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Original Article
Intrathecal Injections in Children With
Spinal Muscular Atrophy: Nusinersen
Clinical Trial Experience
Manon Hache
´,MD
1
, Kathryn J. Swoboda, MD
2
, Navil Sethna, MD, FAAP
3
,
Alan Farrow-Gillespie, MD
4
, Alexander Khandji, MD
5
, Shuting Xia, MS
6
,
and Kathie M. Bishop, PhD
6
Abstract
Nusinersen (ISIS-SMN
Rx
or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular
atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of
nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with
type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse
events were attributed to lumbar puncture. Most common adverse events were headache (n ¼9), back pain (n ¼9), and post–
lumbar puncture syndrome (n ¼8). In a subgroup analysis, adverse events were more frequent in older children, children with
type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures
were successfully performed in children with spinal muscular atrophy; lumbar puncture–related adverse event frequency was
similar to that previously reported in children.
Keywords
lumbar puncture, spinal muscular atrophy, antisense oligonucleotide, drug delivery
Received September 21, 2015. Received revised November 30, 2015. Accepted for publication December 20, 2015.
Advances in the identification of the genetic basis of neurolo-
gic diseases have enabled the emerging development of thera-
pies to treat these diseases based on the known genetic
mechanisms and deficiencies. However, drug delivery to the
central nervous system remains a key challenge. Intrathecal
injection via lumbar puncture provides a direct route of deliv-
ery that has traditionally been focused on malignancy-directed
chemotherapeutics and pain management,
1
but is increasingly
being used in clinical trials assessing neurologic therapies.
2,3
Nusinersen (ISIS-SMN
Rx
or ISIS 396443) is an antisense
oligonucleotide currently in development for spinal muscular
atrophy, an autosomal recessive motor neuron disease associ-
ated with progressive muscular atrophy and weakness involv-
ing limbs and, more variably, bulbar and respiratory muscles.
4,5
Spinal muscular atrophy affects approximately 1:10 000
births,
6
and is classified into clinical subtypes (types 0-4) dif-
ferentiated by age of onset and highest motor function.
7
Nusi-
nersen is designed to alter splicing of SMN2 messenger RNA
and increase the amount of functional SMN protein produced,
thus compensating for the genetic defect in the SMN1 gene.
8,9
Nusinersen, currently under evaluation in phase 3 clinical trials
in infants and children with spinal muscular atrophy, is admi-
nistered via lumbar puncture and intrathecal injection directly
into the cerebrospinal fluid, from where it distributes to the
spinal cord and the brain.
Although lumbar puncture is routinely performed for diag-
nostic and therapeutic purposes in children and infants,
10
it is
infrequently performed in patients with spinal muscular atro-
phy. Lumbar puncture is generally a safe and straightforward
procedure, but side effects, such as headache, back pain, and
transient or persistent cerebrospinal fluid leakage (post–lumbar
1
Division of Pediatric Anesthesia, Columbia University Medical Center, New
York, NY, USA
2
Department of Neurology, Massachusetts General Hospital, Boston, MA,
USA
3
Department of Anesthesiology, Perioperative and Pain Medicine, Boston
Children’s Hospital, Boston, MA, USA
4
Department of Anesthesiology and Pain Management, University of Texas
Southwestern Medical School, Dallas, TX, USA
5
Department of Radiology, Columbia University, New York, NY, USA
6
Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA
Corresponding Author:
Manon Hache
´, MD, Division of Pediatric Anesthesia, Columbia University
Medical Center, 622 W 168th Street, BH 440-N, New York, NY 10032, USA.
Email: mh2289@cumc.columbia.edu
Journal of Child Neurology
2016, Vol. 31(7) 899-906
ªThe Author(s) 2016
Reprints and permission:
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DOI: 10.1177/0883073815627882
jcn.sagepub.com
puncture syndrome), have been documented.
11-13
In addition,
in children with spinal muscular atrophy who often experience
complications such as scoliosis, lumbar punctures might be
technically more challenging to perform. The objective of this
analysis was to summarize our clinical trial experience with
lumbar punctures for intrathecal nusinersen drug delivery in a
phase 1 study in children with spinal muscular atrophy
14
and to
develop recommendations for procedures in a pediatric popu-
lation with a severe neuromuscular disease.
Methods
Standard Protocol Approvals, Registrations, and
Participant Consents
These trials were conducted in compliance with the Declaration of
Helsinki, the International Conference on Harmonisation Good Clinical
Practice guidelines, the European Union Clinical Trials Directive, and
local regulatory requirements. Approval for the study protocols and all
amendments were obtained from Columbia University Medical Center
Institutional Review Board (Approval #AAAI6758 and #AAAK5458).
Written informed consent and assent (if applicable) were obtained
before any evaluations were conducted for eligibility. The trials are
registered on ClinicalTrials.gov (NCT01494701 and NCT01780246).
