ISSN 0017-8748

Headache  doi: 10.1111/head.13602

© 2019 American Headache Society Published by Wiley Periodicals, Inc.

Research Submissions
CSF Pressure, Volume, and Post-Dural Puncture Headache:
A Case-Control Study and Systematic Review
Jonathan H. Smith, MD; Brian Mac Grory, MB, BCh, BAO, MRCP; Richard J. Butterfield, MA;
Babar Khokar, MD; Bryce L. Falk, MSN, RN; Lisa A. Marks, MLS, AHIP

Objectives.—(1) To perform a systematic literature review to evaluate associations between post-dural puncture headache
(PDPH) and opening pressure (OP), closing pressure (CP), and volume of cerebrospinal fluid (V) removed. (2) To perform
a case-control study to evaluate pressure-volume index (PVI) as a novel risk factor for PDPH.
Background.—According to the International Classification of Headache Diagnoses, 3rd Edition (ICHD-3), the diagnosis
of PDPH requires documentation of intracranial hypotension. However, this remains an unproven concept.
Methods.—A systematic literature review was conducted, searching Cochrane Database of Systematic Reviews, Ovid
EMBASE, OVID MEDLINE, Scopus, and Web of Science. Study inclusion required a comparison of headache incidence
following a LP as a function of OP, CP, and/or V.
A retrospective, case-control study with 1:1 matching was conducted utilizing ICHD-3 criteria. Patients with factors
that could influence CSF pressure were excluded.
Results.—In our case-control study, we did not identify a paired difference in either median (95% CI) elastance (0.05
[−0.09, 0.11], P  =  .503) or PVI (4.53 [−7.98, 19.97], P  =  .678). We identified 22 references, evaluating V (n  =  14), OP
(n  =  11), and/or CP (n  =  4). There was no convincing evidence for an association of PDPH with either OP or CP. A
minority of studies documenting an association with V included patients with high-volume CSF removal, and/or stratified
­
patients by the timing of the headache onset.
Conclusions.—The overall risk of PDPH does not appear to be influenced by OP, CP, V or PVI. PDPH may be related
to V in instances of high-volume removal, and depend on the timing of outcome assessment. Future revision of criteria should
consider the existence of immediate and delayed PDPH subtypes, and not presume intracranial hypotension as a mandatory
feature.

Key words: lumbar puncture, intracranial hypotension, cerebrospinal fluid leak, post-LP headache, post-dural puncture headache

(Headache 2019;0:1-15)

From the Department of Neurology,  Mayo Clinic, Scottsdale,

AZ, USA (J.H. Smith and B.L. Falk); Department of
Neurology,  Brown University, Providence, RI, USA (B. Mac
Grory); Division of Biostatistics, Mayo Clinic, Scottsdale, AZ,
USA (R.J. Butterfield); Department of Neurology,  Yale
University, New Haven, CT, USA (B. Khokar); Department
of Library Services, Mayo Clinic, Scottsdale, AZ, USA (L.A.
Marks).
Address all correspondence to J.H. Smith, MD, Department of
Neurology, Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale,
AZ 85259, USA, email: smith.jonathan@mayo.edu
Accepted for publication June 8, 2019.
INTRODUCTION
Post-dural puncture headache (PDPH) is recog-
nized by the International Classification of Headache
Disorders, 3rd Edition (ICHD-3), as a headache de-
veloping within 5  days of a dural puncture, with
objective evidence of low cerebrospinal fluid (CSF)
pressure.1 The incidence of PDPH is 11% (95% con-
fidence interval (CI) 9.1-13.3) when conventional
Conflicts of Interest: None
Data Availability Statement.—All data used in the study analysis
are available on request from the corresponding author (J.H.S.).

