Abstract
Objective:
To determine the feasibility, safety and tolerability of lumbar punctures (LPs) in research participants with early Parkinson disease (PD), subjects without evidence of dopaminergic deficiency (SWEDDs) and healthy volunteers (HC).
Background:
Cerebrospinal fluid (CSF) analysis is becoming an essential part of the biomarkers discovery effort in PD with still limited data on safety and feasibility of serial LPs in PD participants.
DESIGN/METHODS:
Parkinson’s Progression Marker Initiative (PPMI) is a longitudinal observation study designed to identify PD progression biomarkers. All PPMI participants undergo LP at baseline, 6, 12 months and yearly thereafter. CSF collection is performed by a trained investigator using predominantly atraumatic needles. Adverse events (AEs) are monitored by phone one week after LP completion. We analyzed safety data from baseline LPs.
Results:
PPMI enrolled 683 participants (423 PD/196 HC/64 SWEDDs) from 23 study sites. CSF was collected at baseline in 97.5% of participants, of whom 5.4% underwent collection under fluoroscopy. 23% participants reported any related AEs, 68% of all AE were mild while 5.6% were severe. The most common AEs were headaches (13%) and low back pain (6.5%) and both occurred more commonly in HC and SWEDDs compared to PD participants. Factors associated with higher incidence of AEs across the cohorts included female gender, younger age and use of traumatic needles with larger diameter. AEs largely did not impact compliance with the future LPs.
Conclusions:
LPs are safe and feasible in PD research participants. Specific LP techniques (needle type and gauge) may reduce the overall incidence of AEs.
Keywords: Parkinson’s disease, Lumbar puncture, Safety, Adverse events
1. Background
Collection of the cerebrospinal fluid (CSF) is becoming an essential part of the biomarkers development efforts in majority of neurodegenerative diseases. While there is a body of literature demonstrating feasibility of lumbar punctures (LPs) in Alzheimer’s disease (AD) observational studies there still are limited data on repeated LPs in Parkinson’s Disease (PD) population. PD patients notably have higher prevalence of spinal deformities like kyphpscoliosis that could influence the feasibility and safety of LP’s [1,2].
The primary objectives of this analysis were to determine the safety and feasibility of completing LPs in a multicenter study and to report the incidence and type of LP related adverse events (AE) specifically as related to CSF collection methods and LP techniques.
2. Method
We analyzed data from the Parkinson’s Progression Marker Initiative (PPMI), an ongoing observational, international, multicenter study aimed to identify the clinical, serological, genetic, CSF and imaging biomarkers of PD progression in a large cohort of participants with de novo PD (at baseline) compared to healthy controls (HC). The study design and objectives are available at www.ppmi-info.org/study-design. CSF collection is integral for this study. The study was approved by the institutional review board at each site, and participants provided written informed consent. Detailed inclusion and exclusion criteria have been previously published [3]. Conditions precluding LP like prohibitive lumbar spinal disease, hematologic conditions or, anticoagulant use, are exclusionary. This analysis focused on the safety and completion rate of the baseline LP procedure with the assumption that baseline procedure will be expected to have the highest complication rate. Longitudinal analyses were restricted to examining compliance with repeat LPs. Data were downloaded on March 27, 2017.
Among PD and HCs CSF samples were collected at baseline, 6 months and then annually up to 60 months. Subjects without evidence of dopaminergic deficiency (SWEDDs) were followed for 2 years. LP was performed by either the site investigator (SI) or another qualified clinician designated by the SI. Training videos and instructions were provided to make the procedure standardized and reduce the rate of AE. A L4-L5 space approach in seated position using atraumatic 24G Sprotte spinal needle was encouraged however not compulsory. Approximately 15–20 ml of CSF were required to be collected during each procedure. The protocol for LP procedure and CSF collection/processing are available in the PPMI Biologies manual (http://ppmi-info.org/).
Post LP instructions included lying horizontal for 30 min post procedure and avoiding exertional activities for 24-h. Standard preemptive instructions in case of mild to moderate headache included limiting physical activities, increasing oral fluids specifically caffeinated drinks, and trial of acetaminophen or ibuprofen as needed. In case of severe headaches, participants were asked to contact the site study staff.
Post procedure AEs were assessed by the site study staff during the time of visit and via phone 7–10 days following the LP. The relatedness of the AE to the procedure and intensity of AEs as per standard guidelines were judged by the SI. Post LP headache (PLPH) and back pain (PLBP) were considered AEs of interest as the most common AEs reported post LPs. The categorization of post procedural headaches as PLPH was per the SI. All participants who completed the baseline visit were included in the analysis and only LP-related AEs were analyzed.
3. Statistical analysis
Statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC).
