Normal Pressure Hydrocephalus

1.  A 73-year-old man with an unremarkable past
medical history presented after a 3-year
history of progressive forgetfulness and poor
balance as well as recent onset of urinary
incontinence.
 Examination showed impaired memory and
difficulties with calculations and visuospatial
skills. Language was normal. MMSE was
23/30. The rest of the neurologic examination
was notable for diminished postural reflexes
and abnormal gait with signs of gait apraxia.

2.  Laboratory tests did not reveal any treatable cause of
dementia.
 CT brain demonstrated enlarged ventricles and
hypodensity of the white matter.
 Lumbar puncture was performed with normal opening
pressure, and 30 cc of CSF was collected. CSF analysis
was normal.
 The patient’s gait transiently improved with better
stride and improved postural reflexes.

3.  What will you do next?
 What other tests are available to diagnose NPH?
 What are the treatment options available?
 What are the available shunt surgeries and types?
 Can you predict the success of a shunt surgery? If so,
how?

5. Historical aspect
 Hakim-Adams
syndrome /
Hydrocephalic
dementia /
Internal
hydrocephalus
 Salomón Hakim Dow
(1922-2011)
 Colombian
neurosurgeon

6.  In 1965, Hakim and Adams described a syndrome of
 progressive cognitive decline
 gait impairment and
 urinary incontinence in the context of


ventricular dilatation and
normal Pcsf measurement during LP
 a condition subsequently referred to as NPH
Hakim S, Adams RD. The special clinical problem of symptomatic hydrocephalus with normal
cerebrospinal fluid pressure. Observations on cerebrospinal fluid hydrodynamics. J Neurol Sci. Jul-Aug
1965;2(4):307-27.

8. Pathophysiology
 An increased subarachnoid space volume does not
accompany increased ventricular volume.
 Distortion of the central portion of the corona radiata by
the distended ventricles.
 The periventricular white matter anatomically includes the
sacral motor fibers that innervate the legs and the bladder,
thus explaining the abnormal gait and incontinence.
Compression of the brainstem structures (ie,
pedunculopontine nucleus) could also be responsible for
gait dysfunction, particularly the freezing of gait that has
been well described.
 Dementia results from distortion of the periventricular
limbic system.

9. Pathophysiology
• ↓ CSF absorption at the arachnoid villi
• ↑ CSF pressure
• Force = Pressure X Area
• ↑ force against the brain than the same pressure in normal-sized ventricles
• Ventricular enlargement
• With further enlargement of the ventricles, CSF pressure returns to normal

11. Idiopathic
• 50%
Secondary
•
•
•
•
Subarachnoid hemorrhage
Head trauma
Infectious or carcinomatous meningitis
↑ CSF protein levels (including
elevation due to intraspinal tumors)

12. Epidemiology
 The incidence of INPH has been reported to be
between 1.8 cases per 100,000 individuals and 2.2 cases
per 1,000,000 individuals.
 Age > 60 years
 Slight male preponderance
Krauss JK et al. (2004) Normal pressure hydrocephalus: survey on
contemporary diagnostic algorithms and therapeutic decision-making in
clinical practice. Acta Neurochir (Wien) 146: 379–388

13. Guidelines for the Diagnosis and
Management of Idiopathic Normal Pressure
Hydrocephalus
VOLUME 57 | NUMBER 3 |
SEPTEMBER 2005 SUPPLEMENT

15.  History
 Brain imaging
 Clinical
 Physiological

16. 1. History
1.
2.
3.
4.
5.
6.
Insidious onset (versus acute)
Origin after age 40 yr
A minimum duration of at least 3 to 6 mo
No evidence of an antecedent event such as head
trauma, intracerebral hemorrhage, meningitis, or
other known causes of secondary hydrocephalus
Progression over time
No other neurological, psychiatric, or general
medical conditions that are sufficient to explain the
presenting symptoms

17. 2. Brain imaging
Ventricular enlargement not entirely attributable to
cerebral atrophy or congenital enlargement (Evan’s index
0.3 or comparable measure)
2. No macroscopic obstruction to CSF flow
3. At least one of the following supportive features
1.
a)
b)
c)
d)
Enlargement of the temporal horns of the lateral ventricles
not entirely attributable to hippocampus atrophy
Callosal angle of 40 degrees or more
Evidence of altered brain water content, including
periventricular signal changes on CT and MRI not
attributable to microvascular ischemic changes or
demyelination
An aqueductal or fourth ventricular flow void on MRI