1
2 Month 2019
needles are used compared with 4.2% (95% CI 3.3-5.2)
when atraumatic needles are utilized.2 Risk factors
for PDPH include age, female sex, bevel orientation,
and use of traumatic and/or larger bore needles.2,3
However, despite the concept of intracranial hypo-
tension being recognized as part of the diagnostic cri-
teria, the impact of cerebrospinal fluid pressure and
volume indices (eg, opening pressure [OP]) on PDPH
incidence is unclear.4
The diagnosis of PDPH requires evidence of low
cerebrospinal fluid pressure;1 however, it has not been
established whether or not this represents a causative
mechanism. In a series of patients undergoing lumbar
puncture, Marshall noted that the opening pressure
was normal in a subset of patients during a second
lumbar puncture despite concurrent positional head-
ache.5 Further, extremely low pressures at the time of
a second lumbar puncture were noted in a subset of
patients not reporting headaches. Interestingly, in a
double-blind study of 100 healthy volunteers, the in-
cidence of headache was similar whether a diagnostic
or sham lumbar puncture was performed.6 Among
those undergoing the sham puncture, headaches were
more common among those who had expressed con-
cern about developing a headache vs those who did
not (46.7 vs 11.4%, P < .01).
In addition to the routinely reported lumbar
puncture indices, it has been hypothesized that the
change in CSF pressure relative to the volume with-
drawn may be more reflective of PDPH susceptibility.7
In 1925, Alpers observed, “the outstanding feature in
the cases in which there was a headache, however, was
the marked fall in the spinal fluid pressure after the
withdrawal of fluid.”7 The relationship between OP,
closing pressure (CP) and volume removed (V) is cap-
tured by the pressure-volume index (PVI).8 The PVI
is inversely related to craniospinal elastance (E). PVI
has reflected an increased elastance in patients with
idiopathic intracranial hypertension.8 Conversely,
an association has been previously reported between
spontaneous intracranial hypotension and connective
tissue disorders, where dysfunctional tissue elasticity
is present.9
To further explore this topic of clinical and patho-
physiological relevance, we performed both a retro-
spective study to evaluate OP, CP, V, and PVI as risk
factors for PDPH utilizing age- and sex-matched con-
trols. In addition, given the diagnostic weight of pres-
sure and volume concepts to the diagnosis of PDPH,
we performed the first systematic literature review to
synthesize existing knowledge on this topic.
METHODS
Case-Control Study.—Standard Protocol Approvals,
Registrations, and Patient Consents.—The study was
approved by the Mayo Clinic Institutional Review
Board, study # 19-007074.
Participants and Study Design.—Patients were
identified retrospectively from the records of Bryce
L. Falk, M.S., R.N. who conducts an outpatient
lumbar puncture clinic at the Mayo Clinic Arizona
Department of Neurology and maintains a database of
all cases as part of her State Board of Nursing procedural
certification. All cases from January 4, 2005 to
May 24, 2018 were screened, where 197/2869 (6.8%)
had been clinically documented as having PDPH.
Inclusion as a case required fulfillment of ICHD-3
criteria for 7.2.1 Post-dural puncture headache, with
exception of the requirement for documentation of
low CSF pressure and/or radiographic findings of
intracranial hypotension. It was felt that these criteria
impose unproven pathophysiological assumptions
regarding PDPH, and are also impractical for
diagnosis in real-world scenarios. Cases were
excluded where documentation of OP, CP, and V was
not available. Finally, cases with a history of (or dis­
covered to have) disorders of cerebrospinal fluid
dynamics and/or intracranial pressure (eg, normal
pressure hydrocephalus, idiopathic intracranial
hypertension, meningitides), or a history of cranio­
tomy or shunting were excluded.
Controls were identified from the same pop-
ulations as the cases as a consecutive sex- and age-
(±2  years) matched patients, with the identical
exclusion criteria. Matching of 1:1 was considered to
be reasonable on the basis of this being exploratory,
and that many patients were anticipated to not have
sufficient documentation of the required variables for
analysis, making identification of appropriate con-
trols challenging. The methodology for matching was
“by hand.” Starting from newest to oldest all ­patients
were reviewed consecutively for the sex and age
Headache
criterion, and then individual charts were reviewed
for availability of the study variables and exclusion
criteria.
An a priori power analysis was not performed.
For this exploratory study, we aimed to enroll all pos-
sible qualifying patients within the confines of the
available retrospective dataset.
Baseline Characteristics.—Baseline demographic
and clinical characteristics were recorded by chart
abstraction, including age, sex, body mass index
(BMI), needle gauge, body position and headache as
procedural indication. OP, CP, and V were recorded
for all patients.
Calculation of E was performed according to
­established relationships (∆P/∆V),10,11 as follows:
(OP − CP)
E=
V
Calculation of PVI was performed according to
established equations,10,11 as follows:
V
PVI = ( )
OP
log 10 CP
Protocol.—All LPs were performed by a single
nurse injector utilizing a standardized protocol with
either 20 or 22 gauge Quincke needles, all 3.5 inches in
length. Patients receive advice to hydrate prior to and
following the procedure as well as avoid strenuous
activities following the procedure. No premedication
is administered prior to the procedure. Patients
remain lying down for 30 minutes following the LP.
Statistical Analysis.—The primary objective was
to determine whether CSF pressure-volume indices
were associated with PDPH as compared to age- and
sex-matched controls. The primary outcome measure
was considered to be differences in PVI, with
secondary outcomes measures including OP, CP,
V, and E. Descriptive statistics were used including
counts and percentages or medians and interquartile
ranges (IQR), as appropriate. A matched-pairs
