely predict
which patients are likely to improve and for how long following surgical intervention.
An admirable attempt to create evidence-based criteria for the diagnosis of iNPH suggests that categories
such as probable, possible, and unlikely be used, depending on careful clinical evaluations.8 Yet the diagnostic
methods and classification of patients remain inconsistent. In many tertiary centers, patients who meet clinical
criteria for possible iNPH undergo a multiday lumbar
spinal fluid drainage trial, with or without CSF outflow
resistance measurement, to visualize a clinical response to
drainage or abnormal CSF outflow resistance. Still others
use intracranial pressure monitoring of CSF pressure,
and pulsatility, to decide who should undergo a shunt.
Many physicians forego invasive preoperative testing altogether and recommend shunting in all suspected iNPH
patients, despite the relatively poor preoperative prognosis for response to VPS based on clinical criteria alone.
The variability in preoperative and operative management of iNPH provides unique opportunities to understand the pathogenesis of this poorly understood disorder
and could serve as the basis to form an improvement in
our ability to determine who will or will not respond
successfully to VPS, and to determine who will likely
continue to deteriorate with progression to dementia.
Two studies in this issue of Annals of Neurology9,10
address these areas in very different ways. In the first, Leinonen et al at Kuopio University in Finland conducted a
retrospective review of their experience with 468 suspected
iNPH patients who underwent intracranial pressure monitoring and neocortical right frontal brain biopsy as preoperative evaluation. Out of 468 possible iNPH patients
(between 1 and 3 cardinal symptoms and signs, and ventriculomegaly on brain imaging), 219 (46.8%) underwent
VPS based on pressure monitoring results. Follow-up
review of 433 (92.5%) of the patients attempted to relate
the pathological manifestations from the preoperative
brain biopsy with the overall improvement and with the
development of Alzheimer disease (AD). In contrast, the
report by Hamilton and colleagues at the University of
Pennsylvania elected to shunt all patients who met clinical
criteria for possible iNPH (2 of 3 cardinal symptoms or
signs and ventriculomegaly on brain imaging), and carried
out open brain biopsies at the time of shunt placement.
They then related the pathological findings from the brain
biopsy with the response to shunt after a 4-month period.
These 2 studies provide interesting observations, but generate more questions than they answer. Because of their
differing methodologies and results, it is useful to summarize their approaches and findings.
In the Finnish study,9 the authors used immunohistochemistry to examine brain biopsy specimens for the
presence of amyloid b(Ab) aggregates and hyperphosphorylated tau. Patients were retrospectively evaluated for
clinical diagnosis based on available hospital records,
national death registries, and a questionnaire answered by
54% of the 180 patients still alive at the end of 2008.
The median follow-up available in 433 patients was 4.4
years from the time of brain biopsy (ranging from 0 to
17 years). There was no systematic detailed neuropsychological testing or brain imaging used to aid in diagnosis
or follow-up. A total 88% of 433 patients had memory
deficit described at the time of iNPH evaluation. Consistent with the presenting symptoms, the majority of
C 2010 American Neurological Association
of Neurology
patients had some form of cognitive impairment at last
follow-up, consisting of diagnoses such as AD, non-AD
dementia, or mild cognitive impairment. The presence of
Ab and tau, and to a lesser extent Ab alone, in the brain
biopsy tissue increased the likelihood of developing a clinical diagnosis of AD, although no autopsy findings were
reported. Of the 42 patients whose biopsy showed both
Ab and tau aggregates, 34 (81%) had clinically diagnosed
AD on last follow-up. At the time of iNPH evaluation and
brain biopsy, all but 1 of these patients had memory deficit, and memory deficit was the ‘‘leading symptom’’ in the
majority. Of the 144 patients with only Ab aggregates
found in the biopsy, 33% developed clinical AD, but
another 40% developed some other form of dementia.
Among the 247 patients without Ab or tau aggregates,
only 5% developed clinical AD, but 110 (45%) patients
developed other forms of dementia. Curiously, 59 (24%)
of the 247 patients with neither Ab nor tau aggregates
were classified as cognitively unimpaired at follow-up,
although 39 were said to have no memory deficit at the
time of biopsy years previously. Of the 219 patients diagnosed with probable iNPH based on intracranial pressure
monitoring, 168 (77%) improved following shunting,
although the criteria for improvement and length of ultimate follow-up are not disclosed. Shunt response was independent of the presence of AD pathology in this study.
In the much smaller study from the University of
Pennsylvania,10 all 47 patients underwent shunt surgery,
but only 30 (63.8%) patients were eventually followed.
Brain biopsies obtained at the time of right frontal shunt
placement were semiquantitatively assessed for Ab plaques
and hyperphosphorylated tau by immunohistochemistry
and for neuritic plaques by thioflavin S staining. Patients
were stratified into those with no, mild, or moderate-tosevere pathology. Patients with moderate-to-severe pathology at the time of shunt placement had significantly worse
cognitive function than patients without pathology. At 4
months postoperatively, only 2 of the 8 patients with moderate-to-severe pathology improved clinically with shunting, whereas 18 of 22 patients with no or mild pathology
improved in gait, continence, and cognitive functions.