Demographic and PD characteristics are reported for all participants and by group. LP collection characteristics are also reported for all participants. Frequencies of LP-related AEs at baseline were reported by group, and relative risks compared percentages of participants who had each type of AE in PD vs. HC or PD vs. SWEDDs. Fisher’s exact and t-tests were used to compare demographic and LP collection characteristics in participants with LP-related AE vs. no AE at baseline; these comparisons were done in all participants and separately by group. A Fisher s exact test was also used to test for association between the occurrence of LP-related AE at baseline and attempt of LP at the year 1 visit. Relative risk also compared the risk of baseline LP-related AEs in the first 10 LPs attempted vs. the risk of AEs in the remaining LPs adjusted for site. Finally, an ANOVA model was used to compare mean CSF volume collected in all participants according to AE severity at baseline.
4. Results
Between June 2010 and May 2013, PPMI recruited 683 participants (423 PD/196 HC/64 SWEDDs) from 23 study sites. PD and HC were matched by gender and age. Baseline demographics have been previously published and provided in the Supplementary Table 1s [3]. Baseline LP was attempted in 99.4% (679/683) of participants. 91.9% (628/683) participants (393 PD/178 HC/57 SWEDDs) had full CSF collection; 5.6%(n = 38) had partial and 1.9%(n = 13) had no CSF collection. For this analysis, all attempted LPs (99.4%) were included. LP was most commonly performed in the sitting position (61.3%) via the L3-L4 interspace (65.8%) using the 24G atraumatic Sprotte needle (69.4%) [Supplementary Table 2s.]. 5.4% participants underwent collection under fluoroscopy guidance. Syringe suction was the most commonly utilized CSF collection method (60.8%). Mean CSF volume collected was 16.3ml (Standard Deviation 3.8). 78% of CSF samples had hemoglobin level below 200ng/ml indicating low incidence of traumatic LPs.
Total of 180 AEs in 153 (22.5%) participants were reported at baseline across the cohorts. Table 1 provides summary of all LP related AEs presented by groups (PD/HC/SWEDDs). The percent of participants who experienced any AEs was 20.2/26.0/27.4 for PD/HC/SWEDDs respectively. 68.3% of all AE were reported to be mild, 26.1% moderate and 5.6% severe. There were no serious LP related AEs and complications like iatrogenic meningitis or arachnoiditis were not observed. Most common AEs were PLPH, noted in 13% among all participants; 11.6/14.3/19.4% in PD/HC/SWEDD groups respectively, and PLBP, noted in 6.5% among all participants; 5.2/7.7/11.3 in PD/HC/SWEDD groups respectively. Mean resolution time was 4.4(0–182) days for all AEs and 3.4(0–15) days for PLPH. Contrary to expectation, large volume CSF collection was not associated with severity of AEs (p = 0.0301), rather CSF volume was higher in the mild AE group (mean = 17.1 ml) as compared to severe AE group (mean = 16.2 ml), moderate AE group (15 ml), and no AE group (16.2 ml).
Table 1.
LP-related adverse events at baseline by group.
| Adverse Event | Group |
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|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PD Subjects | Healthy Controls | SWEDD Subjects | RR (95% CI) | |||||||||||
|
|
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| (N = 421) | (N = 196) | (N = 62) | ||||||||||||
|
|
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| # of Subjects | % of Subjects | # of Events | Rate | # of Subjects | % of Subjects | # of Events | Rate | # of Subjects | % of Subjects | # of Events | Rate | PD vs. HC | PD vs. SWEDD | |
| Total | 85 | 20.2% | 100 | 0.238 | 51 | 26.0% | 59 | 0.301 | 17 | 27.4% | 21 | 0.339 | 0.78 (0.58, 1.06) | 0.74 (0.47, 1.16) |
| Most Common | ||||||||||||||
| Post-LP Headache | 49 | 11.6% | 49 | 0.116 | 28 | 14.3% | 28 | 0.143 | 12 | 19.4% | 12 | 0.194 | 0.81 (0.53, 1.25) | 0.60 (0.34, 1.06) |