analysis of differences between case and control
groups was conducted. For categorical variables, the
paired differences in proportions of response were
estimated via generalized linear model; normally
approximated 95% confidence intervals and P-values
3
were reported. For continuous variables, the median
difference between matched pairs was estimated and
95% confidence intervals were estimated by bias-
corrected and accelerated bootstrap (BCa) with
2000 samples.12 The differences were then compared
to zero using the Wilcoxon sign-rank test and their
p-values reported.
All statistical tests were 2-sided with P < .05 con-
sidered statistically significant. Analyses were per-
formed in SAS v9.4 (SAS Institute; Cary, NC).
SYSTEMATIC LITERATURE REVIEW
A protocol for our systematic review was devel-
oped a priori in collaboration with a medical librarian
(MAL). The protocol was not registered. The PICOS
question addressed by our systematic review was
posed to emphasized study inclusiveness, as follows:
In patients undergoing a diagnostic lumbar puncture
are OP, CP, and/or V associated with risk of PDPH?
The following databases were searched: Cochrane
Database of Systematic Reviews (2005 to October 10,
2018), Ovid EMBASE (1988 to 2018 Week 41), Ovid
MEDLINE 1946 to present), Scopus (1960 to present)
and Web of Science (1975 to 2018). In all databases,
the following MeSH terms were searched: “Spinal
Puncture,” “Post-Dural Puncture Headache,”
“Cerebrospinal Fluid,” and “Intracranial Pressure.”
The following key/text words were also searched in
each database: “lumbar puncture,” “lp,” “spinal tap,”
“spinal headache,” “lumbar puncture headache,” post
lumbar puncture headache,” “post lp headache,” “lp
headache,” “cerebrospinal fluid,” “pressure volume
indices,” and “pressure-volume indices.” No restric-
tions were placed on the study design for inclusion;
instead, this was recorded a variable in our systematic
review. Individual case reports were excluded, as this
design would not allow a comparison of patients with
or without PDPH. The search strategy generated 711
references, no limitations were applied. An additional
13 references were added as a result of hand searching
for a total of 724 references. Of the total 724 citations,
276 duplicates were removed leaving 448 references
for inclusion or exclusion review. All languages were
included.
Study inclusion criteria required reporting a com-
parison of headache incidence following a diagnostic
4 Month 2019
LP as a function of OP, CP, and/or V. In an effort to
comprehensively evaluate the body of literature, a
specific set of diagnostic criteria were not pre-selected
as necessary for study inclusion. Instead, a descrip-
tion of criteria for diagnosis of post-LP headache was
required and recorded in our review as a variable for
abstraction and analysis. No age restrictions were im-
posed on study selection. Studies were excluded that
evaluated headaches due to spontaneous intracra-
nial hypotension, in addition to dural breach due to
epidural and/or spinal anesthesia, lumbar drainage,
device placement (eg, spinal cord stimulator), cister-
nography, or myelography. Studies on animals were
excluded.
The 448 references were individually reviewed by
one of the investigators (JHS) for study inclusion and
exclusion criteria. Abstracted data included: publi-
cation year, study design, diagnostic criteria used for
PDPH, description and size of patient population, fre-
quency of PDPH, needle types and gauges utilized,
and reported comparisons of OP, CP, and V, where
applicable. The desired outcome was a semi-quantita-
tive (eg, percent of studies showing an effect of a given
variable) and descriptive appraisal of the results. Risk
of bias for individual studies was assessed for cohort
studies using the Newcastle-Ottawa Scale, which
rates 8 items across 3 quality subcategories, includ-
ing selection, comparability and outcome.13 The data
were considered to be too heterogeneous to warrant a
valid meta-analysis
RESULTS
Clinical Characteristics and Group Differences.—
Fifty-three individuals with PDPH were identified
whom met study inclusion and exclusion criteria
(Fig. 1). An equal number of age- and sex-matched
controls were consecutively selected (Table 1).
Headache indication was more common among
PDPH patients [difference in proportion (95% CI)
28.3(11.5, 45.2), P  =  .001]. No other demographic or
clinical characteristics were significantly different
between groups.
Systematic Literature Review.—Manual review
of abstracts and/or full texts identified 22 unique
references evaluating the relationship between CSF
volume and/or pressure measurements and PDPH
Retrospecve LP-clinic
cohort, January 4, 2005-
July 12,2018 (n = 2,869)
Clinically documented
cases of postdural
puncture headache (n =
197)
Pressures not ordered (n =
112), or closing pressure
not recorded (n =17 )
Exclusion of disorders of
CSF and/or intracranial
pressure, including
meningis1 (n = 15)
Final case cohort (n = 53)
Fig. 1.—Selection of study cohort.
incidence (Fig. 2).3,7,14-33 The references included
analysis of V (n = 14), OP (n = 11) and/or CP (n = 4)
(Table 2). Prospective methodology was utilized
by 15 (68.1%) of the articles. ICHD criteria was
utilized to assess the outcome measure of PDPH in 9
(40.9%) of the articles. The frequency of PDPH ranged
from 0.9 to 48.9%, and included sample sizes ranging
from 47 to 3456.
Among studies evaluating V, a significant associa-
tion with PDPH was identified by 4/14 (28.5%).17,20,26,27
An increased volume of CSF withdrawal was associ-
ated with either reduced PDPH risk by 2/4 (50%),17,27 or
increased PDPH risk in 1 study.20 Finally, Monserrate
demonstrated an increased risk with either high or low
volume removal, depending on the timing of the out-
come.26 Chan et al documented an adjusted OR (95%
CI) of 0.17 (0.04-0.79) in comparing 20 mL vs 10 mL
volume removal for any headache occurring within
3 days of the LP.17 Moulder et al evaluated a prospec-
tive cohort utilizing ICHD-2 criteria, reporting an
adjusted OR (95% CI) of 0.52 (0.31-0.87) comparing
volume removal >20 mL to ≤20 mL as a reference.27
Headache 5