19.  Brain imaging findings supportive of an INPH diagnosis
1.
A brain imaging study performed before onset of
symptoms showing smaller ventricular size or without
evidence of hydrocephalus
2. Radionuclide cisternogram showing delayed clearance of
radiotracer over the cerebral convexities after 48–72 h
3. Cine MRI study or other technique showing increased
ventricular flow rate
4. A SPECT-acetazolamide challenge showing decreased
periventricular perfusion that is not altered by
acetazolamide

20. 3. Clinical
 Clinical – Gait disturbance ± Cognition impairment ±
Urinary symptoms
 With respect to gait/balance, at least two of the following
should be present and not be entirely attributable to other
conditions
a)
b)
c)
d)
e)
f)
g)
h)
i)
Decreased step height
Decreased step length
Decreased cadence (speed of walking)
Increased trunk sway during walking
Widened standing base
Toes turned outward on walking
Retropulsion (spontaneous or provoked)
En bloc turning (turning requiring three or more steps for
180 degrees)
Impaired walking balance, as evidenced by two or more
corrections out of eight steps on tandem gait testing

21.  With respect to cognition, evidence of at least two of
the following on examination that is not fully
attributable to other conditions
a)
b)
c)
d)
e)
f)
g)
Psychomotor slowing (increased response latency)
Decreased fine motor speed
Decreased fine motor accuracy
Difficulty dividing or maintaining attention
Impaired recall, especially for recent events
Executive dysfunction, such as impairment in
multistep procedures, working memory, formulation
of abstractions/similarities, insight
Behavioral or personality changes

22.  In the domain of urinary continence, either one of
the following should be present
1.
2.
3.
4.
Episodic or persistent urinary incontinence not
attributable to primary urological disorders
Persistent urinary incontinence
Urinary and fecal incontinence
Or any two of the following should be present
a)
b)
c)
Urinary urgency as defined by frequent perception of a
pressing need to void
Urinary frequency as defined by more than six voiding
episodes in an average 12-hour period despite normal fluid
intake
Nocturia as defined by the need to urinate more than two
times in an average night

23. 4. Physiological
 CSF opening pressure in the range of 5–18 mm Hg (or
70–245 mm H2O) as determined by a lumbar puncture
or a comparable procedure.
 Appropriately measured pressures that are
significantly higher or lower than this range are not
consistent with a probable NPH diagnosis.

24. Comparison of cognitive deficits in
Alzheimer’s disease and NPH

25. Comparison of NPH, Alzheimer’s
and Parkinson’s disease

26. Possible INPH

27. Unlikely INPH
No evidence of ventriculomegaly
2. Signs of increased intracranial pressure such as
papilledema
3. No component of the clinical triad of INPH is
present
4. Symptoms explained by other causes (e.g., spinal
stenosis)
1.

31. Ventricular size
Normal vs. NPH

32. Conditions that may present
similarly to INPH or present
comorbidly

33. What is the role of measuring CSF
OP?
 In normal volunteers, the CSF-OP averages 122 ± 34 mm




H2O (8.8 ± 0.9 mm Hg) LP - left lateral recumbent
position.
In patients with INPH, the CSF-OP averages 150 ± 45 mm
H2O (11 ± 3.3 mm Hg) – Slightly higher than normal
Transient high pressures (“B waves”) are detectable during
prolonged intraventricular monitoring in adults with INPH
.
CSF-OP is a poor measure of the complex temporal profile
of intraventricular pressure variations that occur in
hydrocephalus patients.
CSF-OP measurement may be most useful in identifying
hydrocephalic conditions other than INPH, particularly
when the OP is elevated above 18 mm Hg (245 mm H2O). -

35. Shunt-responsive and shuntnonresponsive INPH
 Favorable response to shunting will vary from 46
to 63% .
 The best indicator for shunt responsiveness was
patients with the complete triad and achieved a
61.2% rate of improvement
 CSF lumbar tap, external lumbar drainage, or CSF
resistance studies.