Phase 1 and Extension Study Designs
The phase 1 study was a first-in-human, open-label, escalating-dose
study to assess the safety, tolerability, and pharmacokinetics of a
single intrathecal dose (1, 3, 6, or 9 mg) of nusinersen in children with
spinal muscular atrophy. Each dose cohort had 6 to 10 participants
(N ¼28). Upon completion, all participants had the opportunity to
enroll in a subsequent extension study and receive additional dosing
with nusinersen. The methods and results of the phase 1 study and its
extension are detailed elsewhere.
14
Briefly, medically stable spinal
muscular atrophy participants 2 to 14 years of age were enrolled in
4 sites in the United States (Boston Children’s Hospital, Boston, MA;
Columbia University Medical Center, New York, NY; UT Southwes-
tern Medical Center–Children’s Medical Center Dallas, Dallas, TX;
and University of Utah School of Medicine, Salt Lake City, UT).
Eligible participants had to be able to complete all study procedures,
meet age-appropriate institutional guidelines for lumbar puncture pro-
cedures, and have a life expectancy of >2 years. Participants were
excluded for serious respiratory insufficiency, hospitalization for sur-
gery or pulmonary event within the past 2 months, active infection at
screening, history of brain or spinal cord disease or bacterial menin-
gitis, presence of implanted cerebrospinal fluid drainage shunt, clini-
cally significant laboratory abnormalities, any ongoing medical
condition that would interfere with the conduct and assessments of
the study, or treatment with another investigational drug within 1
month of screening. Patients with scoliosis were allowed to participate
if, in the opinion of the investigator, a lumbar puncture could be
performed safely.
Lumbar Puncture Procedures
A total of 3 lumbar punctures were scheduled during the 2 trials for
drug delivery and/or follow-up collection of cerebrospinal fluid for
safety and pharmacokinetic analyses. Drug was administered via
intrathecal injection of a 5-mL bolus over 1 to 3 minutes. The protocol
recommended a 22- to 25-gauge spinal anesthesia needle (21-gauge
needle allowed if participant’s weight or condition dictated) and that
the lumbar punctures were performed at the L3-L4 disc space or 1
level above or 1 to 2 levels below, as needed. In all cases, 5 to 6 mL of
cerebrospinal fluid was collected before drug injection. Participants
were encouraged to lie flat for an hour after the procedure. Anesthesia
and/or sedation and fluoroscopy or ultrasonography were permitted to
facilitate the procedure and varied by institution at the discretion of the
investigators at each site.
Participants underwent the first lumbar puncture on day 1 for cer-
ebrospinal fluid collection and nusinersen dosing, the second lumbar
puncture on day 8 or day 29 for cerebrospinal fluid collection, and the
third lumbar puncture during the extension study for cerebrospinal
fluid collection and redosing with nusinersen 9 to 14 months after the
initial lumbar puncture.
Safety and Tolerability
In the phase 1 single-dose study, participants were initially monitored
for safety and tolerability for 29 days (1-mg and 3-mg cohorts) or
85 days (6-mg and 9-mg cohorts) post dosing. Participants enrolled
in the extension study were monitored over 169 days post dosing.
Safety reporting included adverse events related to lumbar puncture,
and a subgroup analysis was performed to compare reported lumbar
puncture–related adverse events by needle size, participant age, and
spinal muscular atrophy type.
Results
A total of 28 children were enrolled and received dosing in the
phase 1 study; 15 children had spinal muscular atrophy type 2
and 13 had spinal muscular atrophy type 3 (Table 1). At base-
line, participant mean (range) age was 6.1 (2.0-14.0) years, 17
were female, 10 were ambulatory, and 13 had scoliosis. One
child had vertical expandable prosthetic titanium rods inserted
and the pedicle screws were inserted into T2, T3, and T4 with
fixation of the growing rods to the pelvis, leaving the lumbar
spine area spared. The first and second lumbar punctures were
performed on 28 and 27 children in the parent study, respec-
tively, and the third on 18 children who re-enrolled in the
extension study. Of the 10 children not re-enrolling, 6 re-
enrolled in a multiple-dose study of nusinersen and 4 decided
not to enroll. Of these, 1 child did not re-enroll for reasons
related to the lumbar puncture procedure. This was a
Table 1. Baseline Demographics of Participants (N ¼28).
Characteristic
Female, n (%) 17 (61)
Mean (range) age, y 6.1 (2.0-14.0)
Mean (SD) weight, kg 23.6 (14.7)
SMA, n (%)
type 2 15 (54)
type 3 13 (46)
Ambulatory, yes, n (%) 10 (36)
Scoliosis, yes, n (%) 13 (46)
Spinal rods, n (%) 1 (4)
Abbreviation: SMA, spinal muscular atrophy.
900 Journal of Child Neurology 31(7)
12-year-old girl with spinal muscular atrophy type 2 who had
severe scoliosis at baseline and in whom the second fluorosco-
pically guided lumbar puncture procedure was not performed
successfully at day 8 in the phase 1 study.