Table 1.—Demographic and Clinical Comparison of PDPH and Control Groups

Controls Paired Difference Paired Difference in

PDPH (n = 53) (n = 53) (Median [95% CI]) Proportion (%(95% CI) P-value

Age (median [IQR]) 42 (34-51) 42 (34-51) 0.0 (NE, NE) .423

Sex (No. F [%]) 39 (73.5) 39 (73.5) 0.0 (NE, NE) NE
BMI (Median [IQR]) 25 (21.3) 25 (23.1) −0.3 (−1.8, 2.2) .855
Headache as indication for 41 (77.36) 26 (49.1) 28.3 (11.5, 45.2) .001
LP (No. [%])
Needle gauge (No. 20 gauge [%]) 27 (50.9) 28 (52.8) −1.8 (−18.8, 15.1) .827
Opening pressure (Median (IQR)) 17.5 (16-21) 17 (14.75-19) 0.5 (−1.0, 2.0) .303
Closing pressure (Median [IQR]) 12 (10.5-13.75) 11 (9.5-13.5) 1.0 (0.0, 2.0) .452
Volume removed (Median [IQR]) 13 (9-18) 12 (9-16.25) 0.5 (−2.0, 3) .624
Elastance (Median [IQR]) 0.47 (0.34-0.63) 0.5 (0.36-0.58) 0.05 (−0.09, 0.11) .503
Pressure-volume index 73.1 (54.95-94.35) 68.58 (55.73-90.11) 4.53 (−7.98, 19.97) .678
(Median [IQR])

BMI = body mass index; NE = non-estimable; PDPH = post-dural puncture headache

Fig. 2.—PRISMA flow diagram.

Hammond et al reported an adjusted OR (95% CI) at post-procedural day 2-5.20 Finally, Monserrate et al
of 1.47 (1.01-2.14) for every additional 5  mL as com- retrospectively analyzed prospectively obtained data,
pared to 0-5 mL removal, based on prospective data documenting a significant association of high-volume
 6

Table 2.—Summary of Studies Reporting Associations of PDPH With V, OP, and/or CP

Frequency
Publication Diagnostic Criteria Patient of PDPH, Needle Gauge, Comparison: Comparison:
References Year Study Design for PDPH Population n (%) Type (%) Comparison: V OP CP

Alcolea et al14 2014 Prospective ICHD-2, asssesed at Memory clinic 140 (20.3) Quincke-20G (24.5) OR (95% CI): 1.06 N/A N/A
cohort day 5-7 patients, Quincke-22G (40.6) (0.95-1.17), P = .3
n = 689 Whitacre-22G
(34.8)
Alpers7 1925 Prospective Any headache within Mental health 16 (17.5) Not reported No direct relationship N/A N/A
cohort 10-14 days of LP inpatients, between amount
n = 91 of fluid withdrawn
and incidence of
headache could be
demonstrated
Barreras et al15 2017 Retrospective Persistent, positional Academic 16 (6) Quincke-20G (77) Mean ± SD N/A N/A
cohort headache within LP clinic, Quincke-22G (12) PDPH: 17 ± 5
1 week of LP, n = 307 Sprotte-22G (4) No PDPH: 17 ± 7
requiring contact Quincke-18G (7) P = .85
with medical team
Bertolotto et al16 2016 Prospective ICHD-3 beta. Neurology 33 (8.8) Quincke-20G (10.6) Median ± IQR N/A N/A
trial 5-15 days after LP patients, Sprotte-22G (16.9) PDPH: 10 (8-14)
n = 376 Whitacre-25G No PDPH: 12 (10-15)
(36.4)
Sprotte-25G (35.8) OR 0.63 (0.35-1.13),
P = .12

