Keywords:
cerebrospinal fluid - headache - post-dural puncture headache - spinal puncture
Palavras-chave:
líquido cefalorraquidiano - cefaleia - cefaleia pós-punção dural - punção espinal
An adult has approximately 150 mL of cerebral spinal fluid (CSF) in the neuroaxis
at one time[1] and it is renewed 3 to 4 times a day[2],[3]. CSF is produced continuously at a rate of 0.4 mL/minute in adults, totaling 500
mL per day[4]. Therapeutic removal of CSF through the dura-mater was first performed independently
by Heinrich Quincke and Walter Wynter in 1891 to relieve raised intracranial pressure[5]. In horizontal decubitus under normal conditions, CSF pressure measured at the lumbar
region ranges from 5 to 15 cm H2O[6].
Although lumbar puncture (LP) is a relatively safe procedure, several adverse effects
have been reported, including headache and intracranial hemorrhage[7]. It is a major iatrogenic cause of morbidity in patients who underwent anesthesia,
epidural blockage, and diagnostic LP[8],[9]. A dural tear yields excessive CSF leakage, leading to intracranial hypotension
and reduced CSF volume[8],[10],[11]; however, dural repair occurs by fibroblastic proliferation of the surrounding tissue
and blood clot formation[6],[12],[13].
August Bier was the first to report the post-dural puncture headache (PDPH) in 1898[2],[9] after injecting 10-15 mg of cocaine in the subarachnoid space of seven patients[11],[14],[15]. PDPH diagnosis is based on its clinical presentation and history of previous LP,
with evidence of slightly increased CSF protein and lymphocytic pleocytosis in the
CSF[16],[17]. In 90% of PDPH patients, headache ensues within 72 hours post LP and is self-limited[1],[11].
Ever since LP has been routinely performed, PDPH incidence was reported ~66%, ranging
from 10–80%[3],[13],[15]. The largest cohort of PDPH ever published included 11,000 patients who underwent
LP and reported 50% occurrence[11]. The introduction of atraumatic needles was responsible by a markedly reduction
in the incidence of PDPH[8],[18],[19]. However, despite the American Academy of Neurology (AAN) recommendations, less
than 2% of neurologists make regular use of it[8],[12],[15],[19]. Yet a variable 10–24% PDPH incidence is reported with Quincke needles[20],[21].
Young adults[17], particularly females, tend to be mode affected (3:1)[13]. A four-fold higher incidence around the fourth decade of life is described[2],[18], while older adults are less susceptible to it[1],[15],[22]. PDPH is also infrequent in clinically demented patients[23] and specifically in normal pressure hydrocephalus[24]. A high incidence is also reported among females with low BMI[12],[19] and higher rates of PDPH are reported post LPs performed at emergency departments[25].
While variable amount of CSF is required for diagnostic tests, samples for fungal
culture or tap test require volumes in excess of 30 mL[22],[24] which can be time consuming. Duration greater than 6 minutes to collect 2 mL of
CSF through a 22G needle allowing free flow was reported[26]. Although most authors recommend free flow CSF collection, some advocate a mild
aspiration by negative pressure can be performed[15],[19],[27],[28],[29]. However, safety and tolerability of this technique were never prospectively reported.
The present study aimed to investigate the incidence of PDPH in patients subjected
to CSF aspiration during LP, comparing it to the standard technique, as well as to
document its safety and tolerability.
METHODS
Design and participants
This study included neurological patients who underwent diagnostic LP from February
2010 to December 2012 at Neurological Institute of Curitiba (Brazil). Outpatients
who attended the emergency department and inpatients that underwent diagnostic LP
were recruited for the study. Subjects had a full anamnesis and neurological examination
performed by a staff member followed by any modality of neuroimaging (i.e. CT or MRI
brain) to exclude contraindications, prior to the LP was recommended and performed.
Exclusion criteria consisted of refusal to take part of the study or consent withdrawal,
lack of recent (<2 days) neuroimaging result, blood diathesis, or the presence of
other medical contraindication - i.e. anticoagulation or lumbar region skin infection
or more than two attempts for a successful LP. All included subjects consented to
participate. Study protocol was approved by the local regulatory board.
Lumbar puncture
LP was performed according to the standard technique adopted within the institution
for diagnostic purposes across a wide spectrum of neurological disorders. Patients
were positioned in left lateral decubitus with knees flexed and back arched. Antisepsis
of the lumbar region was performed; a sterile drape was placed, followed by subcutaneous
infiltration of Xylocaine 1% without vasoconstrictor (5 mL). A Quincke spinal needle
22G (Spinocan®) with metallic stylet was introduced at an angle of ~60o with the skin at the midline. Bevel was oriented longitudinally and the needle was
progressed to the subarachnoid space at the interspace level of L3-L4. In case of
failure, only another attempt at L4-L5 was performed after new infiltration with local
anesthetic. It was followed by spinal manometry and CSF collection into sterile jars.