| Post-LP Back Pain | 22 | 5.2% | 23 | 0.055 | 15 | 7.7% | 15 | 0.077 | 7 | 11.3% | 7 | 0.113 | 0.68 (0.36, 1.28) | 0.46 (0.21, 1.03) |
| Ear | ||||||||||||||
| Tinnitus | 1 | 0.2% | 1 | 0.002 | 0 | 0.0% | 0 | 0.000 | 0 | 0.0% | 0 | 0.000 | . | . |
| Gastrointestinal | ||||||||||||||
| Abdominal pain | 0 | 0.0% | 0 | 0.000 | 1 | 0.5% | 1 | 0.005 | 0 | 0.0% | 0 | 0.000 | . | . |
| Nausea | 4 | 1.0% | 4 | 0.010 | 1 | 0.5% | 1 | 0.005 | 0 | 0.0% | 0 | 0.000 | 1.86 (0.21, 16.53) | . |
| Vomiting | 1 | 0.2% | 1 | 0.002 | 0 | 0.0% | 0 | 0.000 | 0 | 0.0% | 0 | 0.000 | . | . |
| General | ||||||||||||||
| Fatigue | 1 | 0.2% | 1 | 0.002 | 1 | 0.5% | 1 | 0.005 | 0 | 0.0% | 0 | 0.000 | 0.47 (0.03, 7.48) | . |
| Pain | 1 | 0.2% | 1 | 0.002 | 0 | 0.0% | 0 | 0.000 | 0 | 0.0% | 0 | 0.000 | . | . |
| Musculoskeletal | ||||||||||||||
| Musculoskeletal pain | 0 | 0.0% | 0 | 0.000 | 1 | 0.5% | 1 | 0.005 | 0 | 0.0% | 0 | 0.000 | . | . |
| Musculoskeletal stiffness | 2 | 0.5% | 2 | 0.005 | 1 | 0.5% | 1 | 0.005 | 0 | 0.0% | 0 | 0.000 | 0.93 (0.08, 10.20) | . |
| Pain in extremity | 1 | 0.2% | 1 | 0.002 | 0 | 0.0% | 0 | 0.000 | 0 | 0.0% | 0 | 0.000 | . | . |
| Post-LP Back Pain | 22 | 5.2% | 23 | 0.055 | 15 | 7.7% | 15 | 0.077 | 7 | 11.3% | 7 | 0.113 | 0.68 (0.36, 1.28) | 0.46 (0.21, 1.03) |
| Post-LP Injection Site Pain | 4 | 1.0% | 4 | 0.010 | 1 | 0.5% | 1 | 0.005 | 2 | 3.2% | 2 | 0.032 | 1.86 (0.21, 16.53) | 0.29 (0.05, 1.55) |
| Nervous System | ||||||||||||||
| Dizziness | 3 | 0.7% | 3 | 0.007 | 2 | 1.0% | 2 | 0.010 | 0 | 0.0% | 0 | 0.000 | 0.70 (0.12, 4.16) | . |
| Intracranial hypotension | 0 | 0.0% | 0 | 0.000 | 1 | 0.5% | 1 | 0.005 | 0 | 0.0% | 0 | 0.000 | . | . |
| Loss of consciousness | 1 | 0.2% | 1 | 0.002 | 0 | 0.0% | 0 | 0.000 | 0 | 0.0% | 0 | 0.000 | . | . |
| Migraine | 1 | 0.2% | 1 | 0.002 | 0 | 0.0% | 0 | 0.000 | 0 | 0.0% | 0 | 0.000 | . | . |
| Paraesthesia | 0 | 0.0% | 0 | 0.000 | 1 | 0.5% | 1 | 0.005 | 0 | 0.0% | 0 | 0.000 | . | . |
| Parkinson’s disease | 1 | 0.2% | 1 | 0.002 | 0 | 0.0% | 0 | 0.000 | 0 | 0.0% | 0 | 0.000 | . | . |
| Post-LP Headache | 49 | 11.6% | 49 | 0.116 | 28 | 14.3% | 28 | 0.143 | 12 | 19.4% | 12 | 0.194 | 0.81 (0.53, 1.25) | 0.60 (0.34, 1.06) |
| Presyncope | 0 | 0.0% | 0 | 0.000 | 1 | 0.5% | 1 | 0.005 | 0 | 0.0% | 0 | 0.000 | . | . |
| Radicular pain | 2 | 0.5% | 2 | 0.005 | 0 | 0.0% | 0 | 0.000 | 0 | 0.0% | 0 | 0.000 | . | . |
| Syncope | 1 | 0.2% | 1 | 0.002 | 0 | 0.0% | 0 | 0.000 | 0 | 0.0% | 0 | 0.000 | . | . |
| Procedural Related Injuries | ||||||||||||||
| Contusion | 1 | 0.2% | 1 | 0.002 | 0 | 0.0% | 0 | 0.000 | 0 | 0.0% | 0 | 0.000 | . | . |
| Post-LP Injection Site Pain | 3 | 0.7% | 3 | 0.007 | 5 | 2.6% | 5 | 0.026 | 0 | 0.0% | 0 | 0.000 | 0.28 (0.07, 1.16) | . |
Column definitions.
# of Subjects: Number of subjects who had AE.
% of Subjects: Percentage of subjects who had AE.
# of Events: Total number of AEs; includes multiple AEs of same type per subject.
Rate: Number of AEs per total number of subjects.
RR(95% CI): Relative Risk and 95% Confidence Interval for comparing percentages of subjects who had AE in PD subjects vs. healthy controls or PD subjects vs. SWEDD subjects.
Overall the relative risk of having PLPH in PD participants was lower compared to HCs (RR – 0.81, 95% CI – 0.53–1.25) and SWEDDs (RR – 0.60, 95% CI 0.34–1.06). Similarly, the relative risk of having PLBP was also lower in PD subgroup compared to HCs (RR 0.68, 95% CI 0.36–1.28) and SWEDDs (RR 0.46, 95% CI 0.21–1.03).
There was higher relative risk of having AEs in the first 10 baseline LPs compared to the remaining LP’s when adjusted for the site (RR = 1.4% CI = 1.05–1.84). 76.4% of participants who had baseline LP related AEs and 87% of participants without LP related AEs went on to attempt the LP procedure at Year 1. At the end of 60 months, a total of 66% of expected participants completed the LP procedure.