36. Leonardo da Vinci (1452–1519): anatomic study of the ventricular system
with the infundibulum of the third ventricle in exaggerated proportion, in
accordance with Galen

37. Predictive Value of Radionuclide
Cisternography
 Pre-CT era
 Injecting an isotope (131I labeled serum albumin or 111In
pentetate) via a lumbar puncture, followed by intermittent
two-dimensional gamma imaging over the course of 24 to
48 hours.
 Two “abnormal” isotope distribution and time course
patterns were noted in hydrocephalic patients:
 1) ventricular reflux and
 2) delayed ascent and prolonged activity of the isotope over the
cerebral convexities.
• Evidence-based support for its use in INPH does not
support its continued use on a routine basis.

39. Summary
 Based on the one Class III study, cisternography does
not improve the diagnostic accuracy of identifying
INPH and therefore is not included as an option.

40. Predictive Value of ICP Monitoring
 The average opening pressures in the cited INPH
studies range from 8.8 ± 1.3 mm Hg to 14.62 ± 1.5 mm
Hg.
 Many secondary NPH patients present with low or
“normal” ICPs, although the finding of a baseline
elevated ICP raises the suspicion of secondary NPH.
 A consensus of European and United States experts,
combined with the results of limited published works,
placed the expected range of INPH opening pressure
between 60 and 240 mm H2O, or 4.4 to 17.6 mm Hg.

41.  It has been proposed that the increased frequency
in B waves is indicative of lowered compliance
and/or may play an important role in the
pathophysiology of the ventriculomegaly and
neuronal dysfunction.
 On the basis of expert opinion, an upper limit of
240 mm H2O (17.6 mm Hg) has been selected as
acceptable for analysis as an INPH patient.

43. Summary
 The measurement of ICP should be considered during
the diagnostic/prognostic phase of INPH.
 An elevated ICP should prompt a reassessment to rule
out a secondary cause of NPH.
 Class III evidence does not currently support
continuous ICP monitoring to determine the
frequency of B or A waves.

44. Predictive Value of CSF Removal
via High-volume “Tap Test”
 In the classic description of NPH by Adams et al.,
three hydrocephalic patients were presented, two
posttraumatic and one diagnosed as having INPH.
 In each patient, a spinal tap was performed, and a
volume of CSF on the order of 15 ml was removed,
with improvement noted in all three patients.
 The “tap test,” has evolved in that now most
clinicians who use it tend to remove much larger
volumes of CSF (40–50 ml).

45.  Most experts agree that an objective improvement in
gait, either by a quantitative method or by blinded
videotape review, is preferable.
 The usefulness of before-and-after neuropsychiatric
testing has not been validated for this test or even
surgical treatment of INPH, and the degree of
improvement in any variable also lacks validation.
 Moreover, INPH patients have normal daily
fluctuations in symptoms, and that motivation can
transiently improve performance.

47. Summary
 On the basis of a single Class II study1, the test had only
62% sensitivity and 33% specificity.
 A multicenter Class II study2 did report a 100% positive
predictive rate.
 Given these limited data, the CSF tap test may have good
PPV for INPH; however, specificity is low, suggesting that
many patients who might benefit from shunting will be
missed.
 The tap test therefore is listed as a Guideline for the
prognostic evaluation of INPH, with the caveat that INPH
candidates not be excluded on the basis of a negative tap
test.
1. Malm M, Kristensen B, Karlsson T, Fagerlund M, Elfuerson J, Ekstedt J: The predictive value of
cerebrospinal fluid dynamic tests in patients with the idiopathic adult hydrocephalus syndrome. Arch
Neurol 52:783–789, 1995.
2. Walchenbach R, Geiger E, Thomeer RT, Vanneste J: The value of temporary external lumbar CSF drainage
in predicting the outcome of shunting on normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry
72:503–506, 2002.

48. Predictive Value of the ELD Test
 ELD was initially described by Haan and Thomeer and
consisted of draining 10 ml of CSF per hour for a period of
72 hours (total, 720 ml). Now, 300 ml × 5 days
 Prolonged external catheter drainage imposes increased
risks of complications
 Overdrainage complications can occur as a result of
inadvertent catheter disconnections or changes in patient
position, which may result in very large and rapid CSF loss.
 Patients with severe short-term memory dysfunction are at
highest risk because of lowered patient compliance with
remaining still in bed.

50.  ↑ sensitivity compared with the CSF tap test
 More patients who do not improve with a large-volume
CSF tap test will show improvement with prolonged
drainage and benefit from shunting.
 The PPV is high, ranging from 80 to 100%
 The most effective test for identifying INPH.
However, hospital admission is required.