Participants were enrolled and treated in 4 sites; the institu-
tional lumbar puncture procedures used in each site are
reported in Table 2. Both cutting-tip and atraumatic (pencil-
point) spinal needles were used and the general practice was to
Table 2. Comparison of Lumbar Puncture Procedural Differences Between the Study Sites.
a
Lumbar
Puncture
Procedural
Details
Columbia University
(n ¼28)
University of Utah
(n ¼25)
Boston Children’s
Hospital (n ¼10)
University of Texas
(n ¼10)
Needle
size(s)
used
21, 22, 25, or 27 gauge 21, 22, or 25 gauge 24 or 22 gauge 22 or 25 gauge
Needle
type(s)
Whitacre 3.0-inch spinal
needle
Whitacre spinal needles Sprotte 35-mm 24-
gauge spinal needle
Quincke 25-mm 22-
gauge spinal needle
Quincke 1.5- to 3-in.
spinal needle
Placement L2-L3, L3-L4, L4-L5 L2-L3, L3-L4, L4-L5 L3-L4, L4-L5, L5-S1 L3-L4 or L4-L5
Fluoroscopy,
yes/no
Yes
b
No
c
No
c
Yes
d
Ultrasound,
yes/no
No No Yes No
Anesthesia
and/or
sedation,
yes/no
Yes Yes Yes Yes
If yes,
type(s)
Inhalational anesthesia:
sevoflurane +nitrous
oxide
IV sedation: remifentanil,
midazolam, propofol,
fentanyl
Other: 1% lidocaine
Inhalational anesthesia:
sevoflurane +nitrous
oxide
IV sedation: midazolam
+ketamine
Inhalational
anesthesia:
sevoflurane and/or
nitrous oxide
IV sedation: propofol
Inhalational
anesthesia:
sevoflurane and
nitrous oxide
IV sedation: propofol
Topical: EMLA cream
Specialty of
performing
clinician
Neuroradiologist
(lumbar puncture)
Neurologist (drug
administration)
Pediatric anesthesiologist
(anesthesia/sedation)
Neurologist (lumbar
puncture/drug
administration)
Anesthesiologist, nurse
practitioner, or sedation
nurses (anesthesia/
sedation)
Pediatric
anesthesiologist
(entire procedure)
Pediatric
anesthesiologist
(entire procedure)
Participant
position
Prone position on the
angiography table
Left lateral decubitus
position or supporting
sitting
Lateral decubitus
position
Left lateral position
Place of
procedure
Interventional diagnostic
suite (part of the
department of radiology)
Rapid treatment unit or
outpatient clinic suite
within the hospital
setting
Operating room Operating room
Monitoring ECG, pulse oximetry,
non-invasive blood
pressure, end-tidal CO
2
,
temperature
ECG, oxygen saturation,
and expired CO
2e
Oxygen saturation and
heart rate monitoring
f
ECG, pulse oximetry,
oscillometric blood
pressure, and end-
tidal CO
2
Ventilation was
spontaneous or
assisted
ECG, pulse oximetry,
blood pressure,
temperature, and
end-tidal CO
2
Abbreviations: ECG, electrocardiogram; IV, intravenous.
a
n’s indicate the number of lumbar punctures performed at each site (total 73).
b
Fluoroscopy was used routinely per institutional practice.
c
Only in some participants.
d
In participants with severe scoliosis only.
e
For children receiving lumbar puncture.
f
For children receiving IV sedation.
Hache
´et al 901
perform the procedure in the lateral decubitus or prone position
by pediatric anesthesiologists, neurologists, or neuroradiolo-
gists in either inpatient or outpatient settings. All sites per-
formed the procedure under intravenous (midazolam,
ketamine, fentanyl, remifentanil, and/or propofol) or inhaled
anesthesia/sedation (sevoflurane and/or nitrous oxide). Some
sites also reported the use of topical anesthesia (EMLA cream)
or locally injected lidocaine (Table 2).
A total of 74 lumbar punctures were attempted and 73 pro-
cedures were performed. The majority of lumbar punctures
were carried out using either a 22- (48%) or 25-gauge (37%)
needle inserted in the L3-L4 (44%) or L4-L5 (29%) space.
Nearly half (44%) of the lumbar punctures were guided using
fluoroscopy (Table 3).
Of the 73 lumbar punctures performed, the majority (n ¼50;
68%) had no complications; lumbar puncture–related adverse
events were reported in 23 (32%; Table 4). The most common
adverse events were headache (9 events), back pain (9 events),
and post–lumbar puncture syndrome (8 events; post–dural
puncture headache with or without vomiting), and all events
resolved without long-term complications. The timing of the
adverse events varied; 67%(n ¼6) of the headaches occurred
12 to 72 hours post lumbar puncture, whereas back pain was
reported 0 to 48 hours post procedure (Figure 1). Fifty percent
Table 3. Summary of Procedural Details per Lumbar Puncture.
