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,

INTRODUCTION
AZ, USA (J.H. Smith and B.L. Falk); Department of Post-dural puncture headache (PDPH) is recog-
Neurology,  Brown University, Providence, RI, USA (B. Mac nized by the International Classification of Headache
Grory); Division of Biostatistics, Mayo Clinic, Scottsdale, AZ, Disorders, 3rd Edition (ICHD-3), as a headache de-
USA (R.J. Butterfield); Department of Neurology,  Yale
University, New Haven, CT, USA (B. Khokar); Department veloping within 5  days of a dural puncture, with
of Library Services, Mayo Clinic, Scottsdale, AZ, USA (L.A. objective evidence of low cerebrospinal fluid (CSF)
Marks). pressure.1 The incidence of PDPH is 11% (95% con-
Address all correspondence to J.H. Smith, MD, Department of fidence interval (CI) 9.1-13.3) when conventional
Neurology, Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale,
AZ 85259, USA, email: [email protected]
Conflicts of Interest: None
Data Availability Statement.—All data used in the study analysis
Accepted for publication June 8, 2019. 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) factors for PDPH utilizing age- and sex-matched con-
when atraumatic needles are utilized.2 Risk factors trols. In addition, given the diagnostic weight of pres-
for PDPH include age, female sex, bevel orientation, sure and volume concepts to the diagnosis of PDPH,
and use of traumatic and/or larger bore needles.2,3 we performed the first systematic literature review to
However, despite the concept of intracranial hypo- synthesize existing knowledge on this topic.
tension being recognized as part of the diagnostic cri-
teria, the impact of cerebrospinal fluid pressure and METHODS
volume indices (eg, opening pressure [OP]) on PDPH Case-Control Study.—Standard Protocol Approvals,
incidence is unclear.4 Registrations, and Patient Consents.—The study was
The diagnosis of PDPH requires evidence of low approved by the Mayo Clinic Institutional Review
cerebrospinal fluid pressure;1 however, it has not been Board, study # 19-007074.
established whether or not this represents a causative Participants and Study Design.—Patients were
mechanism. In a series of patients undergoing lumbar identified retrospectively from the records of Bryce
puncture, Marshall noted that the opening pressure L. Falk, M.S., R.N. who conducts an outpatient
was normal in a subset of patients during a second lumbar puncture clinic at the Mayo Clinic Arizona
lumbar puncture despite concurrent positional head- Department of Neurology and maintains a database of
ache.5 Further, extremely low pressures at the time of all cases as part of her State Board of Nursing procedural
a second lumbar puncture were noted in a subset of certification. All cases from January 4, 2005 to
patients not reporting headaches. Interestingly, in a May 24, 2018 were screened, where 197/2869 (6.8%)
double-blind study of 100 healthy volunteers, the in- had been clinically documented as having PDPH.
cidence of headache was similar whether a diagnostic Inclusion as a case required fulfillment of ICHD-3
or sham lumbar puncture was performed.6 Among criteria for 7.2.1 Post-dural puncture headache, with
those undergoing the sham puncture, headaches were exception of the requirement for documentation of
more common among those who had expressed con- low CSF pressure and/or radiographic findings of
cern about developing a headache vs those who did intracranial hypotension. It was felt that these criteria
not (46.7 vs 11.4%, P < .01). impose unproven pathophysiological assumptions
In addition to the routinely reported lumbar regarding PDPH, and are also impractical for
puncture indices, it has been hypothesized that the diagnosis in real-world scenarios. Cases were
change in CSF pressure relative to the volume with- excluded where documentation of OP, CP, and V was
drawn may be more reflective of PDPH susceptibility.7 not available. Finally, cases with a history of (or dis­
In 1925, Alpers observed, “the outstanding feature in covered to have) disorders of cerebrospinal fluid
the cases in which there was a headache, however, was dynamics and/or intracranial pressure (eg, normal
the marked fall in the spinal fluid pressure after the pressure hydrocephalus, idiopathic intracranial
withdrawal of fluid.”7 The relationship between OP, hypertension, meningitides), or a history of cranio­
closing pressure (CP) and volume removed (V) is cap- tomy or shunting were excluded.
tured by the pressure-volume index (PVI).8 The PVI Controls were identified from the same pop-
is inversely related to craniospinal elastance (E). PVI ulations as the cases as a consecutive sex- and age-
has reflected an increased elastance in patients with (±2  years) matched patients, with the identical
idiopathic intracranial hypertension.8 Conversely, exclusion criteria. Matching of 1:1 was considered to
an association has been previously reported between be reasonable on the basis of this being exploratory,
spontaneous intracranial hypotension and connective and that many patients were anticipated to not have
tissue disorders, where dysfunctional tissue elasticity sufficient documentation of the required variables for
is present.9 analysis, making identification of appropriate con-
To further explore this topic of clinical and patho- trols challenging. The methodology for matching was
physiological relevance, we performed both a retro- “by hand.” Starting from newest to oldest all ­patients
spective study to evaluate OP, CP, V, and PVI as risk were reviewed consecutively for the sex and age
Headache 3