Chan et al17 2018 Retrospective Any headache as- Untreated 30 (25.8) Standard cutting- Multivariate OR (95% N/A N/A
cohort sessed at day 3 acute HIV edge or atrau- CI),
after LP patients, matic needles 20 mL vs 10mL (Ref):
n = 116 0.17 (0.04-0.79),
P = .024
Duits et al19 2016 Prospective ICHD-2, within Memory 296 (8.6) Cutting edge (83.1) OR (95% CI), N/A N/A
cohort 2 weeks patients, Atraumatic (15.7) 5-12 vs <5 mL (Ref):
n = 3456 1.02 (0.67-1.57)
25G (27.6) >12 vs <5 mL (Ref):
0.96 (0.55-1.7)
23-24G (6)
22G (31.7)
21G (8.7)
19-20G (25.3)
Month 2019
 Table 2.—Continued
Headache

Frequency
Publication Diagnostic Criteria Patient of PDPH, Needle Gauge, Comparison: Comparison:
References Year Study Design for PDPH Population n (%) Type (%) Comparison: V OP CP

Hammond 2011 Prospective Not specified, Neurology 53 (28.3) Quincke-20G (37.9) Adjusted OR (95% N/A N/A
et al 20 cohort 2-5 days after LP patients, CI):
n = 187 Quincke-22G (31.5) Each additional 5 mL
vs 1-5mL (Ref): 1.47
(1.01-2.14)
Sprotte-22G (30.4) P = .04

Han et al32 2015 Retrospective Not specified, Memory 23 (48.9) Quincke-20G N/A Non-significant N/A
(Abstract) cohort 7-14 days after LP patients and by logistic
“controls,” regression
n = 47 (data not
available)
Hannerz21 1997 Prospective “Confirmed when Neurology 29 (29) 22G N/A Non-significant N/A
cohort the pain was much patients with (data for
more intense in the headache specific com-
upright position disorders, parison not
than before the lum- n = 100 reported)
bar puncture, if it
interfered with daily
living by forcing the
patient to lie down
to relieve the pain,
and if it returned to
the initial intensity
within 14 days after
the lumbar punc-
ture,” within 1 week
after LP
Hilton-Jones 1982 Prospective Any headache, Neurology 29 (38) Standard wire-20G N/A Mean ± SD N/A
et al 22 trial 24-72 hours after inpatients, PDPH:
LP n = 76 13.9 ± 4.8
No PDPH:
13.8 ± 4.4
Non-significant
(specific P
value not
reported)
7
 8

Table 2.—Continued

Frequency
Publication Diagnostic Criteria Patient of PDPH, Needle Gauge, Comparison: Comparison:
References Year Study Design for PDPH Population n (%) Type (%) Comparison: V OP CP

Khlebtovsky 2015 Prospective ICHD-2, within Neurology 37 (27.6) 20G (61.1) N/A PDPH not more N/A
et al 23 cohort 24 hours inpatients, 22G (31.2) likely in pa-
n = 144 tients with OP
>22 (28.5%)
vs <22 (18%)
cmH2O
(P = .078)

Kim et al24 2012 Prospective ICHD-2, immediate Neurology 22 (31.4) 22G cutting needle Mean ± SD Mean ± SD Mean ± SD
trial patients,
PDPH: 24.5 ± 12.9 PDPH: PDPH:
n = 70
12.9 ± 5.1 10.9 ± 4.3
No PDPH: 23.6 ± 8.3 No PDPH: No PDPH:
13 ± 5.8 10.2 ± 5.7
P = .747 P = .968 P = .764
Kuntz et al25 1992 Prospective Headache that Lumbar punc- 83 (36.5) 20G (96.8) Mean ± SD Mean ± SD Mean ± SD
cohort improved or ture clinic, 22G (3.2) PDPH: 12.4 ± 5.1 PDPH: PDPH:
disappeared with n = 501 15.2 ± 4.2 9.3 ± 3.4
recumbency and No PDPH: 12.9 ± 8.3 No PDPH: No PDPH:
that occurred on 14.9 ± 3.5 8.7 ± 3.9
P reported only as P reported only P reported
1 or more of the
“non-significant” as “non- only as
7 follow-up days,
significant” “non-signifi-
with day 1 being
cant”
the day of the LP
Mac Grory and 2015 Retrospective Documentation of Lumbar punc- 36 (16.5) Quincke-22G Mean ± SD Mean ± SD Mean ± SD
Khokhar33 cohort headache that ture clinic, PDPH: 21.8 ± 10 PDPH: 21.5 ± 9 PDPH:
began within n = 218 15.8 ± 4.4
5 days of proce- No PDPH: 20.6 ± 9.4 No PDPH: No PDPH:
dure, and was 20.3 ± 9 14.3 ± 5.4
P = .5 P = .48 P = .12
attributed to LP.
Monserrate 2015 Retrospective Not specified Participants Immediate Sprotte-22G (74.9) Multivariable OR N/A N/A
et al 26 cohort in the postpro- (95% CI):
Dominantly cedural
Inherited head-
Alzheimer ache: 73
Networkd, (21.5)
n = 338
PDPH at Sprotte-24G (19.2) Immediate postproce-
24-hours: dural headache
59 (17.4)
Other (5.9) 1.63 (1.15-2.33)/ 5 mL,
P = .007
Month 2019
 Table 2.—Continued