51. Predictive Value of CSF Ro
 Ro = Impedance of flow offered by the CSF absorption
pathways.
 Katzman test - a pump introduces mock CSF fluid / saline
at a known rate via a needle placed in the lumbar SA space.
 The Ro is the difference in the final steady-state pressure
reached and the initial pressure divided by the infused flow
rate.
 The bolus method involves injecting usually 4 ml, into the
lumbar subarachnoid space at a rate of 1 ml/s. The
advantage of the bolus method is that it also provides a
measure of the brain compliance, as defined by the
pressure-volume index
Katzman R, Hussey F: A simple constant-infusion manometric test for
measurement of CSF absorption: Part I—Rationale and method. Neurology 20:534–544,
1970.

53.  The sole Class II prospective study found marginal
sensitivity, specificity, and PPV values.
 The reported accuracy of resistance measures may be
higher than that of the CSF tap test.
 Therefore, determination of CSF Ro may be helpful in
increasing prognostic accuracy for identifying INPH
when tap test results are negative.
Malm M, Kristensen B, Karlsson T, Fagerlund M, Elfuerson J, Ekstedt J:
The predictive value of cerebrospinal fluid dynamic tests in patients
with the idiopathic adult hydrocephalus syndrome. Arch Neurol
52:783–789, 1995.

54. Predictive Value of Aqueductal
CSF Flow Velocity
 It has been proposed that NPH patients have a higher
CSF flow velocity through the cerebral aqueduct.
 This was first noted by an exaggerated aqueductal flow
void on axial MRI scans
 For example, Luetmer et al. suggested that velocities
greater than 18 ml/min were predictive for good
outcome after shunting.
 The pathophysiological basis of increased CSF flow
void velocity in INPH has not been established.
Luetmer PH, Huston J, Friedman JA, Dixon GR, Petersen RC, Jack CR, McClelland RL, Ebersold MJ:
Measurement of cerebrospinal fluid flow at the cerebral aqueduct by use of phase contrast magnetic
resonance imaging: Technique validation and utility in diagnosing idiopathic normal pressure
hydrocephalus. Neurosurgery 50:534–544, 2002.

55. PCCMR imaging CSF dynamic study in a 74-year-old patient with NPH.
A, Midline sagittal T1-weighted MR imaging is used to graphically describe the
phase-contrast cine series. The section is placed at the level of the inferior
colliculus, perpendicular to a line drawn through the distal aqueduct.
B, Axial section in which region of interest is drawn as close as possible to the
aqueduct border.
C, Respective absolute values of CSF during 16 cardiac phases are reported on
the graph. The flow plot demonstrates sinusoidal pattern of flow where
negative values represent aqueductal systolic CSF volume (microliter) outflow
and positive values represent diastolic CSF volume inflow.
Scollato A et al. AJNR Am J Neuroradiol 2008;29:192-197
©2008 by American Society of Neuroradiology

56. Summary
 On the basis of current evidence, neither MRI CSF
flow void sign nor quantitative CSF flow velocity
seems to have significant diagnostic value.
 However, CSF stroke volume may potentially have
greater prognostic value than aqueductal flow void.
 The prognostic role of MRI for shunt-responsive INPH
requires further study.

57. Identifying Shunt-responsive
Patients
 Clinical Evaluation
 Supplemental Testing
 Tap Test
 Resistance Testing
 External Lumbar Drainage

59.  Without further supplemental testing, the degree of
certainty for improvement after shunt placement for
probable and possible INPH ranges from as high as
61% to less than 50%
 One or more of the following three tests is
recommended: CSF tap test, Ro determination,
and/or ELD; based on desired prognostic value,
personal experience, and equipment/personnel
availability

60.  CSF OP - In identifying other hydrocephalic conditions
 Radionuclide Cisternography - Does not improve





diagnostic accuracy
ICP monitoring
 In diagnostic / prognostic phase
 No evidence to support ICP monitoring for A / B waves
CSF tap test - Good PPV, but many patients who might
benefit from shunting will be missed
ELD test - Increased sensitivity and PPV
CSF Ro- increasing prognostic accuracy for identifying
INPH when tap test results are negative
Aqueductal CSF Flow Velocity - neither MRI CSF flow
void sign nor quantitative CSF flow velocity seems to have
significant diagnostic value.

