BRIEF REPORT: CLINICAL SCIENCE
Flow Rate of Cerebrospinal Fluid Through a Spinal
Needle Can Accurately Predict Intracranial Pressure
in Cryptococcal Meningitis
Tom H. Boyles, MA, BMBCh, MRCP(UK), MD, DTM&H, Cert ID (SA),*
Elizabeth Gatley, MBChB, Dip HIV Man (SA),* Sean Wasserman, MBChB, MMed, FCP (SA), Cert ID (SA),*
and Graeme Meintjes, MBChB, FRCP(UK), FCP(SA), MPH, PhD*†‡
Background: Patients with HIV-associated cryptococcal menin-
gitis (CM) commonly present with raised intracranial pressure (ICP).
Aggressive management of raised ICP reduces mortality but requires
manometers, which are unavailable in most resource-limited settings.
The law of Poiseuille states that the rate of flow of liquid through
a tube is directly proportional to the difference in pressure between
each end, and it may be possible to indirectly determine ICP by
measuring flow of CSF through a spinal needle rather than using
a manometer.
Methods: A convenience sample of CM patients requiring lumbar
puncture (LP) (with 22-G spinal needle) for ICP measurement and
control were enrolled. ICP was first measured using a narrow bore
manometer. After removing the manometer, the number of drops of
CSF flowing from the spinal needle in 15 seconds was counted.
Results: Thirty-two patients had 89 LPs performed (range, 1–23).
Fifty-four had high opening pressure with a CSF flow rate of 16–200
drops/min, and 35 had normal pressure with a CSF flow rate of 8–
140 drops/min. Area under the fitted receiver operator character
curve was 0.89. A flow rate cutoff to define high pressure of $40
drops/min correctly classified 75 of 89 LPs (accuracy 84%).
Conclusions: It is technically feasible to indirectly estimate CSF
pressure to an accuracy that is clinically useful by counting drops of
Received for publication June 9, 2016; accepted September 6, 2016.
From the *Division of Infectious Diseases and HIV Medicine, Department of
Medicine, Faculty of Health Sciences, University of Cape Town, Cape
Town, South Africa; †Clinical Infectious Diseases Research Initiative, Institute
of Infectious Disease and Molecular Medicine, Faculty of Health Sciences,
University of Cape Town, Cape Town, South Africa; and ‡Department of
Medicine, Khayelitsha District Hospital, Cape Town, South Africa.
G.M. is supported by the Wellcome Trust (098316), the South African
Research Chairs Initiative of the Department of Science and Technology
and National Research Foundation (NRF) of South Africa (Grant No
64787), NRF incentive funding (UID: 85858), and the South African
Medical Research Council through its TB and HIV Collaborating Centres
Programme with funds received from the National Department of Health
(RFA# SAMRC-RFA-CC: TB/HIV/AIDS-01-2014).
G.M. received remuneration for attending a fungal advisory board meeting of
Gilead Sciences and has received speaker remuneration from Sanofi
Aventis. The other authors have no funding or conflicts of interest to
disclose.
Correspondence to: Tom H. Boyles, MA, BMBCh, MRCP(UK), MD,
DTM&H, Cert ID (SA), Groote Schuur Hospital, Observatory, Cape
Town, South Africa 7937 (e-mail: tomboyles@yahoo.com).
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CSF flowing from a spinal needle. The optimal cutoff value for
defining high pressure using a standard 22-G spinal needle is
$40 drops/min. These findings have the potential to improve CM
management in resource-limited settings.