Outpatients had the CSF collected by free flow, as much as required for the diagnostic
tests proposed. Inpatients had CSF collected by mild aspiration via negative pressure
with a glass syringe at a rate 3 mL/minute. Upon collection, a compressive dressing
was applied and all subjects were instructed to remain in horizontal decubitus for
60 minutes. All samples were taken immediately to the onsite pathology laboratory
for CSF analysis.
Data collection
Demographic data including sex, age, amount of CSF collected, opening pressure, method
of collection, and the encounter where the procedure occurred were obtained from patients’
files. CSF biochemical characteristics were collated from onsite pathology laboratory
reports and BMI, when available, was obtained from dietician’s reports. BMI data was
not available for outpatients. Two weeks after the diagnostic LP, subjects were inquired
personally or via phone call about the occurrence of PDPH, as defined by The International
Classification of Headache Disorders 2nd (ICHD-2)[30] asking a simple question: “Did you experience headache up to seven days after the
diagnostic lumbar puncture, that was triggered a few minutes after assuming upright
position and subsided within 30 minutes after reclining?”. Dichotomous answers allowed
(YES or NO) were recorded.
Statistical analyses
IBM SPSS v24.0 (IBM Corp., Armonk, NY, USA) was used for data analysis. Missing values
analysis and binary indicator (0=available, 1=missing) of the variables of interest
were used to investigate missing data patterns. Categorical variables such as sex,
method of CSF collection, and age group were summarized with numbers (n) and percentages
(%). The normality distribution of the continuous variables such as age, BMI, opening
pressure, volume of CSF collected, CSF red blood cell count, mononuclear cell count,
and protein levels was investigated using the Shapiro-Wilk test, concluding that all
variables are not normally distributed. Descriptive statistics of non-normally distributed
variables were expressed as median (interquartile range - IQR). Differences between
groups were tested using chi-square and Mann-Whitney test for categorical and continuous
non-parametric variables respectively. Logistic regression was used to investigate
the relationship between volume of CSF collected and PDPH.
Outcomes
The primary outcome was to determine the rate of PDPH post CSF aspiration during LP
and identify differences in outcomes using individuals and CSF biochemical characteristics.
The secondary outcome was to compare the rate of PDPH by free flow versus mild aspiration within the institution and to discuss against the relevant literature
available.
RESULTS
A total of 336 patients were eligible for the study ([Figure 1]). Missing PDPH data amounted to 99 cases (29.5%), of which 87 were lost follow-up
and the remaining were unable to speak (n=7) or recall (n=5). A pattern was identified
for the missing BMI data (33.3%). There was a strong association between missing BMI
and missing PDPH data (chi-square=40.276; d.f.=1; p<0.001), and missing BMI and method
of CSF collection (chi-square=27.937; d.f.=1; p<0.001), with a greater number of participants
missing BMI measurements if recruited during an ED presentation (53.9%) versus inpatients (24.4%). Given the study design this is most likely indicative of protocol
failure with collecting BMI data during an ED presentation. Information on opening
pressure was missing in 19 cases (5.7%) but was not significantly associated with
PDPH missing values, as none of the other predictors. For these reasons analysis was
limited to the participants with complete information on PDPH (n=237) and BMI was
excluded from the analysis.
Figure 1 CONSORT flowchart of patients’ recruitment, enrolment, interventions and primary
outcomes per arm.LP: lumbar puncture; CSF: cerebrospinal fluid; PDPH: post-dural puncture
headache.
Demographic of subjects and their CSF laboratorial features according to the method
of CSF collection are displayed in [Table 1]. Group CSF aspiration (n=163) had 91 females (55.8%) and had median age of 52 years,
whereas group free CSF flow (n=74) was composed of 48 females (64.8%) and had a median
age of 42 years. Gender difference between groups was not significant (p=0.191). Aspiration
group presented a significantly larger volume of CSF collected than the free flow
group (p=0.011).
Table 1
Participants’ characteristics according to the method of CSF collection.
|
Method of CSF collection
|
Aspiration (n=163)
|
Free flow (n=74)
|
p-value
|
|
Female, n (%)
|
91 (55.8)
|
48 (64.9)
|
0.191
|
|
Age (years), median (IQR)
|
52 (35–69)
|
42 (30–54)
|
0.002*
|
|
Age under 65 years, n (%)
|
113 (69.3)
|
63 (85.1)
|
0.010*
|
|
Opening pressure (cmH2O), median (IQR)
|
16 (13.5–21.0)
|
17 (13.00–19.00)
|
0.818
|
|
Volume of CSF collected (ml), median (IQR)
|
10 (5–15)
|
7 (5–10)
|
0.011*
|
|
CSF red blood cells count (x106/L), median (IQR)
|
1 (0.3–3.0)
|
1 (0.3–4.0)
|
0.760
|
|
CSF Mononuclear cells count (x106/L), median (IQR)
|
0 (0–0)
|
0 (0–0)
|
0.858
|
|
CSF protein level, median (mg/dl) (IQR)
|
45.60 (34.20–63.25)
|
41.85 (31.75–65.25)
|
0.391
|
CSF: cerebrospinal fluid; cmH2O: centimeters of water; IQG: interquartile range; *indicates statistically significant.