criterion, and then individual charts were reviewed were reported. For continuous variables, the median
for availability of the study variables and exclusion difference between matched pairs was estimated and
criteria. 95% confidence intervals were estimated by bias-
An a priori power analysis was not performed. corrected and accelerated bootstrap (BCa) with
For this exploratory study, we aimed to enroll all pos- 2000 samples.12 The differences were then compared
sible qualifying patients within the confines of the to zero using the Wilcoxon sign-rank test and their
available retrospective dataset. p-values reported.
Baseline Characteristics.—Baseline demographic All statistical tests were 2-sided with P < .05 con-
and clinical characteristics were recorded by chart sidered statistically significant. Analyses were per-
abstraction, including age, sex, body mass index formed in SAS v9.4 (SAS Institute; Cary, NC).
(BMI), needle gauge, body position and headache as
procedural indication. OP, CP, and V were recorded SYSTEMATIC LITERATURE REVIEW
for all patients. A protocol for our systematic review was devel-
Calculation of E was performed according to oped a priori in collaboration with a medical librarian
­established relationships (∆P/∆V),10,11 as follows: (MAL). The protocol was not registered. The PICOS
question addressed by our systematic review was
(OP − CP)
E= posed to emphasized study inclusiveness, as follows:
V
In patients undergoing a diagnostic lumbar puncture
Calculation of PVI was performed according to are OP, CP, and/or V associated with risk of PDPH?
established equations,10,11 as follows: The following databases were searched: Cochrane
Database of Systematic Reviews (2005 to October 10,
V
PVI = ( ) 2018), Ovid EMBASE (1988 to 2018 Week 41), Ovid
OP
log 10 CP MEDLINE 1946 to present), Scopus (1960 to present)
and Web of Science (1975 to 2018). In all databases,
Protocol.—All LPs were performed by a single the following MeSH terms were searched: “Spinal
nurse injector utilizing a standardized protocol with Puncture,” “Post-Dural Puncture Headache,”
either 20 or 22 gauge Quincke needles, all 3.5 inches in “Cerebrospinal Fluid,” and “Intracranial Pressure.”
length. Patients receive advice to hydrate prior to and The following key/text words were also searched in
following the procedure as well as avoid strenuous each database: “lumbar puncture,” “lp,” “spinal tap,”
activities following the procedure. No premedication “spinal headache,” “lumbar puncture headache,” post
is administered prior to the procedure. Patients lumbar puncture headache,” “post lp headache,” “lp
remain lying down for 30 minutes following the LP. headache,” “cerebrospinal fluid,” “pressure volume
Statistical Analysis.—The primary objective was indices,” and “pressure-volume indices.” No restric-
to determine whether CSF pressure-volume indices tions were placed on the study design for inclusion;
were associated with PDPH as compared to age- and instead, this was recorded a variable in our systematic
sex-matched controls. The primary outcome measure review. Individual case reports were excluded, as this
was considered to be differences in PVI, with design would not allow a comparison of patients with
secondary outcomes measures including OP, CP, or without PDPH. The search strategy generated 711
V, and E. Descriptive statistics were used including references, no limitations were applied. An additional
counts and percentages or medians and interquartile 13 references were added as a result of hand searching
ranges (IQR), as appropriate. A matched-pairs for a total of 724 references. Of the total 724 citations,
analysis of differences between case and control 276 duplicates were removed leaving 448 references
groups was conducted. For categorical variables, the for inclusion or exclusion review. All languages were
paired differences in proportions of response were included.
estimated via generalized linear model; normally Study inclusion criteria required reporting a com-
approximated 95% confidence intervals and P-values parison of headache incidence following a diagnostic
4 Month 2019