4.1. Factors affecting the incidence of any LP related AE
We then explored what participant and procedure characteristics were associated with the LP related AE’s (Table 2). AEs were higher among the females overall (F: 30.5%, M: 18.2%, p = 0.0004), driven by the HC (F: 38.6%, M: 19.1%, p = 0.004) and SWEDDs (F: 45.8%, M: 15.8%, p = 0.018) subgroup. Among all participants, those who had AE were younger (p = 0.004). This age difference was significant in HC (p = 0.04) but not in PD (p = 0.2) or SWEDDs (p = 0.08). Weight and CSF volume had no significant effect on the incidence of AE. Use of atraumatic Sprotte and high gauge Quincke needle were associated with lower incidence of AEs among all participants (p = 0.004). These results were driven by the PD subgroup (p = 0.006) as they were not significant in the HC and SWEDD subgroups. CSF collection method, LP site, and LP position had no significant bearing on the incidence of AEs among all participants and across the subgroups. CSF hemoglobin level which was considered a proxy for traumatic LP’s, also did not have any impact on the AE’s. Only age was associated with severity of the AEs (p = 0.0085), older participants had lower odds of developing moderate/severe as compared to mild AEs (OR- 0.955, CI: 0.923, 0.988).
Table 2.
Incidence of all LP-Related AEs at baseline based on LP procedure characteristics.
| Variable | All Subjects | PD Subjects | Healthy Controls | SWEDD Subjects | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
|
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| AE | No AE | p-value | AE | No AE | p-value | AE | No AE | p-value | AE | No AE | p-value | |
| Age | 0.1073 | 0.5752 | 0.1777 | 0.6316 | ||||||||
| < 56 years | 52 (27.23%) | 139 (72.77%) | 27 (23.68%) | 87 (76.32%) | 18 (32.73%) | 37 (67.27%) | 7 (31.82%) | 15 (68.18%) | ||||
| 56–65 years | 56 (22.67%) | 191 (77.33%) | 29 (19.08%) | 123 (80.92%) | 21 (27.63%) | 55 (72.37%) | 6 (31.58%) | 13 (68.42%) | ||||
| > 65 years | 45 (18.67%) | 196 (81.33%) | 29 (18.71%) | 126 (81.29%) | 12 (18.46%) | 53 (81.54%) | 4 (19.05%) | 17 (80.95%) | ||||
| Gender | 0.0004 | 0.1603 | 0.0038 | 0.0180 | ||||||||
| Male | 80 (18.18%) | 360 (81.82%) | 50 (18.12%) | 226 (81.88%) | 24 (19.05%) | 102 (80.95%) | 6 (15.79%) | 32 (84.21%) | ||||
| Female | 73 (30.54%) | 166 (69.46%) | 35 (24.14%) | 110 (75.86%) | 27 (38.57%) | 43 (61.43%) | 11 (45.83%) | 13 (54.17%) | ||||
| Type of Needle | 0.0039 | 0.0060 | 0.0782 | 0.3473 | ||||||||
| 20g Quincke | 19 (38.78%) | 30 (61.22%) | 14 (42.42%) | 19 (57.58%) | 3 (27.27%) | 8 (72.73%) | 2 (40.00%) | 3 (60.00%) | ||||
| 22g Quincke | 20 (30.30%) | 46 (69.70%) | 12 (27.27%) | 32 (72.73%) | 6 (42.86%) | 8 (57.14%) | 2 (25.00%) | 6 (75.00%) | ||||
| 25g Quincke | 1 (7.69%) | 12 (92.31%) | 0 (0.00%) | 8 (100.0%) | 1 (50.00%) | 1 (50.00%) | 0 (0.00%) | 3 (100.0%) | ||||
| 22g Sprotte | 12 (18.75%) | 52 (81.25%) | 4 (10.26%) | 35 (89.74%) | 6 (28.57%) | 15 (71.43%) | 2 (50.00%) | 2 (50.00%) | ||||
| 24g Sprotte | 92 (19.53%) | 379 (80.47%) | 51 (17.71%) | 237 (82.29%) | 32 (22.22%) | 112 (77.78%) | 9 (23.08%) | 30 (76.92%) | ||||
| 18g | 4 (50.00%) | 4 (50.00%) | 1 (20.00%) | 4 (80.00%) | 2 (100.0%) | 0 (0.00%) | 1 (100.0%) | 0 (0.00%) | ||||
| Unknown/Missing | 5 (62.50%) | 3 (37.50%) | 3 (75.00%) | 1 (25.00%) | 1 (50.00%) | 1 (50.00%) | 1 (50.00%) | 1 (50.00%) | ||||
| Method of Collection | 0.0857 | 0.3769 | 0.1713 | 0.5676 | ||||||||
| Gravity | 66 (25.58%) | 192 (74.42%) | 36 (22.09%) | 127 (77.91%) | 22 (31.88%) | 47 (68.12%) | 8 (30.77%) | 18 (69.23%) | ||||
| Syringe Suction | 82 (19.85%) | 331 (80.15%) | 46 (18.11%) | 208 (81.89%) | 28 (22.40%) | 97 (77.60%) | 8 (23.53%) | 26 (76.47%) | ||||
| Unknown/Missing | 5 (62.50%) | 3 (37.50%) | 3 (75.00%) | 1 (25.00%) | 1 (50.00%) | 1 (50.00%) | 1 (50.00%) | 1 (50.00%) | ||||
| Lumbar Puncture Site | 0.2801 | 0.3671 | 0.3285 | 0.7516 | ||||||||