a
Lumbar Puncture Procedural Details
First Lumbar
Puncture
(n ¼28)
Second Lumbar
Puncture
(n ¼27)
Third Lumbar
Puncture
(n ¼18)
Total No. of Lumbar
Punctures
(N ¼73)
Gauge of needle
21 2 (7) 1 (4) 0 3 (4)
22 13 (46) 14 (52) 8 (44) 35 (48)
24 4 (14) 2 (7) 1 (6) 7 (10)
25 9 (32) 9 (33) 9 (50) 27 (37)
27 0 1 (4) 0 1 (1)
Needle insertion site
L2-L3 4 (14) 8 (30) 5 (28) 17 (23)
L3-L4 11 (39) 13 (48) 8 (44) 32 (44)
L4-L5 12 (43) 5 (19) 4 (22) 21 (29)
L5-S1 1 (4) 1 (4) 1 (6) 3 (4)
Use of fluoroscopy, yes 14 (50) 12 (44) 6 (33) 32 (44)
Treatment for post–lumbar puncture
syndrome, yes
b
5 (18) 1 (4) 1 (6) 7 (10)
a
Values are n (%).
b
Participants were treated for post–lumbar puncture headache with acetaminophen, ibuprofen, and/or caffeine citrate.
Table 4. Summary of Reported Lumbar Puncture–Related Adverse Events.
Adverse Event
First Lumbar Puncture
(n ¼28)
Second Lumbar Puncture
(n ¼27)
Third Lumbar Puncture
(n ¼18)
All Lumbar Punctures
(N ¼73)
Patients,
n (%)
Events,
n
Patients,
n (%)
Events,
n
Patients,
n (%)
Events,
n
Total,
n (%)
a
Total Events,
n
Patients reporting 1 adverse event 9 (32) 20 8 (30) 10 6 (33) 8 23 (32) 38
Headache 4 (14) 4 4 (15) 4 1 (6) 1 9 (12) 9
Back pain 2 (7)
b
3 3 (11) 3 3 (17) 3 8 (11) 9
Post–lumbar puncture syndrome 5 (18)
b
6 1 (4) 1 1 (6) 1 7 (10) 8
Nausea 2 (7) 2 0 0 0 0 2 (3) 2
Puncture site pain 1 (4) 1 1 (4) 1 0 0 2 (3) 2
Paresthesia 1 (4) 1 0 0 0 0 1 (1) 1
Pain in extremity 0 0 1 (4) 1 0 0 1 (1) 1
Procedural nausea 0 0 0 0 1 (6) 1 1 (1) 1
Procedural pain 0 0 0 0 1 (6) 1 1 (1) 1
Vomiting 1 (4) 1 0 0 0 0 1 (1) 1
Puncture site reaction 1 (4) 1 0 0 0 0 1 (1) 1
Dehydration 1 (4) 1 0 0 0 0 1 (1) 1
Hypotension 0 0 0 0 1 (6) 1 1 (1) 1
a
Total number of adverse events in all 73 lumbar punctures performed.
b
Participants reporting >1 adverse event after each lumbar puncture were counted only once for the lumbar puncture.
902 Journal of Child Neurology 31(7)
(n ¼4) of the post–lumbar puncture syndrome events occurred
between 12 and 48 hours, with the remaining occurring after
72 hours (Figure 1). All 8 incidences of post–lumbar puncture
syndrome were managed with acetaminophen, ibuprofen, and/
or caffeine citrate for headache. All 8 cases of post–lumbar
puncture syndrome resolved with conservative therapy, and
none of the 7 participants needed an epidural blood patch. In
1 case, a blood patch was performed prophylactically during
the second lumbar puncture procedure in a patient who had
experienced a post–dural puncture headache following the first
procedure. No post–dural puncture headache resulted after the
second procedure. Resolution of the post–lumbar puncture syn-
drome occurred between 4 hours and 5 days, with the majority
of the events (50%of cases) lasting 1 to 2 days.
A subgroup analysis compared lumbar puncture complica-
tions with needle size, participant age, and spinal muscular
atrophy type and demonstrated that headache, back pain, and
post–lumbar puncture syndrome were observed more fre-
quently when a 21- or 22-gauge needle was used, in older
children (8-14 years of age), and in children with spinal mus-
cular atrophy type 3 (Table 5).
Discussion
Lumbar puncture–related adverse events are well documented
in children and infants,
11-13
with the most common complica-
tions being back pain and headache with an incidence of 11%
to 40%and 12%to 33%, respectively.
11,12,15
Although the
incidence of post–lumbar puncture syndrome in children is not
well reported, 4%to 11%of the reported headaches are classi-
fied as post–dural puncture headaches.
11,12,15
In addition to
headache, post–lumbar puncture syndrome can also include
transient effects of backache, dizziness, nausea with or without
vomiting, numbness, and lower extremity weakness.
16,17
In
rare cases, more severe symptoms have been reported, such
as intracranial hypotension, epidural hematoma, and cauda
equina syndrome.
18,19
In this phase 1 study and its extension,
73 lumbar punctures were performed for cerebrospinal fluid
collection and/or intrathecal drug administration in children
with spinal muscular atrophy. Approximately one-third of the
procedures were associated with adverse events, most com-
monly with headache, back pain, and post–lumbar puncture
syndrome, and the majority occurred within 72 hours after the
procedure. A subgroup analysis demonstrated that the highest
incidence of adverse events was reported in older children,
children with spinal muscular atrophy type 3, and when a larger
21- or 22-gauge needle was used.