LP as a function of OP, CP, and/or V. In an effort to

Retrospecve LP-clinic
comprehensively evaluate the body of literature, a cohort, January 4, 2005-
specific set of diagnostic criteria were not pre-selected July 12,2018 (n = 2,869)
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 Clinically documented
cases of postdural
abstraction and analysis. No age restrictions were im- puncture headache (n =
posed on study selection. Studies were excluded that 197)

evaluated headaches due to spontaneous intracra-

nial hypotension, in addition to dural breach due to
Pressures not ordered (n =
epidural and/or spinal anesthesia, lumbar drainage, 112), or closing pressure
device placement (eg, spinal cord stimulator), cister- not recorded (n =17 )
nography, or myelography. Studies on animals were
excluded.
The 448 references were individually reviewed by Exclusion of disorders of
CSF and/or intracranial
one of the investigators (JHS) for study inclusion and pressure, including
exclusion criteria. Abstracted data included: publi- meningis1 (n = 15)

cation year, study design, diagnostic criteria used for

PDPH, description and size of patient population, fre-
quency of PDPH, needle types and gauges utilized, Final case cohort (n = 53)
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 Fig. 1.—Selection of study cohort.
variable) and descriptive appraisal of the results. Risk
of bias for individual studies was assessed for cohort incidence (Fig. 2).3,7,14-33 The references included
studies using the Newcastle-Ottawa Scale, which analysis of V (n = 14), OP (n = 11) and/or CP (n = 4)
rates 8 items across 3 quality subcategories, includ- (Table 2). Prospective methodology was utilized
ing selection, comparability and outcome.13 The data by 15 (68.1%) of the articles. ICHD criteria was
were considered to be too heterogeneous to warrant a utilized to assess the outcome measure of PDPH in 9
valid meta-analysis (40.9%) of the articles. The frequency of PDPH ranged
from 0.9 to 48.9%, and included sample sizes ranging
RESULTS from 47 to 3456.
Clinical Characteristics and Group Differences.— Among studies evaluating V, a significant associa-
Fifty-three individuals with PDPH were identified tion with PDPH was identified by 4/14 (28.5%).17,20,26,27
whom met study inclusion and exclusion criteria An increased volume of CSF withdrawal was associ-
(Fig. 1). An equal number of age- and sex-matched ated with either reduced PDPH risk by 2/4 (50%),17,27 or
controls were consecutively selected (Table 1). increased PDPH risk in 1 study.20 Finally, Monserrate
Headache indication was more common among demonstrated an increased risk with either high or low
PDPH patients [difference in proportion (95% CI) volume removal, depending on the timing of the out-
28.3(11.5, 45.2), P  =  .001]. No other demographic or come.26 Chan et al documented an adjusted OR (95%
clinical characteristics were significantly different CI) of 0.17 (0.04-0.79) in comparing 20 mL vs 10 mL
between groups. volume removal for any headache occurring within
Systematic Literature Review.—Manual review 3 days of the LP.17 Moulder et al evaluated a prospec-
of abstracts and/or full texts identified 22 unique tive cohort utilizing ICHD-2 criteria, reporting an
references evaluating the relationship between CSF adjusted OR (95% CI) of 0.52 (0.31-0.87) comparing
volume and/or pressure measurements and PDPH 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 Month 2019