Overall 17.7% of the participants experienced PDPH within the 14 days follow-up period.
Breakdown of this value according to the method of CSF collection was 16.5% of PDPH
for aspiration versus 20.2% for free CSF flow. This difference was not statistically significant (p=0.489).
Most of the participants belonged to the younger group aged under 65 (n=176 vs n=61).
The number of participants with PDPH was much larger in the younger group (n=37; 21%)
than in the older group (n=5; 8%). The younger participants were significantly more
likely to experience PDPH (RR=2.565; CI 1.05–6.229). Univariate analysis results are
provided in [Table 2]. A logistic regression revealed association between volume and the occurrence of
PDPH when the method of CSF collection was included in the model. For each additional
1 mL of CSF collected, the odds of developing PDPH is 6% higher (OR=1.063; CI 1.007–1.121;
p=0.027). Because of small number of cells in the CSF, it was not possible to perform
a multivariate analysis including age group and method of CSF collection. Instead,
a subgroup analysis on participants younger than 65 (n=176) was performed ([Table 3]). No significant associations emerged when comparing the key parameters in the younger
population for the occurrence of PDPH. Finally, there were not statistically significant
differences between the methods of CSF collection.
Table 2
Determinants of PDPH: displaying p values for univariate analysis.
|
Characteristic
|
No PDPH (n=195)
|
PDPH (n=42)
|
p-value
|
|
Female, n (%)
|
111 (56.9)
|
28 (66.7)
|
0.245
|
|
Age (years), median (IQR)
|
52.0 (31-66)
|
45.5 (35–57)
|
0.438
|
|
Age under 65 years, n (%)
|
139 (71.3)
|
37 (88.1)
|
0.024
|
|
Method of CSF collection
|
|
0.489
|
|
Free Flow, n (%)
|
136 (69.7)
|
27 (64.3)
|
|
|
Aspiration, n (%)
|
59 (30.3)
|
15 (35.7)
|
|
CSF Opening pressure (cmH2O), median (IQR)
|
16 (13.0–21.0)
|
16 (13.5–19.5)
|
0.930
|
|
Volume of CSF collected (ml), median (IQR)
|
10 (5–15)
|
7 (5–10)
|
0.690
|
|
CSF Red blood cell count (x106/L), median (IQR)
|
1 (0.3–3.6)
|
1 (0.3–2.0)
|
0.534
|
|
CSF Mononuclear cell count (x106/L), median (IQR)
|
0 (0–0)
|
0 (0–0)
|
0.156
|
|
CSF protein level, median (mg/dl) (IQR)
|
46.65 (33.60–66.20)
|
38.85 (34.30–50.10)
|
0.150
|
PDPH: post-dural puncture headache.
Table 3
Results of subgroup analysis (under 65 years).
|
Characteristic
|
No PDPH (n = 139, 79%)
|
PDPH (n = 37, 21%)
|
p value
|
|
Female, n (%)
|
82 (59.0)
|
27 (73.0)
|
0.120
|
|
Age (years), median (IQR)
|
41 (27–53)
|
43 (35–52)
|
0.257
|
|
Method of CSF collection
|
|
|
0.631
|
|
Aspiration, n (%)
|
88 (63.3)
|
25 (67.6)
|
|
|
Free Flow, n (%)
|
51 (36.7)
|
12 (32.4)
|
|
|
CSF opening pressure (cmH2O), median (IQR)
|
17 (14–21)
|
16 (13–20)
|
0.666
|
|
Volume of CSF collected (ml), median (IQR)
|
7 (5–10)
|
6 (5–10)
|
0.458
|
|
CSF red cell count (n), median (IQR)
|
1.0 (0.3–5.0)
|
1.0 (0.3–2.0)
|
0.500
|
|
CSF mononuclear cells count (x106/L), median (IQR)
|
0 (0–0)
|
0 (0–0)
|
0.124
|
|
CSF protein level (mg/dl), median (IQR)
|
47.30 (30.80–68.80)
|
37.70 (34.30–47.80)
|
0.282
|
DISCUSSION
Occurrence of PDPH was found to be similar between the two methods of CSF collection
tested. To be consistent, the AAN recommendations of introducing the needle with the
bevel oriented longitudinally[1],[6],[15],[18], reinsertion of the stylet prior to needle withdraw[31], and avoiding multiple attempts[16] were followed. Needles 25 to 22G are recommended for diagnostic LP. The use of 22G
needles were elected for this study, being most suitable for spinal manometry allowing
optimal CSF flow[6],[13],[26] and widely used. Additionally, larger gauge needles do require less negative pressure
to aspirate CSF at the same flow rate, compared to a thinner one. A paramedian approach
was described by some authors to reduce risk of PDPH[2],[11]. However, midline access provides easier identification of anatomical structures
and was adopted in the study. That approach has recently not been proved to reduce
the risk of PDPH as compared to the latter[32]. Although bed rest post LP had been described to reduce PDPH severity[1] or delay its onset[18], several studies failed to prove it to be more effective than early ambulation after
LP in the prevention of PDPH[10],[33]. Despite the lack of evidence, we opted for keeping all patients resting in bed
post LP for 1 hour.