Using a 24-gauge needle or smaller atraumatic needle
inserted with the bevel parallel to the dura fibers had been
suggested to considerably reduce damage to the dura and con-
sequently decrease the risk for cerebrospinal fluid leak after
lumbar puncture,
20,21
including in children.
11,22
Needle type
(atraumatic or traumatic) may have a greater impact on the
reported incidence of post–dural puncture headache than nee-
dle size. Turnbull et al
21
found the incidence of post–dural
puncture headache varied from 0.6%to 4%(22 gauge) and
0%to 14.5%(25 gauge) with an atraumatic (Whitacre) needle
versus 36%(22 gauge) and 3%to 25%(25-gauge) with a trau-
matic cutting-tip (Quincke) needle, respectively. Although
using an atraumatic needle may reduce the incidence of post–
lumbar puncture syndrome, some studies have identified
increased failure rate
23,24
and paresthesia
23
when using an
atraumatic needle versus a cutting-tip spinal needle. However,
differences in success rate were not found in other
studies.
15,22,25
Nearly half of the lumbar punctures were successfully car-
ried out in children with spinal muscular atrophy using a
24-gauge spinal needle or smaller and, consequently, were
Figure 1. Time of onset of headache, back pain, and post–lumbar puncture syndrome. Most common lumbar puncture–associated adverse
events (N ¼73) and their time of onset are shown.
a
Time of onset for 2 cases of back pain were not reported.
Hache
´et al 903
associated with reduced incidence of headache and post–lum-
bar puncture syndrome compared with procedures performed
using a 21- or 22-gauge needle. After initial experiences, all
investigational sites switched to using a smaller needle size,
except when use of a larger needle size was required (eg, sco-
liosis). The higher incidence of adverse events, particularly
headaches, observed among older children and/or in children
with spinal muscular atrophy type 3 were likely related to the
use of larger bore/gauge spinal needles, cutting-tip needles (eg,
Quincke type), multiple attempts, and/or due to technical dif-
ficulties resulting from increased body weight and the presence
of scoliosis or excessive lumbar lordosis.
In most cases, post–dural puncture headache can be success-
fully treated with conservative therapy, consisting of bed rest in
prone or lateral position, hydration, oral or intravenous caf-
feine, anti-nausea or antiemetic therapy, and/or analge-
sics.
20,21,26,27
However, in children with post–dural puncture
headaches persisting >48 hours or that worsen despite the use
of conservative therapy, a therapeutic epidural blood patch may
be indicated.
27,28
Although there is conflicting evidence, some
studies also support the use of a prophylactic blood patch to
prevent post–dural puncture headache; however, none of these
studies included children.
29
In this study, all post–dural punc-
ture headaches resolved with conservative treatment of bed
rest, adequate hydration, and administration of caffeine and
other analgesics, and therapeutic epidural blood patches proved
unnecessary.
Other considerations that may facilitate lumbar puncture
success in children include patient positioning and the use of
spinal ultrasound. Few studies in children and infants have
compared the feasibility of lumbar puncture in upright versus
lateral recumbent position. Both the seated and lateral decubi-
tus position with hip flexion increased the interspinous space
compared with hip neutral positions and may increase lumbar
puncture success rate.
30-33
The use of spinal ultrasound may
facilitate the lumbar puncture procedure,
34,35
and is favored
over fluoroscopy in children, particularly if repeated proce-
dures are planned, to minimize radiation exposure and cost.
36
In this study, lumbar punctures were performed in the lateral
decubitus or prone position, and nearly half of the lumbar
punctures were successfully done without ultrasound and/or
fluoroscopy. However, in patients with spinal muscular atrophy
with scoliosis, spinal rods, or other hardware, the use of ima-
ging may be warranted to facilitate the procedure and increase
the success of intrathecal medication delivery. Lumbar punc-
tures were successfully performed in the participants with sco-
liosis (13 in the first procedure, 12 in the second procedure, and
11 in the third procedure) and in the one child who had spinal
rods. The second fluoroscopy-guided procedure was unsuc-
cessful in only 1 patient because of scoliosis. This suggests that
in some cases scoliosis might hinder lumbar puncture success
in children with spinal muscular atrophy, but the frequency
needs to be confirmed in larger studies.
General anesthesia and/or sedation are routinely performed
in children to reduce procedure-related anxiety, pain, and dis-
tress, and to increase the overall success rate of lumbar punc-
ture.
37-39
However, increasing concerns about the impact of
repeated anesthesia exposure on the developing nervous system
in infants and young children must be carefully considered
when repeated procedures are planned.