61. Surgical management of INPH
 Selected patients can make a remarkable and prolonged
improvement after the placement of a shunt
 Risk-benefit ratio
 The 72-hour external lumbar drainage test may give some
indication
 Systemic anticoagulation: Standard neurosurgical
precautions should be taken, including stopping
antiplatelet medications for the required period before
surgery and not restarting them immediately. There are no
studies or expert consensus addressing whether or not
restarting full anticoagulation with warfarin is a
contraindication to a CSF shunt for INPH.

62. Is there a penalty for delaying
treatment?
 The “natural history” of untreated INPH has not been
studied well.
 There is no published documentation on INPH
patients returning to normal without treatment.
 Conversely, there are no published reports
demonstrating that INPH is invariably a progressive
disorder.

63. Response to Surgical Intervention
 Many, if not most, INPH patients have comorbid brain
conditions.
 Periventricular white matter ischemia is commonly seen in
INPH patients. Patients with severe cerebrovascular disease
do not respond as well to shunting but may still derive
some benefit from the procedure.
 The neurological decline sometimes seen despite shunt
placement in INPH may be related to the progression of
comorbid conditions
 Even temporary improvements ranging from 1 to 3 years
may make a substantial difference in quality of life.

64. Complications Associated with
Shunting
 Anesthesia-related risks (such as myocardial infarction)
 Acute intracerebral hemorrhage is the primary






“procedure-related” risk
Infection
Seizures
Shunt obstruction
Subdural fluid collection and hematoma
Overdrainage headaches
Shunt underdrainage (failure to improve despite a patent
shunt).

65. Subdural effusion vs. hematoma
 The incidence of subdural hematomas after a shunt for
INPH is from 2 to 17%
 To what extent subdural effusions are a risk factor of a
subdural hematoma?
 Small subdural effusions may be clinically silent
 Conversely, the incidence of subdural effusions seems to
be related to the degree of shunt drainage, because the
incidence was greater in low- versus medium-pressure
valves

67. Schematic of the first clinically successful regulatory
valve for control of hydrocephalus, introduced by Nulsen
and Spitz in 1949.
Nulsen F, Spitz EB. Treatment of hydrocephalus by direct shunt from
ventricle to jugular vein. Surg Forum 1951;2:399-409

68. Does the type of valve affect the
incidence of subdural collection?
 Unclear.
 The use of flow-limiting valves or ASDs to reduce the
incidence of subdural hematomas has yet to be proved.
 Adjustable valves allow more conservative treatment of
subdural effusions by adjustment of valve pressure.
 If preoperative intracranial pressure is measured
routinely, valve type or pressure is selected on the basis
of reasonable physiological grounds and follow-up
neuroimaging studies are obtained in a timely manner,
then the incidence rate of subdural hematomas
presumably will be minimized.

69. Which shunt to perform?
 VP shunt vs. VA shunt - no prospective or retrospective
study in INPH
 VA shunts - preferred for INPH by some experts.
 Shunt nephrosis, caused by a long-standing undiagnosed
low-grade shunt infection has not been reported in INPH
patients.
 Lumboperitoneal shunt can be considered, if VP shunt is
contraindicated
 Mechanical malfunctions
 Fewer options of valve types
 Ventriculopleural shunts were historically more popular
 Pleural effusions
 Used only when no other option is available or if maximum
CSF drainage is desired.
 Ventriculo-superior sagittal sinus shunts, but long-term
results are still pending

70. When to avoid VP shunt?
 History of peritonitis
 History of peritoneal adhesions from multiple
previous abdominal operations
 Severe constipation
 Truncal obesity
 Pre-existing seizure disorder

71. Any role for ETV?
 May be beneficial in NPH patients who demonstrate
high ventricular CSF outflow resistance in
combination with low lumbar CSF outflow
resistance

72. Valve Type and/or Setting
Selection






Simple Differential-pressure Valves
Valve opens if the pressure difference exceeds a set value.
A spring-loaded ball check valve / leaves of a slit valve
Low-pressure (20–40 mm H2O), medium-pressure (50–90
mm H2O), and high-pressure (100–140 mm H2O)
The valve pressure settings were relatively small compared
with the negative ICP developed by a hydrostatic column of
CSF draining to the peritoneum in the upright position
(siphoning).
In vivo, mean CSF flow rates may be significantly ↓as the
valve mechanism is closed mojority of the time
Expert opinion strongly recommends against the use of
dorsal-slit valves for INPH due to overdrainage.