Concordant with Seupaul and colleagues[25], we found that PDPH occurred more frequently in those who underwent LP in the emergency
department. The incidence reported in this manuscript meets with the commonly reported
30% incidence of PDPH in this setting[16]. Nonetheless, in those whom the CSF was aspirated, findings were unexpected. The
authors hypothesised the incidence of PDPH would be greater with CSF aspiration, when
in fact it proved to be marginally lower. Although this difference was not statistically
significant, it could be explained by a thicker dural membrane in those individuals.
Amorim and colleagues have already demonstrated that a thinner dura-mater accounts
for 50% higher CSF leakage compared to a thicker one[2]. This phenotype is inherent to individuals and cannot be attributed as a bias of
selection. Furthermore, Valença et al.[34] demonstrated that CSF leakage is variable within an individual as a result of variable
dural thickness. These findings have the potential to explain the opposite direction
of our findings.
Several studies report increased incidence of PDPH in younger patients, particularly
females[35],[36]. We found similar trends in our study, however sex did not show to play a role.
Also, older age seems to be protective, regardless of the method of CSF collection
used. Similar to our findings, low incidence of PDPH in the elderly was also observed
by Malm and colleagues[22].
Unlike other authors who also did not demonstrate any relationship between the amount
of CSF collected and PDPH occurrence[16],[37], our findings revealed a slight increase in the occurrence of PDPH. This was not
as marked as Hammond and colleagues conclusions[12], who reported 1.8-fold higher risk of PDPH for each extra 5ml of CSF collected.
Additionally, similarly to our findings, recently Monserrate and colleagues[38] reported a protective effect of collecting CSF volumes of up to 30 mL, albeit safely
and tolerably. Alike to Kim and colleagues[7], we found that the opening pressure measured during spinal manometry in the lateral
decubitus was not related to PDPH occurrence.
The term “blood patch” emerged in 1962[1]. It alluded that traumatic LP (i.e. “bloody tap” - presence of >5 red blood cells/mm3 of CSF)[12] was associated with lower incidence of PDPH[6],[13]. This association did not emerge in our sample given the very low red blood cell
count in the CSF samples across the two distinct methods of CSF collection.
Finally, the fact that protein levels were not statistically different between the
two methods of CSF collection, regardless of the PDPH occurrence or not, suggests
that mild aspiration of the CSF may not cause red or white cells lysis. This would
be a concern which could invalidate CSF analysis as demonstrated by Chow and Schmidley[39] from CSF samples obtained from a traumatic LP left for a prolonged period unrefrigerated.
In spite of being the first study ever to investigate the use of this technique for
clinical diagnostic LP, when sometimes a large amount of CSF is required, this study
has several limitations. Firstly, an observational study design is not ideal. Despite
a potential selection bias, an institutional regulation only allowed the use of glass
syringes with inpatients. Secondly, there was a substantial amount of missing data,
particularly BMI in patients that were not admitted after the procedure, which may
have contributed to a less precise analysis. Also, there may be bias of selection
of techniques according to the location where patients were first seen by the treating
physician and had the LP done. However, these limitations are outweighed by the lack
of increased rates of PDPH when comparing both techniques. In contrast, the strengths
include the novel investigation and the relatively large cohort analyzed with the
technique. Nonetheless, the study may pave the way for future investigations with
more rigid protocols targeting for specific age groups, headache onset, intensity,
and duration or other features commonly associated with this condition.
Therefore, this study demonstrates that the aspiration of the CSF during LP is not
associated with increased rates of PDPH compared to the standard technique (free flow).
This adds to safety for performing a mild CSF aspiration, particularly when larger
amounts of CSF are required in older patients. This is a valuable technique that could
be employed at a busy neurology department, when the ideal conditions are met, without
increasing the risk of PDPH.