40
All 73 lumbar punc-
tures performed in this study were performed using either intra-
venous (midazolam, ketamine, fentanyl, remifentanil, and/or
propofol) or inhaled anesthesia/sedation (sevoflurane, nitrous
oxide), with no associated complications reported. Children
with spinal muscular atrophy who have moderate to severe
muscle weakness and/or severe scoliosis are at higher risk for
hypoventilation and respiratory compromise. Thus, if deep
sedation or general anesthesia is used, assisted ventilation may
Table 5. Summary of Reported Lumbar Puncture–Related Adverse Events by Subgroup.
a
Adverse Event
Gauge of
Needle: 21/22
(n ¼38)
Gauge of
Needle:
24/25/27
(n ¼35)
Patient Age:
2-7 y
(n ¼47)
Patient Age:
8-14 y
(n ¼26)
Patients With
SMA type 2
(n ¼39)
Patients With
SMA type 3
(n ¼34)
Total No. of
Procedures
(N ¼73)
Headache 8 (21) 1 (3) 3 (6) 6 (23) 4 (10) 5 (15) 9 (12)
Back pain 5 (13) 3 (9) 4 (9) 4 (15) 2 (5) 6 (18) 8 (11)
Post–lumbar puncture
syndrome
5 (13) 2 (6) 2 (4) 5 (19) 2 (5) 5 (15) 7 (10)
Nausea 2 (5) 0 1 (2) 1 (4) 1 (3) 1 (3) 2 (3)
Puncture site pain 2 (5) 0 1 (2) 1 (4) 2 (5) 0 2 (3)
Paresthesia 1 (3) 0 0 1 (4) 0 1 (3) 1 (1)
Pain in extremity 1 (3) 0 1 (2) 0 1 (3) 0 1 (1)
Procedural nausea 0 1 (3) 1 (2) 0 1 (3) 0 1 (1)
Procedural pain 1 (3) 0 0 1 (4) 0 1 (3) 1 (1)
Vomiting 1 (3) 0 1 (2) 0 1 (3) 0 1 (1)
Puncture site reaction 1 (3) 0 1 (2) 0 1 (3) 0 1 (1)
Dehydration 1 (3) 0 1 (2) 0 1 (3) 0 1 (1)
Hypotension 1 (3) 0 1 (2) 0 1 (3) 0 1 (1)
Abbreviation: SMA, spinal muscular atrophy.
a
Values are n (%).
904 Journal of Child Neurology 31(7)
be required by either non-invasive or invasive means. The use
of local topical or subcutaneous anesthesia may help decrease
the requirements for sedation. Based on our experience in this
study, we recommend the most minimal use of sedative med-
ications or anesthesia to permit safe and effective completion
of the procedure.
The limitations of this study include a small sample size and
the limited number of lumbar puncture procedures performed.
Further experiences with lumbar puncture in children and
infants with spinal muscular atrophy are needed to add to this
knowledge.
Conclusions
In summary, repeated lumbar punctures were successfully per-
formed in children with spinal muscular atrophy in the initial
nusinersen clinical studies. The frequency of lumbar puncture–
related adverse events in children with spinal muscular atrophy
was similar to that previously reported in children and infants,
and were mainly limited to headache, back pain, and post–
lumbar puncture syndrome. A 24-gauge needle or smaller was
successfully used in children with spinal muscular atrophy to
perform lumbar puncture with lower incidence of complica-
tions, suggesting that using a 24-gauge or smaller needle would
likely reduce the chance of adverse events. Bed rest, adequate
hydration, oral caffeine, and/or analgesics were sufficient to
resolve post–lumbar puncture headache/syndrome without the
need of a therapeutic blood patch in all patients. Provisions for
ultrasound guidance may be warranted in future research pro-
tocols given the potential benefit of reduced radiation exposure
compared to fluoroscopy, especially in cases of serial proce-
dures for repeated drug delivery. Overall, we conclude that
intrathecal delivery of medication is feasible, safe, and well
tolerated. Our experience may prove useful for guiding the
development of best practice strategies for safe and effective
intrathecal delivery of nusinersen and/or other promising emer-
ging therapies for spinal muscular atrophy.
Author Note
Clinical trial registration: ClinicalTrials.gov identifiers: NCT01494701
(An Open-label Safety, Tolerability, and Dose-Range Finding Study of
ISIS SMN
Rx
in Patients With Spinal Muscular Atrophy; URL: https://
clinicaltrials.gov/ct2/show/NCT01494701) and NCT01780246 (An
Open-label Safety and Tolerability Study of ISIS SMN
Rx
in Patients
With Spinal Muscular Atrophy Who Previously Participated in ISIS
396443-CS1; URL: https://clinicaltrials.gov/ct2/show/NCT01780246)
Acknowledgments
The authors thank the study participants and their parents/families, the
study staff, study coordinators, and additional investigators (Drs Clau-
dia Chiraboga, Basil Darras, and Susan Iannoconne) at the clinical
trial sites who made the studies possible, and the SMA Foundation.
Biogen provided funding for medical writing support in the develop-
ment of this paper; Maria Hovenden from Excel Scientific Solutions
wrote the first draft of the manuscript based on input from authors, and
Kristen DeYoung from Excel Scientific Solutions copyedited and
styled the manuscript per journal requirements. Biogen reviewed and
provided feedback on the paper. The authors had full editorial control
of the paper, and provided their final approval of all content.