Key Words: cryptococcal meningitis, manometer, intracranial
pressure, HIV
(J Acquir Immune Defic Syndr 2017;74:e64–e66)
INTRODUCTION
Cryptococcal meningitis (CM) is a common oppor-
tunistic infection among adults with HIV worldwide and is
responsible for more than 130,000 deaths per year in sub-
Saharan Africa alone.1,2 The mortality rate in sub-Saharan
Africa has been estimated at 70% compared with 55% in
other low- and middle-income countries and 10%–20% in
high-income countries.3,4 Elevated intracranial pressure
(ICP), defined as cerebrospinal fluid (CSF) opening pres-
sure (OP) of .250 mm H2O, is associated with an increased
mortality,4–6 and recent studies have suggested that thera-
peutic lumbar punctures (LP) to control CSF pressure are
associated with improved survival.7,8 Therefore, routine
measurement of ICP and aggressive management of raised
pressure with repeated LP is recommended in treatment
guidelines.9,10
The standard method of ICP measurement is with
a manometer; however, these are unavailable in most low-
resource settings.11 A validated alternative is to use intrave-
nous giving sets with a tape measure,7 but even this method
requires resources that may not always be available. The law
of Poiseuille states that
8mlQ
Dp ¼
pr4
where Dp is the difference in pressure between the 2 ends of
a fluid filled tube of length (l) and internal radius (r), m is the
viscocity of the fluid, and Q is the volumetric flow rate.12 We
hypothesized that when using a spinal needle with constant
length and internal radius, it may be possible to indirectly
determine ICP by measuring the number of drops of CSF
flowing from the end of the needle.
J Acquir Immune Defic Syndr  Volume 74, Number 3, March 1, 2017
J Acquir Immune Defic Syndr  Volume 74, Number 3, March 1, 2017
METHODS
Study Population
A convenience sample of adult patients with CM
confirmed by CSF cryptococcal antigen testing and/or culture
was identified at 3 hospitals in Cape Town, South Africa:
Groote Schuur, New Somerset, and False Bay. Patients gave
written informed consent to participate in the study. The study
was approved by the University of Cape Town Human
Research Ethics Committee (Ref 643/2014).
Reference Method of Measuring ICP
Clinicians from the team primarily caring for the patient
performed LPs when clinically indicated. A 22-gauge (which
are typically color-coded black) spinal needle of 90-mm
length was used for all LPs. With the patient lying in a lateral
position, ICP was measured using a standard narrow gauge
manometer by attaching it to the spinal needle and allowing
CSF to rise to a constant height. Raised ICP was defined as an
OP .250 mm H2O.
Investigational Method for Estimating ICP
Immediately following reference measurement of ICP,
the manometer was disconnected from the spinal needle and
the number of drops of CSF falling from the hub of the needle
in the first 15 seconds was counted. This was converted to
a flow rate in drops/min.
Statistical Analysis
Receiver operator character (ROC) analysis was used
to quantify the discriminative ability of flow rate to determine
an appropriate cutoff for the presence of high pressure as
measured by manometry. The area under the curve and 95%
confidence intervals were calculated. Diagnostic accuracy
was determined by sensitivity, specificity, negative predictive
value and positive predictive value, and test accuracy. The
optimal cutoff was determined by performance characteristics
and clinical utility. All statistical analyses were performed
using StataCorp. 2013. Stata Statistical Software: Release 13.
College Station, TX: StataCorp LP.
RESULTS
From April 2015 to April 2016, 32 patients (31 HIV
infected, 21 men) were recruited, and 89 LPs were
performed (range, 1–23 LPs per patient). OP as measured
by standard manometry was raised on 54 occasions with
CSF drop rate median of 92 drops/min and range 16–200
drops/min. OP was normal on 35 occasions with CSF drop
rate median of 28 drops/min and range 8–140 drops/min.
The area under the ROC curve for drop rate was 0.89
(Fig. 1). An optimal cutoff value of $40 drops/min was
chosen because this represents the greatest accuracy and
prioritized sensitivity over specificity, as false-negative results
are more likely to cause harm to a patient than false-positive
results. Using this cutoff, 75 of 89 LPs were correctly
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CSF Pressure by Drop Rate
FIGURE 1. ROC curve for measurement of CSF pressure by
flow rate of CSF through a spinal needle compared with
a reference standard of manometry. Area under the ROC curve
was 0.89.
classified (accuracy 84%). Sensitivity was 91%, specificity
74%, positive predictive value 84%, negative predictive value
84%, positive likelihood ratio 3.53, and negative likelihood
ratio 0.12 (Table 1).