(>30 mL) removal compared to 17-30 mL for immedi- The data concerning V appears to be more nu-
ate post-procedural headache, and an association for anced, with the majority of studies not documenting
low-volume (<17 mL) removal compared to 17-30 mL an association. Instances of documented association
for headache at 24 hours.26 are notable for inclusion of cases with high-volume
Among studies evaluation OP, an association with removal (>20 mL,17,27 >30 mL26), and/or dissection of
PDPH was reported by 2/11 (18.1%).3,28 Park et al con- the interaction between timing of headache and vol-
cluded that lower CSF pressure was associated with ume removal.26 Accordingly, high-volume loss may
PDPH.28 However, on inspection of the data, the 95% predispose to immediate headache, but subsequently
CI of the OR included 1, indicating that the risk of facilitate earlier dural closure, as higher volumes are
PDPH was just as likely independent of OP. Similarly, associated with 24  hour headache risk reduction.26
Vilming et al concluded that a reduced risk of PDPH Patients with <17  mL collection were more likely to
was observed in patients with a higher than average CSF require a therapeutic blood patch as compared with
pressure.3 The authors observe that a spike in PDPH in- patients who had 17-30  mL removal.26 That patients
cidence is seen among patients with an OP between 13-16 with immediate vs delayed onset of PDPH might have
cmH2O, as compared to those with an OP >16 cmH2O distinct temporal and prognostic profiles (eg, require-
(P  <  .025). However, no difference was seen when pa- ment for blood patch) challenging common assump-
tients are compared with an OP <16 cmH2O and >16 tions. Pending further prospective study, clinicians
cmH2O. Of concern in interpreting this result is that the may at the least be aware that patients with a delayed
evaluation of patients as a group with OP 13-16 cmH2O onset of symptoms might be more likely to require
was not determined a priori. Further, an excessive num- eventual epidural blood patching.
ber of comparisons (n = 58) are made in this manuscript, We did not identify any convincing evidence for
significantly increasing the probability of a type I error. E or PVI as a marker of PDPH risk, with our study
Among studies evaluating CP, no association was being the first to evaluate it as a primary outcome
demonstrated with PDPH in any study. measure. Alpers felt a relationship between elastance
Overall, individual studies were graded with and PDPH existed, but did not conduct a formal com-
a median of 6 stars (IQR: 5.5-7), indicating inclu- parison.7 Hilton-Jones et al comments on the mean
sion of generally good quality studies by Agency of change in pressure after removal of 10 mL of CSF as
Healthcare Research and Quality standards (Table 3). statistically similar in patients with and without head-
ache.22 Therefore, both Alpers and Hilton-Jones eval-
DISCUSSION uated E, although did not comment on it by name.
PDPH is classified as a headache attributed to PVI as evaluated in our current study is less influ-
low CSF pressure, yet the data reported here, as well enced by OP, making it a more specific marker of cra-
as the majority of studies identified in our systematic niospinal E. Prior studies have not evaluated E or PVI
literature review do not justify this conclusion. We did in patients with immediate vs delayed onset of PDPH,
not identify any convincing evidence demonstrating and the retrospective nature of our current work did
an association of either OP or CP with PDPH risk. not allow for a valid analysis of latency to onset.
The 2 studies reporting an association with OP,3,28 ei- Limitations of our case-control study include the
ther concluded so erroneously with an OR including retrospective study design, reliance on an estimate
1,28 or had significant methodological flaws, includ- of pressure-volume index (as opposed to direct mea-
ing excessive hypothesis testing.3 Of note, however, is surement) and the limitations inherently imposed by
that the standard point measurement of a CSF col- a single point measurement of a continuous measure
umn may be misleading as pressure may vary over (eg, CSF pressure), which often does not reflect the
time.34,35 Re-evaluation of these associations with mean or range of pressures observed over a 1-hour ob-
30-60 minute CSF pressure averages, and determina- servation.37 Therefore, given the limitations of a sin-
tion of peak pulse amplitudes would better approxi- gle point measurement of pressure and that distinct
mate a gold-standard assessment of these covariates.36 phases of the pressure-volume curve may exist, our
Headache 13