Frequency
Publication Diagnostic Criteria Patient of PDPH, Needle Gauge, Comparison: Comparison:
Headache

References Year Study Design for PDPH Population n (%) Type (%) Comparison: V OP CP

< 17 vs 17-30 mL
(Ref): 0.98 (0.3-
3.22), P = .98
>30 vs 17-30 mL
(Ref): 3.73 (1.45-
9.59), P = .006
PDPH at 24-hours
0.77 (0.56-1.06)/5 mL,
P = .11
< 17 vs 17-30 mL
(Ref): 3.07 (1.11-
8.49), P = .04
>30 vs 17-30 mL
(Ref): 0.57 (0.15-
2.14), P = .4
de Almeida 2011 Prospective Any headache fol- Research 38 (5.6) Atraumatic 22G OR (95% CI): N/A N/A
et al18 cohort lowing the LP … volunteers By ICHD-2 ≥13 mL vs <13 mL
[assessed] usually at the HIV criteria: 6 (Ref): 0.58 (0.28-
within 48 hours of Neurobe­ (0.9) 1.2), P = .13
their LP havioral
Research
Center,
n = 675

Moulder et al 27 2017 Prospective ICHD-2, 7 days after Alzheimer 42 (11.9) Quincke (46) Adjusted OR (95% N/A N/A
cohort LP Disease CI):
Center Sprotte (53.9) >20 mL vs ≤20 mL
participants, (Ref): 0.52 (0.31-
n = 352 0.87), P < .05
20G (5.6)
22G (37.7)
24G (28.6)
25G (6.2)
Park et al28 2014 Retrospective ICHD-3 beta Tertiary hospi- 36 (8.7) Quincke-22G N/A Median ± IQR N/A
cohort tal database, PDPH: 10 (1-19)
n = 413 No PDPH: 10
9

(1-38)
 10

Table 2.—Continued

Frequency
Publication Diagnostic Criteria Patient of PDPH, Needle Gauge, Comparison: Comparison:
References Year Study Design for PDPH Population n (%) Type (%) Comparison: V OP CP

P = .009
Adjusted OR
(95% CI):
1 (1-1.03),
P = .015
Quinn et al 29 2013 Retrospective Any headache oc- Amyotrophy 40 (22.8) Cutting (57.7) “No effect of…vol- N/A N/A
cohort curring within lateral Atraumatic (42.2) ume of CSF drawn
72 hours of LP sclerosis on risk of [PDPH],”
patients, specific data not
n = 175 reported
van Oosterhout 2013 Prospective ICHD-2R, around Migraine 64 (32.2) Quincke N/A Mean ± SD N/A
et al30 cohort 3 days after LP research PDPH:
participants, 18.3 ± 4.6
n = 199 No PDPH:
17.4 ± 4.2
P = .184
Adjusted OR
(95% CI):
1.057 (0.969-
1.153),
P = .209
Vilming et al3 1989 Prospective, Any postural head- Neurologic 112 (37.3) 22G N/A Chi-square: N/A
single-blind ache, 4-6 days after inpatients, < 16 (43/137,
trial LP n = 300 31.3%) vs
>16 (33/120,
27.5%), non-
significant
13-16 (51/69,
73.9%) vs
>16 (33/120,
27.5%),
P < .025
Wang et al31 2015 Prospective ICHD-2 Hospital 23 (28.8) Quincke-22G N/A Mean ± SD Mean ± SD
cohort inpatients, PDPH: 15.1 ± 4 PDPH:
n = 80 11.2 ± 4.2
No PDPH: No PDPH:
16.2 ± 5.8 11.3 ± 4.2
P = .472 P = .923
Month 2019
 Headache

Table 3.—The Newcastle-Ottawa Quality Assessment Scale of Included Cohort Studies