Author Contributions
MH, KJS, NS, AK, and AF-G coordinated and supervised data col-
lection and performed study procedures (eg, lumbar punctures or
anesthesia) at the 4 clinical sites, critically reviewed and revised the
manuscript, and approved the final manuscript as submitted. SX car-
ried out the initial data analyses, reviewed and revised the manuscript,
and approved the final manuscript as submitted. KB conceptualized
and designed the study, participated in the data analysis, reviewed and
revised the manuscript, and approved the final manuscript as
submitted.
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this article:
KJS has received funding for clinical trial contracts from Ionis Phar-
maceuticals, Inc. She was working at the Department of Neurology,
University of Utah, at the time of the study. SX is a full-time employee
of Ionis Pharmaceuticals, Inc. KB was a full-time employee of Ionis
Pharmaceuticals, Inc. at the time of the study and manuscript
preparation.
Funding
The authors disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: This study was
funded by Ionis Pharmaceuticals, Inc. This research received no spe-
cific grant from any funding agency in the public, commercial, or not-
for-profit sectors. Funding for medical writing support was provided
by Biogen. AF-G’s institution has received funding from Ionis Phar-
maceuticals, Inc. through other departments. The phase 1
(NCT01494701) and extension (NCT01780246) clinical studies were
funded by Ionis Pharmaceuticals, Inc.
Ethical Approval
Approval for the study protocols and all amendments were obtained
from Columbia University Medical Center Institutional Review Board
(IRB) (Approval nos. AAAI6758 and AAAK5458). Written informed
consent and assent (if applicable) were obtained before any evalua-
tions were conducted for eligibility.
References
1. Papisov MI, Belov VV, Gannon KS. Physiology of the intrathecal
bolus: the leptomeningeal route for macromolecule and particle
delivery to CNS. Mol Pharm. 2013;10:1522-1532.
2. Miller TM, Pestronk A, David W, et al. An antisense oligonucleo-
tide against SOD1 delivered intrathecally for patients with SOD1
familial amyotrophic lateral sclerosis: a phase 1, randomised,
first-in-man study. Lancet Neurol. 2013;12:435-442.
3. National Institute for Health and Care Excellence. Multiple
sclerosis. Management of multiple sclerosis in primary and sec-
ondary care. NICE Guidance. Published November 2003.
4. Crawford TO, Pardo CA. The neurobiology of childhood spinal
muscular atrophy. Neurobiol Dis. 1996;3:97-110.
5. Lefebvre S, Burglen L, Reboullet S, et al. Identification and char-
acterization of a spinal muscular atrophy-determining gene. Cell.
1995;80:155-165.
Hache
´et al 905
6. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371:
2120-2133.
7. Russman BS. Spinal muscular atrophy: clinical classification and
disease heterogeneity. J Child Neurol. 2007;22:946-51.
8. Hua Y, Sahashi K, Hung G, et al. Antisense correction of SMN2
splicing in the CNS rescues necrosis in a type III SMA mouse
model. Genes Devel. 2010;24:1634-1644.
9. Hua Y, Vickers TA, Okunola HL, Bennett CF, Krainer AR. Anti-
sense masking of an hnRNP A1/A2 intronic splicing silencer
corrects Ital splicing in transgenic mice. Am J Hum Genet.
2008;82:834-848.
10. Bonadio W. Pediatric lumbar puncture and cerebrospinal fluid
analysis. J Emerg Med. 2014;46:141-150.
11. Lowery S, Oliver A. Incidence of postdural puncture headache
and backache following diagnostic/therapeutic lumbar puncture
using a 22G cutting spinal needle, and after introduction of a
25G pencil point spinal needle. Paediatr Anaesth. 2008;18:
230-234.
12. Ebinger F, Kosel C, Pietz J, Rating D. Headache and backache
after lumbar puncture in children and adolescents: a prospective
study. Pediatrics. 2004;113:1588-1592.
13. Kiechl-Kohlendorfer U, Unsinn KM, Schlenck B, Trawo¨ger R,
Gassner I. Cerebrospinal fluid leakage after lumbar puncture in
neonates: incidence and sonographic appearance. AJR Am J
Roentgenol. 2003;181:231-234.
14. Chiriboga C SK, Darras BT, Iannaccone ST, et al. Results from a
phase 1 study of nusinersen (ISIS-SMN
RX
) in children with spinal
muscular atrophy. Neurology. 2016;86(10):890-897.
15. Kokki H, Heikkinen M, Turunen M, Vanamo K, Hendolin H.
Needle design does not affect the success rate of spinal anaesthe-
sia or the incidence of postpuncture complications in children.
Acta Anaesthesiol Scand. 2000;44:210-213.
16. Koch BL, Moosbrugger EA, Egelhoff JC. Symptomatic spinal
epidural collections after lumbar puncture in children. AJNR
Am J Neuroradiol. 2007;28:1811-1816.