| L2-L3 Interspace | 7 (20.59%) | 27 (79.41%) | 4 (17.39%) | 19 (82.61%) | 1 (14.29%) | 6 (85.71%) | 2 (50.00%) | 2 (50.00%) | ||||
| L3-L4 Interspace | 93 (20.81%) | 354 (79.19%) | 47 (17.87%) | 216 (82.13%) | 34 (23.94%) | 108 (76.06%) | 12 (28.57%) | 30 (71.43%) | ||||
| L4-L5 Interspace | 41 (26.97%) | 111 (73.03%) | 25 (24.27%) | 78 (75.73%) | 14 (35.00%) | 26 (65.00%) | 2 (22.22%) | 7 (77.78%) | ||||
| Unknown/Missing | 12 (26.09%) | 34 (73.91%) | 9 (28.13%) | 23 (71.88%) | 2 (28.57%) | 5 (71.43%) | 1 (14.29%) | 6 (85.71%) | ||||
| Subject position during LP | 0.0737 | 0.5083 | 0.1688 | 0.3495 | ||||||||
| Sitting, leaned over | 98 (23.56%) | 318 (76.44%) | 50 (19.84%) | 202 (80.16%) | 37 (29.60%) | 88 (70.40%) | 11 (28.21%) | 28 (71.79%) | ||||
| Lying, curled up on side | 41 (17.52%) | 193 (82.48%) | 25 (16.67%) | 125 (83.33%) | 13 (20.00%) | 52 (80.00%) | 3 (15.79%) | 16 (84.21%) | ||||
| Unknown/Missing | 14 (48.28%) | 15 (51.72%) | 10 (52.63%) | 9 (47.37%) | 1 (16.67%) | 5 (83.33%) | 3 (75.00%) | 1 (25.00%) | ||||
| CSF Hemoglobin | 0.4815 | 0.8795 | 0.2845 | 0.4681 | ||||||||
| < 200 ng/ml | 115 (21.70%) | 415 (78.30%) | 66 (20.12%) | 262 (79.88%) | 37 (24.03%) | 117 (75.97%) | 12 (25.00%) | 36 (75.00%) | ||||
| 200 ng/ml or above | 32 (24.62%) | 98 (75.38%) | 16 (19.05%) | 68 (80.95%) | 12 (34.29%) | 23 (65.71%) | 4 (36.36%) | 7 (63.64%) | ||||
| Missing | 6 (31.58%) | 13 (68.42%) | 3 (33.33%) | 6 (66.67%) | 2 (28.57%) | 5 (71.43%) | 1 (33.33%) | 2 (66.67%) | ||||
Note: p-values come from Fisher’s Exact Tests.
4.2. Factors affecting the incidence of LP related headaches
PLPH were more common in the younger age group (mean age: 58.1 years, p = 0.001) and in participants with shorter height (mean height 170.1 cms, p = 0.01) overall. Association with age was driven by SWEDDs (p = 0.018) subgroup, while height was not significant in any subgroups. In the multivariate analysis, older age (OR 0.954, CI-0.930–0.978), male gender (OR - 0.477, CI- 0.283-0.805) and use of 24G Sprotte needle as compared to 18 G Quincke needle (OR 0.108, CI-0.021-0.563) had lower odds of PLPH. Sitting LP position had higher odds of PLPH when compared to lying down LP position (OR- 2.274, CI: 1.223–4.230). CSF collection method or LP site had no statistically significant effect on PLPH. Body mass Index (BMI), weight and volume of CSF collected had no significant effect on the incidence of PLPH when controlled for gender.
5. Discussion
To our knowledge, our analysis is the first to report data on LPs in a multicenter longitudinal study of PD participants. Our data support and build on the experience reported in the AD studies [4–7].The rate of any AEs in AD studies ranged from 11.3 to 36% with PLPH between 0.93 and 24% and PLBP from 4 to 17% [5–10]. Studies which exclusively used atraumatic Sprotte and Whitacre needles reported much lower AE with PLPH as low as 0.93% [7,9,11]. In our cohort, 23% of all participants and 20% of PD participants experienced any form of AE’s well within the spectrum previously reported in AD population [4–7,9–11]. As expected PLPH and PLBP were the most common AEs interestingly with a lower rate in PD subgroup. Majority of AEs were mild (58%) with unexpectedly lower incidence of moderate to severe AE in older age group. The same was true for lower incidence of PLPH in older age group which is likely a contributor to lower rate of PLPH in our cohort in comparison to general population [5,6,10–12]. Females had a higher rate of AE consistent with previous studies and males had lower odds of developing PLPH [5,10]. The reason for gender effect is not clear as neither BMI nor height were significant. Volume of CSF did not have an impact on the incidence of AE’s consistent with the previous studies [10]. This is reassuring considering that research studies might require a higher volume to reserve fluid for future analysis.