Selection Comparability Outcome

Representativeness (Clinical Selection of Outcome Controls for Follow-up

Populations Undergoing a Non-Exposed not Present Needle Type Duration of at Follow-up Total Stars (Out
Reference Diagnostic LP) Cohort Ascertainment at Start and/or Size Assessment least 5 Days Adequacy of 9 Possible)

Alcolea et al14 * * ** * * * 7
Alpers7 * * * 3
Barreras et al15 * * * ** * * 7
Bertolotto et al16 * * * * ** * * * 9
Chan et al17 * * ** * * 6
Duits et al19 * * ** * * * 7
Hammond et al20 * * * * * 5
Han et al32 * * * * * 5
Hannerz21 * * * * * 5
Hilton-Jones et al22 * * * ** * * 7
Khlebtovsky et al23 * * * ** * * 7
Kim et al24 * * * ** * 6
Kuntz et al25 * * * * * * 6
Mac Grory and * * * ** * 6
Khokhar33
Monserrate et al26 * * ** * * 6
de Almeida et al18 * * ** * * 6
Moulder et al27 * * * ** * * * 8
Park et al28 * * * ** * * 7
Quinn et al29 * * * * 4
van Oosterhout et al30 * * ** * * 6
Vilming et al3 * * * ** * 6
Wang et al31 * * * ** * * * 8
11
12
(>30 mL) removal compared to 17-30 mL for immedi-
ate post-procedural headache, and an association for
low-volume (<17 mL) removal compared to 17-30 mL
for headache at 24 hours.26
Among studies evaluation OP, an association with
PDPH was reported by 2/11 (18.1%).3,28 Park et al con-
cluded that lower CSF pressure was associated with
PDPH.28 However, on inspection of the data, the 95%
CI of the OR included 1, indicating that the risk of
PDPH was just as likely independent of OP. Similarly,
Vilming et al concluded that a reduced risk of PDPH
was observed in patients with a higher than average CSF
pressure.3 The authors observe that a spike in PDPH in-
cidence is seen among patients with an OP between 13-16
cmH2O, as compared to those with an OP >16 cmH2O
(P  <  .025). However, no difference was seen when pa-
tients are compared with an OP <16 cmH2O and >16
cmH2O. Of concern in interpreting this result is that the
evaluation of patients as a group with OP 13-16 cmH2O
was not determined a priori. Further, an excessive num-
ber of comparisons (n = 58) are made in this manuscript,
significantly increasing the probability of a type I error.
Among studies evaluating CP, no association was
demonstrated with PDPH in any study.
Overall, individual studies were graded with
a median of 6 stars (IQR: 5.5-7), indicating inclu-
sion of generally good quality studies by Agency of
Healthcare Research and Quality standards (Table 3).
DISCUSSION
PDPH is classified as a headache attributed to
low CSF pressure, yet the data reported here, as well
as the majority of studies identified in our systematic
literature review do not justify this conclusion. We did
not identify any convincing evidence demonstrating
an association of either OP or CP with PDPH risk.
The 2 studies reporting an association with OP,3,28 ei-
ther concluded so erroneously with an OR including
1,28 or had significant methodological flaws, includ-
ing excessive hypothesis testing.3 Of note, however, is
that the standard point measurement of a CSF col-
umn may be misleading as pressure may vary over
time.34,35 Re-evaluation of these associations with
30-60 minute CSF pressure averages, and determina-
tion of peak pulse amplitudes would better approxi-
mate a gold-standard assessment of these covariates.36
Month 2019
The data concerning V appears to be more nu-
anced, with the majority of studies not documenting
an association. Instances of documented association
are notable for inclusion of cases with high-volume
removal (>20 mL,17,27 >30 mL26), and/or dissection of
the interaction between timing of headache and vol-
ume removal.26 Accordingly, high-volume loss may
predispose to immediate headache, but subsequently
facilitate earlier dural closure, as higher volumes are
associated with 24  hour headache risk reduction.26
Patients with <17  mL collection were more likely to
require a therapeutic blood patch as compared with
patients who had 17-30  mL removal.26 That patients
with immediate vs delayed onset of PDPH might have
distinct temporal and prognostic profiles (eg, require-
ment for blood patch) challenging common assump-
tions. Pending further prospective study, clinicians
may at the least be aware that patients with a delayed
onset of symptoms might be more likely to require
eventual epidural blood patching.
We did not identify any convincing evidence for
E or PVI as a marker of PDPH risk, with our study
being the first to evaluate it as a primary outcome
measure. Alpers felt a relationship between elastance
and PDPH existed, but did not conduct a formal com-
parison.7 Hilton-Jones et al comments on the mean
change in pressure after removal of 10 mL of CSF as
statistically similar in patients with and without head-
ache.22 Therefore, both Alpers and Hilton-Jones eval-
uated E, although did not comment on it by name.
PVI as evaluated in our current study is less influ-