DISCUSSION
This study shows for the first time that it is possible to
measure ICP indirectly by measuring the flow rate of CSF
through a spinal needle at LP in patients with CM. The area
under the ROC curve of 0.89 when assessed in comparison to
standard manometry suggests good predictive power. Using
a standard 22-G spinal needle, a flow rate of $40 drops of
CSF/min predicts raised versus normal ICP with an accuracy
of 84% and a sensitivity of 91%, meaning that there were few
cases with raised OP missed using the flow rate method.
It is not surprising that an imperfect relationship
between ICP and CSF flow rate was found as several
assumptions, which may not be entirely valid, must be made
when applying the law of Poiseuille to the flow of CSF
through a spinal needle. Importantly, viscosity of CSF is
assumed to be constant, but this is unlikely given the
variability in protein and glucose content of CSF in patients
with CM13; unfortunately, many therapeutic LP samples were
not sent for analysis because of resource constraints, so we
are not able to correlate these variables with flow rate.
Cryptococcus neoformans has a polysaccharide capsule, and
TABLE 1. Flow Rate of CSF With a Cutoff Value of $40 Drops/
Min Compared with a Reference Standard of Manometry
Raised ICP .25 Normal ICP #25
on Manometry on Manometry Total
$40 drops/min 49 9 57
,40 drops/min 5 26 32
Total 54 35 89
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Boyles et al J Acquir Immune Defic Syndr  Volume 74, Number 3, March 1, 2017
viscosity might also vary with fungal burden. It should also
be noted that 24 of 89 LPs were from a single patient, which
could have weighted the flow rate results if the CSF viscosity
in this individual varied from the norm. The size of CSF
drops is also assumed to be constant but is likely to vary for
similar reasons. Rate of flow is proportional to the forth
power of the internal radius of the needle and therefore very
sensitive to any inconsistencies in the manufacture of spinal
needles. There were 5 false-negative results when OP was
high but flow rate was ,40 drops/min; one possible reason
might be that the bevel of the needle moved while removing
the manometer such that the entire needle opening was no
longer within the subarachnoid space.
Guidelines suggest repeating LPs in patients with
raised ICP when symptoms persist or recur9; however, there
is evidence that the use of therapeutic LPs is associated with
an improvement in survival regardless of initial ICP.8 It may
therefore be reasonable for future guidelines to recommend
at least 2 LPs for all patients. If the novel method of ICP
measurement were used and any 1 of 2 LPs with flow rate
$40 drops of CSF/min was used to meet the definition of
raised ICP, this would reduce the chance of false-
negative results.
An important limitation of the study is that the
reference standard of measuring ICP was not performed by
a single individual. LPs were performed by clinicians caring
for patients, and there was inevitably a variation in the
experience of the clinicians. A second limitation is that
measuring CSF pressure by manometry released CSF and
lowered the ICP when estimated subsequently using flow
rate. This effect was minimized using narrow-gauge man-
ometers, but it may mean that the true flow rate related to
high OP is slightly . 40 drops/min. Any error in this
direction favors over rather than underestimating OP. The
strength of the study was that the investigational method was
performed by a variety of clinicians with variable experience,
which suggests that this method is generalizable to other
clinical settings. Future research will be necessary to
determine optimal cutoff points for flow rate of CSF using
spinal needles with different internal radius and length.
Future work might also determine the influence of protein
level and fungal burden in the CSF on flow rate.
In conclusion, while measurement of ICP at LP in high-
resource or research settings should be performed by standard
manometry, the measurement by flow rate of CSF through
a spinal needle is accurate enough to be used for clinical care
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of patients with CM in low-resource settings, although sites
wanting to use this method may need to do their own
validation according to needle sizes available at their site.
This means that ICP can be determined quickly without the
need for manometers that are costly and not currently
available in most resource-limited clinical settings and has
the potential to improve the care of patients with
this condition.
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