The lower rate of AEs could be attributed to increased utilization of atraumatic Sprotte needle and lying down LP position in our cohort. Sprotte needle is associated with reduced incidence and severity of AEs particularly PLPH [12,13]. Our analysis also demonstrates significantly lower incidence of AE with higher gauge traumatic needle, although this finding is not supported by the recent Cochrane review [12]. While the rate of PLPH was 13% in our cohort, it could have been potentially lower when compared to AD studies that exclusively used atraumatic needles [7,9,11].
While our analysis focused on baseline LP procedure highlighting high baseline LP rate of 99%, PPMI longitudinal data demonstrate fairly high percent LP retention rate over 5 years. The presence of AE’s did not affect the subsequent LPs as 76% participants with AE at baseline attempted LP at year 1 and 66% of expected participants completed LP at 60 months. Our data reaffirm the feasibility of performing multiple LP’s in cohorts of participants with PD with significant completion rate even at 60 months.
6. Conclusion
In summary, consistent with the data reported in the AD literature, our analysis shows that LP is overall safe and feasible in PD participants and can be routinely utilized in clinical trials and as a diagnostic test in the future if indicated. Based on our findings, apart from receiving formal training in performing LP, the clinicians and investigators planning to perform routine LPs are encouraged to use atraumatic Sprotte needles and lying down LP position to reduce the risk of AEs. Higher volume of CSF was not an obstacle for a safe procedure. Lastly, we also want to emphasize the importance of community education to increase acceptance of LPs as commonly utilized procedures in PD clinical trials.
Supplementary Material
Acknowledgements
Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org.
Study funding
PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, including Abbvie, Avid Radiopharmaceuticals, Biogen Idee, Bristol-Myers Squibb, Covance, Eli Lilly & Co., F. Hoffman-La Roche, GE Healthcare, Genentech, GlaxoSmithKline, Lundbeck, Merck, MesoScale, Piramal, Pfizer, Prevail and UCB.
Author financial disclosures
Neha Prakash reports no disclosures.
Tanya Simuni has served as a consultant received consulting fees from Acadia, Abbvie, Allergan, Anavex, Avid, GE Medical, Eli Lilly and Company, Harbor, Ibsen, IMPAX, Lundbeck, Merz, Inc., the National Parkinson Foundation, Navidea, Pfizer, TEVA Pharmaceuticals, UCB Pharma, Voyager, US World Meds, and the Michael J. Fox Foundation for Parkinson’s Research; Dr. Simuni has served as a speaker and received an honorarium from Acadia, IMPAX, Lundbeck, TEVA Pharmaceuticals, and UCB Pharma; Dr Simuni is on the Scientific advisory board for Anavex, Sanofi, MJFF. Dr. Simuni sits on the Advisory Board for IMPAX; Dr. Simuni has received research funding from the NINDS, MJFF, NPF, TEVA Pharmaceuticals, Auspex, Biotie, Civitas, Acorda, Lundbeck, Neuroderm, NINDS, National Institutes of Health, Northwestern Foundation, and the Michael J. Fox Foundation for Parkinson’s Research; Dr. Simuni received funding support for educational programs from GE Medical, TEVA, and Lundbeck.
Chelsea Caspell-Garcia reports no disclosures.
Christopher Coffey- Serves on the scientific advisory board for data safety and monitoring for NINDS and NIA, received a speaker honorarium for presenting a short course at Rho, Inc., is a consultant for ZZ Biotech, LLC, received research support from the Michael J. Fox Foundation, and is supported by NIH/NINDS, U01 NS077352, PI, 10/01/11-09/30/18 (2) NIH/NINDS, U01 NS077108, PI, 10/01/11-09/30/16 (3) NIH/NHLBI, U01 HL091843, PI, 08/01/09-02/28/15(4) NIH/NHLBI, U01 NS038529, PI, 12/01/09-12/31/13 NIH/NINDS, (5) U01 NS079163, 08/05/2012-07/31/2015 (6) NIH/NINDS, U01 NS082329, 07/15/2013-06/30/2018 (7) NIH/NINDS, U01 NS084495, 09/15/2013-07/31/2018.
Andrew Siderowf receives research grant support from the National Institute of Neurological Disorders and Stroke and the Michael J. Fox Foundation and serves as a consultant for Biogen, Denali, and Voyager Therapeutics.
Caroline M. Tanner serves on the Scientific Advisory Boards of the Michael J. Fox Foundation and the National Spasmodic Dysphonia Association as a voluntary consultant, and has provided paid consulting services to Pfizer Pharmaceuticals. She receives grant support from the Michael J. Fox Foundation, the Parkinson’s Disease Foundation, the Department of Defense and the National Institutes of Health.