enced by OP, making it a more specific marker of cra-
niospinal E. Prior studies have not evaluated E or PVI
in patients with immediate vs delayed onset of PDPH,
and the retrospective nature of our current work did
not allow for a valid analysis of latency to onset.
Limitations of our case-control study include the
retrospective study design, reliance on an estimate
of pressure-volume index (as opposed to direct mea-
surement) and the limitations inherently imposed by
a single point measurement of a continuous measure
(eg, CSF pressure), which often does not reflect the
mean or range of pressures observed over a 1-hour ob-
servation.37 Therefore, given the limitations of a sin-
gle point measurement of pressure and that distinct
phases of the pressure-volume curve may exist, our
Headache
study does not preclude the possibility of PVI being
a contributor to PDPH pathophysiology. Finally,
our methodology of selecting controls “by hand”
was approached using a systematic and consecutive
technique, but nonetheless remains an important
limitation, potentially imposing bias that could have
been avoided with a non-manual technique.
The pathophysiology of PDPH has remained elu-
sive, with the working hypothesis that a state of intra-
cranial hypotension is created following the lumbar
puncture, which in turn results in vasodilation and/or
traction of pain-sensitive intracranial structures.4 An
alternative hypothesis is that fragments of tissue are
released in to the CSF as a result of trauma during
lumbar puncture, causing meningeal irritation. This is
a compelling hypothesis given that it would not require
changes in intracranial pressure to mediate headache.
However, the ICHD-3 requires documentation by OP
and/or neuroimaging evidence of intracranial hypo-
tension. However, the sensitivity and specificity of
these criteria have not been specifically field-tested.
Iatrogenic meningeal enhancement is thought to be
unusual in unselected patients with an MRI head
obtained on average within 5  days following LP.38
Further, a prospective cohort study of 20 participants
undergoing LP with an 18G needle and 10  mL vol-
ume removal, documented reduction in intracranial
CSF volume in 19/20 (95%).39 However, no measurable
change in the position of the cerebellar tonsils was de-
tected following the LP in any patient. Further, a sta-
tistical difference in intracranial volume loss was not
detected by those with or without PDPH. In a larger,
prospective cohort, a more extensive and more rostral
distribution of periradicular leaks and epidural CSF
collections was observed in patients reporting PDPH
than those without.31 Opening or closing pressures
were not associated with the presence of these radio-
graphic findings. These results call into question the
role of intracranial hypotension in patients with PDPH.
Alternatively, patients with PDPH may be structurally
predisposed to more severe tears, and/or have relatively
impaired repair capacity following dural injury.
A definitive, future study of interest (albeit inva-
sive) would be to perform computed tomography my-
elography in a prospective controlled PDPH cohort
to more directly assess the putative structural culprit
13
underlying PDPH pathophysiology. A role for PVI in
immediate vs delayed subtypes would be of potential
future interest. While excluded from the current work,
future evaluation of PDPH risk in patients with nor-
mal pressure hydrocephalus may provide insight into
a potentially protective role of an elevated baseline
volume buffer. CSF tryptase, a mast cell specific pro-
tein, may also serve as a putative biomarker of dural
tear.40 Future work should specify hypothesis testing
at discrete time-points following LP, where differing
pathophysiology may exist.
CONCLUSIONS
PDPH is likely a heterogeneous diagnosis, with
likely time-dependent pathophysiological mecha-
nisms following the LP. Future revision of diag-
nostic criteria should consider the possibility of
immediate and delayed PDPH subtypes, and not
presume intracranial hypotension as mandatory for
the diagnosis.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Jonathan H. Smith, Lisa A. Marks, Richard J.
Butterfield
(b)  Acquisition of Data
Jonathan H. Smith, Brian Mac Grory, Babar

Khokar, Bryce L. Falk, Lisa A. Marks
(c)  Analysis and Interpretation of Data
Jonathan H. Smith, Brian Mac Grory, Richard J.
Butterfield, Babar Khokar
Category 2
(a) Drafting the Manuscript
Jonathan H. Smith, Brian Mac Grory, Babar

Khokar, Bryce L. Falk, Lisa A. Marks
(b)  Revising It for Intellectual Content
Jonathan H. Smith, Brian Mac Grory, Richard J.
Butterfield, Lisa A. Marks
Category 3
(a) Final Approval of the Completed Manuscript
Jonathan H. Smith, Brian Mac Grory, Richard J.
Butterfield, Babar Khokar, Bryce L. Falk, Lisa A.
Marks
14
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