What can be concluded from these 2 studies and
prior literature? The presence of AD pathology in patients
with possible iNPH, particularly the combination of high
Ab and tau plaque burden, likely predicts the development
of AD and poor short-term outcome with shunting. These
patients typically have advanced cognitive deficits at the
time of iNPH evaluation. Less invasive options such as
lumbar drainage trial, with objective evaluation of clinical
response to CSF drainage, may be able to screen patients
with possible iNPH who have AD pathology, without subjecting them to surgery. In addition, amyloid-based posi416
tron emission tomography imaging and CSF analysis for
decreased Ab and increased tau/phosphorylated tau need
to be studied for their utility as preoperative predictive
tests in this patient population.11,12 It is critical to maximize outcomes and minimize risks of surgery in elderly
patients with possible iNPH. In the study by Hamilton et
al, 2 of the 37 shunted patients had surgical complications
that prevented their follow-up evaluation, including 1
death; another 3 patients had postoperative health complications not directly related to the surgical procedure,
including 1 death.
The most important conclusion of these studies is
that we currently do not have satisfactory means to determine preoperatively which patients with iNPH will benefit
from VPS without a brain biopsy. We also do not know
how long their treatment benefit may last, or what factors
ultimately predict improvement in quality of life. These
are not trivial issues. With an ever aging population and
‘‘75 becoming the new 65,’’ it is important to deepen our
understanding of iNPH and its complex relationship with
AD and other dementias. The 2 studies reported here provide compelling results but highlight the need for a more
aggressive approach and re-evaluation of the methods of
preoperative diagnosis. They also suggest that rigorous longitudinal studies that include detailed patient examinations
using validated outcome scales; advanced amyloid imaging; Ab and tau measurements in brain and cerebrospinal
fluid; and long-term clinical follow-up by experienced
multidisciplinary teams are needed to determine in which
patients CSF diversion is safe and cost-effective in iNPH.
Potential Conflicts of Interest
R.M. has served on the Safety Monitoring Board for
Guy McKhann, MD1
Richard Mayeux, MD, MSc2
Department of Neurosurgery, Columbia University Medical Center,
New York, NY
Gertrude H. Sergievsky Center, Taub Institute for Research on
Alzheimer’s Disease and the Aging Brain, and Departments of
Neurology, Psychiatry, and Epidemiology, Columbia University,
New York, NY
Adams RD, Fisher CM, Hakim S, et al. Symptomatic occult hydrocephalus with ‘‘normal’’ cerebrospinal-fluid pressure: a treatable
syndrome. N Engl J Med 1965;273:117–126.
Hakim S, Adams RD. The special clinical problem of symptomatic
hydrocephalus with normal cerebrospinal fluid pressure: observations on cerebrospinal fluid hydrodynamics. J Neurol Sci 1965;2:
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McKhann and Mayeux: Brain Drain
Brean A, Eide PK. Prevalence of probable idiopathic normal pressure hydrocephalus in a Norwegian population. Acta Neurol
Scand 2008;118:48–53.
Relkin N, Marmarou A, Klinge P, et al. Diagnosing idiopathic
normal-pressure hydrocephalus. Neurosurgery 2005;57:S4–S16;
discussion ii–v.
Fife TD. Clinical features of normal pressure hydrocephalus. Barrow Q 2003;19:10–15.
Klinge P, Marmarou A, Bergsneider M, et al. Outcome of shunting
in idiopathic normal-pressure hydrocephalus and the value of outcome assessment in shunted patients. Neurosurgery 2005;57:
S40–S52; discussion ii–v.
Leinonen V, Savolainen S, Rummukainen J, et al. Amyloid and tau
protein in cortical brain biopsy and Alzheimer disease. Ann Neurol
Hamilton R, Patel S, Lee S, et al. Lack of shunt response in suspected idiopathic NPH with AD pathology. Ann Neurol 2010;68:
Gangemi M, Maiuri F, Naddeo M, et al. Endoscopic third ventriculostomy in idiopathic normal pressure hydrocephalus: an Italian
multicenter study. Neurosurgery 2008;63:62–67; discussion 7–9.
Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal
fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol
Marmarou A, Bergsneider M, Klinge P, et al. The value of supplemental prognostic tests for the preoperative assessment of idiopathic normal-pressure hydrocephalus. Neurosurgery 2005;57:
S17–S28; discussion ii–v.
Nordberg A, Rinne JO, Kadir A, Langstrom B. The use of PET in
Alzheimer disease. Nat Rev Neurol 2010;6:78–87.
October, 2010
DOI: 10.1002/ana.22212
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approach, bottom, drain, hydrocephalus, pressure, brain, norman
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