Karl Kieburtz serves as a consultant for the National Institutes of Health (NIH, NINDS), Acorda, Astellas Pharma, AstraZeneca, Auspex, Biotie, Britannia, Cangene, CHDI, Civitas, Clearpoint Strategy Group, Clintrex, Cynapsus, INC Research, Inteclsis, Lilly, Lundbeck, Medavante, Medivation, Melior Discovery, Neuroderm, Neurmedix, Omeros, Otsuka, Pfizer, Pharma2B, Prothena/Neotope/Elan Pharmaceutical, Raptor Pharmaceuticals, Roche/Genentech, Sage Bionetworks, Biotie, Stealth Peptides, Synagile, Teikoku Pharma, Titan, Turing Pharmaceuticals, Upsher-Smith, US WorldMeds, Vaccinex, Voyager, and Weston Brain Institute. Dr Kieburtz receives research grants from thr National Institutes of Health, Michael J. Fox Foundation, and Teva.
Brit Mollenhauer is employed by Parcacelsus Kliniken Germany and the University Medical Center Goettingen; BM has received independent research grants from TEVA-Pharma, Desitin, Boehringer Ingelheim, GE Healthcare and honoraria for consultancy from Bayer Schering Pharma AG, Roche, AbbVie, TEVA-Pharma, Biogen, UCB and for presentations from GlaxoSmithKline, Orion Pharma, TEVA-Pharma and travel costs from TEVA-Pharma. BM is member of the executive steering committee of the Parkinson Progression Marker Initiative and the Systemic Synuclein Sampling Study of the Michael J. Fox Foundation for Parkinson’s Research and has received grants from the BMBF, EU, Parkinson Fonds Deutschland, Deutsche Parkinson Vereinigung, Michael J. Fox Foundation for Parkinson’s Research, Stifterverband für die deutsche Wissenschaft, and has scientific collaborations with Roche, Bristol Myers Squibb, Ely Lilly, Covance and Biogen.
Douglas Galasko receives research funding from National Institutes of Health, Michael J. Fox Foundation, and Eli Lilly and Esai. He is a paid Editor for Alzheimer’s Research and Therapy. He is a consultant for vTv Therapeutics and serves on a DSMB for Prothena.
Tatiana Foroud has received funding from The Michael J. Fox Foundation, the NIH, San Diego State University, The University of Texas at Austin, and Waggoner Center for Alcohol and Addiction Research.
Lana M. Chahine receives research support from the Michael J. Fox Foundation, has received travel payment from MJFF to MJFF conferences, is a paid consultant to MJFF, receives research support for a clinical trial sponsored by Voyager Therapeutics, received travel payments from Voyager Therapeutics to Investigator meeting, and receives royalties from Wolters Kluwel (for book authorship).
Daniel Weintraub has received research funding or support from Michael J. Fox Foundation for Parkinson’s Research, National Institutes of Health, Novartis Pharmaceuticals, Department of Veterans Affairs, Avid Radiopharmaceuticals, Alzheimer’s Disease Cooperative Study, and the International Parkinson and Movement Disorder Society; honoraria for consultancy from Acadia, Biogen, Biotie (Acorda), Bracket, Clintrex LLC, Eisai Inc., Eli Lilly, Lundbeck, Roche, Takeda, UCB, and the CHDI Foundation; license fee payments from the University of Pennsylvania for the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP) and Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease - Rating Scale (QUIP-RS); royalties from Wolters Kluweland; and fees for legal consultation for lawsuits related to medication prescribing in patients with Parkinson’s disease.
Renee Wilson has no disclosures to report.
Nichole Daegele has no disclosures to report.
Vanessa Arnedo is employed by The Michael J. Fox Foundation.
Mark Frasier is employed by The Michael J. Fox Foundation.
Todd Sherer is employed by The Michael J. Fox Foundation.
Kenneth Marek is a consultant for Pfizer, GE Healthcare, Merck, Lilly, BMS, Piramal, Prothena, Neurophage, nLife, Roche, and receives funding for the following grants: W81XWH-06-1-0678 Establishing an ‘at risk’ cohort for Parkinson Disease Neuroprevention using olfactory testing and DAT imaging, DOD, Investigator 10/1/06–09/30/15; Parkinson Progression Marker Initiative (PPMI), Michael J. Fox Foundation, Principal Investigator 6/15/09–6/14/18; DAT imaging in LRRK2 family members, the Michael J. Fox Foundation, Principal Investigator 1/15/10–1/14/15. Ownership in Molecular Neuroimaging, LL.
Footnotes
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.parkreldis.2018.12.025.