17. Ng WH, Drake JM. Symptomatic spinal epidural CSF collection
after lumbar puncture in a young adult: case report and review of
literature. Childs Nerv Syst. 2010;26:259-262.
18. Gordon N. Spontaneous intracranial hypotension. Dev Med Child
Neurol. 2009;51:932-935.
19. Amini A, Liu JK, Kan P, Brockmeyer DL. Cerebrospinal fluid
dissecting into spinal epidural space after lumbar puncture caus-
ing cauda equina syndrome: review of literature and illustrative
case. Childs Nerv Syst. 2006;22:1639-1641.
20. Ahmed SV, Jayawarna C, Jude E. Post lumbar puncture headache:
diagnosis and management. Postgrad Med J. 2006;82:713-716.
21. Turnbull DK, Shepherd DB. Post-dural puncture headache: patho-
genesis, prevention and treatment. Br J Anaesth. 2003;91:718-729.
22. Apiliogullari S, Duman A, Gok F, Akillioglu I. Spinal needle
design and size affect the incidence of postdural puncture head-
ache in children. Paediatr Anaesth. 2010;20:177-182.
23. Sharma SK, Gambling DR, Joshi GP, Sidawi JE, Herrera ER. Compar-
ison of 26-gauge Atraucan and 25-gauge Whitacre needles: insertion
characteristics and complications. Can J Anaesth. 1995;42:706-710.
24. Thomas SR, Jamieson DR, Muir KW. Randomised controlled
trial of atraumatic versus standard needles for diagnostic lumbar
puncture. BMJ. 2000;321:986-990.
25. Kokki H, Hendolin H, Turunen M. Postdural puncture headache
and transient neurologic symptoms in children after spinal anaes-
thesia using cutting and pencil point paediatric spinal needles.
Acta Anaesthesiol Scand. 1998;42:1076-1082.
26. Basurto Ona X, Martı´nez Garcı´a L, Sola` I, Bonfill Cosp X. Drug
therapy for treating post-dural puncture headache. Cochrane
Database Syst Rev. 2011;8:CD007887.
27. Janssens E, Aerssens P, Allie¨t P, Gillis P, Raes M. Post-dural
puncture headaches in children. A literature review. Eur J
Pediatr. 2003;162:117-121.
28. Kokki M, Sjo¨vall S, Kokki H. Epidural blood patches are effective
for postdural puncture headache in pediatrics—a 10-year experi-
ence. Paediatr Anaesth. 2012;22:1205-1210.
29. Boonmak P, Boonmak S. Epidural blood patching for preventing
and treating post-dural puncture headache. Cochrane Database
Syst Rev. 2010;1:CD001791.
30. O
¨ncel S, Gu
¨nlemez A, Anik Y, Alvur M. Positioning of infants in
the neonatal intensive care unit for lumbar puncture as determined
by bedside ultrasonography. Arch Dis Child Fetal Neonatal Ed.
2013;98:F133-F135.
31. Abo A, Chen L, Johnston P, Santucci K. Positioning for lumbar
puncture in children evaluated by bedside ultrasound. Pediatrics.
2010;125:e1149-e1153.
32. Apiliogullari S, Duman A, Gok F, Ogun CO, Akillioglu I. The
effects of 45 degree head up tilt on the lumbar puncture success
rate in children undergoing spinal anesthesia. Paediatr Anaesth.
2008;18:1178-1182.
33. Molina A, Fons J. Factors associated with lumbar puncture suc-
cess. Pediatrics. 2006;118:842-844.
34. Kil HK, Cho JE, Kim WO, Koo BN, Han SW, Kim JY. Prepunc-
ture ultrasound-measured distance: an accurate reflection of epi-
dural depth in infants and small children. Reg Anesth Pain Med.
2007;32:102-106.
35. Kim S, Adler DK. Ultrasound-assisted lumbar puncture in pedia-
tric emergency medicine. J Emerg Med. 2014;47:59-64.
36. Yu SD, Chen MY, Johnson AJ. Factors associated with traumatic
fluoroscopy-guided lumbar punctures: a retrospective review.
AJNR Am J Neuroradiol. 2009;30:512-515.
37. Ljungman G, Gordh T, So¨rensen S, Kreuger A. Lumbar puncture
in pediatric oncology: conscious sedation vs. general anesthesia.
Med Pediatr Oncol. 2001;36:372-379.
38. Pinheiro JM, Furdon S, Ochoa LF. Role of local anesthesia
during lumbar puncture in neonates. Pediatrics. 1993;91:
379-382.
39. Anghelescu DL, Burgoyne LL, Faughnan LG, Hankins GM,
Smeltzer MP, Pui CH. Prospective randomized crossover evalua-
tion of three anesthetic regimens for painful procedures in chil-
dren with cancer. J Pediatr. 2013;162:137-141.
40. Psaty BM, Platt R, Altman RB. Neurotoxicity of generic anesthe-
sia agents in infants and children: an orphan research question in
search of a sponsor. JAMA. 2015;313:1515-1516.
906 Journal of Child Neurology 31(7)