study does not preclude the possibility of PVI being underlying PDPH pathophysiology. A role for PVI in
a contributor to PDPH pathophysiology. Finally, immediate vs delayed subtypes would be of potential
our methodology of selecting controls “by hand” future interest. While excluded from the current work,
was approached using a systematic and consecutive future evaluation of PDPH risk in patients with nor-
technique, but nonetheless remains an important mal pressure hydrocephalus may provide insight into
limitation, potentially imposing bias that could have a potentially protective role of an elevated baseline
been avoided with a non-manual technique. volume buffer. CSF tryptase, a mast cell specific pro-
The pathophysiology of PDPH has remained elu- tein, may also serve as a putative biomarker of dural
sive, with the working hypothesis that a state of intra- tear.40 Future work should specify hypothesis testing
cranial hypotension is created following the lumbar at discrete time-points following LP, where differing
puncture, which in turn results in vasodilation and/or pathophysiology may exist.
traction of pain-sensitive intracranial structures.4 An
alternative hypothesis is that fragments of tissue are CONCLUSIONS
released in to the CSF as a result of trauma during PDPH is likely a heterogeneous diagnosis, with
lumbar puncture, causing meningeal irritation. This is likely time-dependent pathophysiological mecha-
a compelling hypothesis given that it would not require nisms following the LP. Future revision of diag-
changes in intracranial pressure to mediate headache. nostic criteria should consider the possibility of
However, the ICHD-3 requires documentation by OP immediate and delayed PDPH subtypes, and not
and/or neuroimaging evidence of intracranial hypo- presume intracranial hypotension as mandatory for
tension. However, the sensitivity and specificity of the diagnosis.
these criteria have not been specifically field-tested.
Iatrogenic meningeal enhancement is thought to be STATEMENT OF AUTHORSHIP
unusual in unselected patients with an MRI head
Category 1
obtained on average within 5  days following LP.38
(a) Conception and Design
Further, a prospective cohort study of 20 participants
Jonathan H. Smith, Lisa A. Marks, Richard J.
undergoing LP with an 18G needle and 10  mL vol-
Butterfield
ume removal, documented reduction in intracranial
(b)  Acquisition of Data
CSF volume in 19/20 (95%).39 However, no measurable
Jonathan H. Smith, Brian Mac Grory, Babar

change in the position of the cerebellar tonsils was de-
Khokar, Bryce L. Falk, Lisa A. Marks
tected following the LP in any patient. Further, a sta-
(c)  Analysis and Interpretation of Data
tistical difference in intracranial volume loss was not
Jonathan H. Smith, Brian Mac Grory, Richard J.
detected by those with or without PDPH. In a larger,
Butterfield, Babar Khokar
prospective cohort, a more extensive and more rostral
distribution of periradicular leaks and epidural CSF Category 2
collections was observed in patients reporting PDPH (a) Drafting the Manuscript
than those without.31 Opening or closing pressures Jonathan H. Smith, Brian Mac Grory, Babar

were not associated with the presence of these radio- Khokar, Bryce L. Falk, Lisa A. Marks
graphic findings. These results call into question the (b)  Revising It for Intellectual Content
role of intracranial hypotension in patients with PDPH. Jonathan H. Smith, Brian Mac Grory, Richard J.
Alternatively, patients with PDPH may be structurally Butterfield, Lisa A. Marks
predisposed to more severe tears, and/or have relatively
impaired repair capacity following dural injury. Category 3
A definitive, future study of interest (albeit inva- (a) Final Approval of the Completed Manuscript
sive) would be to perform computed tomography my- Jonathan H. Smith, Brian Mac Grory, Richard J.
elography in a prospective controlled PDPH cohort Butterfield, Babar Khokar, Bryce L. Falk, Lisa A.
to more directly assess the putative structural culprit Marks
14 Month 2019

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