References
- [1].Rabin ML, Earnhardt MC, Patel A, Ganihong I, Kurlan R, Postural, bone, and joint Disorders in Parkinson’s disease, Mov. Disord. Clin. Pract 3 (2016) 538–547, 10.1002/mdc3.12386. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Choi HJ, Smith JS, Shaffrey CI, Lafage VC, Schwab FJ, Ames CP, Matsumoto M, Baik JS, Ha Y, Coronal plane spinal malalignment and Parkinson’s disease: prevalence and associations with disease severity, Spine J. 15 (2015) 115–121, 10.1016/j.spinee.2014.07.004. [DOI] [PubMed] [Google Scholar]
- [3].Simuni T, Siderowf A, Lasch S, Coffey CS, Caspell-Garcia C, Jennings D, Tanner CM, Trojanowski JQ, Shaw LM, Seibyl J, Schuff N, Singleton A, Kieburtz K, Toga AW, Mollenhauer B, Galasko D, Chahine LM, Weintraub D, Foroud T, Tosun D, Poston K, Arnedo V, Frasier M, Sherer T, Chowdhury S, Marek K, Longitudinal change of clinical and biological measures in early Parkinson’s disease: Parkinson’s progression Markers initiative cohort, Mov. Disord 33 (2018) 771–782, 10.1002/mds.27361. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Menéndez-González M, Routine lumbar puncture for the early diagnosis of Alzheimer’s disease. Is it safe? Front. Aging Neurosci 6 (2014) 65, 10.3389/fnagi.2014.00065. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [5].Alcolea D, Martínez-Lage P, Izagirre A, Clerigué M, Carmona-Iragui M, Alvarez RM, Fortea J, Balasa M, Morenas-Rodríguez E, Lladó A, Grau O, Blennow K, Lleó A, Molinuevo JL, Feasibility of lumbar puncture in the study of cerebrospinal fluid biomarkers for Alzheimer’s disease: a multicenter study in Spain, J. Alzheimers. Dis 39 (2014) 719–726, 10.3233/JAD-131334. [DOI] [PubMed] [Google Scholar]
- [6].Duits FH, Martinez-Lage P, Paquet C, Engelborghs S, Lleó A, Hausner L, Molinuevo JL, Stomrud E, Farotti L, Ramakers IHGB, Tsolaki M, Skarsgård C, Åstrand R, Wallin A, Vyhnalek M, Holmber-Clausen M, Forlenza OV, Ghezzi L, Ingelsson M, Hoff EI, Roks G, de Mendomça A, Papma JM, Izagirre A, Taga M, Struyfs H, Alcolea DA, Frölich L, Balasa M, Minthon L, Twisk JWR, Persson S, Zetterberg H, van der Flier WM, Teunissen CE, Scheltens P, Blennow K, Performance and complications of lumbar puncture in memory clinics: results of the multicenter lumbar puncture feasibility study, Alzheimer’s Dementia 12 (2016) 154–163, 10.1016/j.jalz.2015.08.003. [DOI] [PubMed] [Google Scholar]
- [7].Peskind E, Nordberg A, Darreh-Shori T, Soininen H, Safety of lumbar puncture procedures in patients with Alzheimer’s disease, Curr. Alzheimer Res 6 (2009) 290–292 http://www.ncbi.nlm.nih.gov/pubmed/19519311. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [8].the A.D.N.I, Vidoni Eric D., Morris Jill K., Raider Kayla, Burns Jeff, Reducing post lumbar puncture headaches with small bore atraumatic needles, J. Clin. Neurosci 21 (2014) 536–537, 10.1016/j.jocn.2013.07.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Peskind ER, Riekse R, Quinn JF, Kaye J, Clark CM, Farlow MR, Decarli C, Chabal C, Vavrek D, Raskind MA, Galasko D, Safety and acceptability of the research lumbar puncture, Alzheimers Dis. Assoc. Disord 19 (2005) 220–225, 10.1097/01.wad.0000194014.43575.fd. [DOI] [PubMed] [Google Scholar]
- [10].Moulder KL, Besser LM, Beekly D, Blennow K, Kukull W, Morris JC, Factors influencing successful lumbar puncture in alzheimer research, Alzheimers Dis. Assoc. Disord 31 (2017) 287–294, 10.1097/WAD.0000000000000209. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Linker G, Mirza N, Manetti G, Meyer M, Putnam KT, Sunderland T, Fine-needle, negative-pressure lumbar puncture: a safe technique for collecting CSF, Neurology 59 (2002) 2008–2009, 10.1212/01.WNL.0000038360.01635.39. [DOI] [PubMed] [Google Scholar]
- [12].Arevalo-Rodriguez I, Muñoz L, Godoy-Casasbuenas N, Ciapponi A, Arevalo JJ, Boogaard S, Roqué i Figuls M, Needle gauge and tip designs for preventing post-dural puncture headache (PDPH), Cochrane Database Syst. Rev (2017), 10.1002/14651858.CD010807.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Nath S, Koziarz A, Badhiwala JH, Alhazzani W, Jaeschke R, Sharma S, Banfield L, Shoamanesh A, Singh S, Nassiri F, Oczkowski W, Belley-Côté E, Truant R, Reddy K, Meade MO, Farrokhyar F, Bala MM, Alshamsi F, Krag M, Etxeandia-Ikobaltzeta I, Kunz R, Nishida O, Matouk C, Selim M, Rhodes A, Hawryluk G, Almenawer SA, Atraumatic versus conventional lumbar puncture needles: a systematic review and meta-analysis, Lancet 391 (2018) 1197–1204, 10.1016/S0140-6736(17)32451-0. [DOI] [PubMed] [Google Scholar]
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