76. 




Antisiphon Devices (ASDs)
Mechanisms developed to counteract gravity-dependent
drainage
The ASD is situated in series distal to a differentialpressure valve.
Effective in preventing postural intracranial hypotension.
For INPH, siphoning has not been proved to be harmful.
In patients in whom the baseline ICP is truly normal
(including the lack of frequent B waves), placing a shunt
with an ASD that is aimed at producing a normal
intracranial pressure may be ineffective

78. Flow-limiting valves
 NMT Orbis-Sigma and Phoenix valves
 Multistage differential-pressure valves that, in at least one
operating mode, limit the CSF flow rate by narrowing the
aperture through the differential pressure valve
mechanism.
 Valves are designed to operate in the flow-rate-limiting
mode under “normal” conditions and then switch to a high
flow rate under conditions of high intracranial pressure.
 The Codman FloGuard valve is a recently introduced valve
that adds in series a dual-stage flow-limiting device to an
adjustable differential pressure valve. It is designed to
prevent gravity-dependent overdrainage by selectively
reducing high CSF flow rates when the patient is the
upright position.

81. 



Dual-stage Differential-pressure Valve Designs
The Miethke dual-switch valve uses a dual-stage
differential pressure valve design to prevent overdrainage
complications.
High-density tantalum spheres move within the valve in
response to gravity so that the supine and upright positions
have low-pressure or very-high-pressure (400 mm H2O)
differential-pressure valve settings, respectively.
The effectiveness of the Miethke dual-switch valve for
INPH has not been established.
A lower incidence of subdural hematoma formation with
the Miethke dual-switch valve as compared with the OrbisSigma and simple differential-pressure valves.

83. 




Adjustable (“Programmable”) Valves
Adjustable valves have been designed that allow for the
opening pressure of the differential-pressure valve
mechanism to be changed noninvasively.
The Sophy and Codman-Medos valves
PS Medical Strata valve (incorporating an ASD)
Codman FloGuard valve (a flow-restricting device)
An advantage has not been established in a
prospective manner.

86. Sophy valve

87. All programmable
valves work on the
same principle:
Magnetically movable
rotor changes pre-load of
spring supporting ball in
cone

88. Dutch NPH study – valve comparison
 Valve pressures selected were low (30–40 mm H2O) vs.




medium (50–90 mm H2O).
Valve pressure selection does not make a difference in NPH
No evidence suggesting the usefulness of a programmable
valve - may not be valid or reasonable, given the reported
experience with adjustable valves for INPH, in which the
much higher valve pressures than those used in the Dutch
NPH study were optimal for the management
The valve pressures used in the Dutch NPH study were too
low given the high incidence of subduraleffusions.
It is premature to conclude that valve pressure setting is
inconsequential with regard to outcome with INPH.

89.  The choice of valve type and setting should be based
on empirical reasoning and a basic understanding of
shunt hydrodynamics.
 The most conservative choice is a valve incorporating
an ASD, with the understanding that underdrainage
(despite a low opening pressure) may occur in a small
percentage of patients because of the ASD.
 Programmable valve may be beneficial in the
management of INPH because of the ability to manage
both underdrainage and overdrainage problems
nonoperatively.

91. Flow chart for management of
subdural fluid collections

92. Flow chart for management of
nonresponders

93. Flow chart for surgical
management of the INPH patient

94. Points to remember
 The most effective supplemental test for identifying
surgery responsive INPH is – ELD in excess of 300 ml
 The commonest and often the first symptom in
patients with NPH is – gait impairment
 The most likely component of the symptom triad to
improve after CSF diversion is – gait abnormality

95. Update
Diagnostic marker for iNPH
CSF protein lipocalin-type prostaglandin D synthase
(L-PGDS)
1. Brooks M. CSF Protein a Diagnostic Marker for Idiopathic NPH? Medscape Medical News. July 05, 2013. Available at
http://www.medscape.com/viewarticle/807381. Accessed July 16, 2013.
2. Nishida N, Nagata N, Toda H, Ishikawa M, Urade Y, Iwasaki K. L-PGDS could be a surrogate marker of frontal lobe
dysfunction in idiopathic NPH [abstract 1014]. Available at
http://www.mdsabstracts.com/abstract.asp?MeetingID=798&id=107057. Accessed July 16, 2013.