Keywords:
Muscular Atrophy, Spinal - Antisense Oligonucleotide - Spinal Puncture - Survival
of Motor Neuron 1 Protein - Motor Neuron Disease
Palavras-chave:
Atrofia Muscular Espinal - Oligonucleotídeo Antisenso - Punção Espinhal - Proteína
1 de Sobrevivência do Neurônio Motor - Doença dos Neurônios Motores
INTRODUCTION
Spinal muscular atrophy (SMA) is a neurodegenerative disease of lower motor neurons
from spinal cord and motor nuclei of brainstem, leading to axial and proximal limb
weakness associated with ventilatory insufficiency and spinal deformity. The most
common form of SMA is caused by deletions or disease-causing variants in the survival
motor neuron 1 (SMN1) gene, which segregates as an autosomal recessive trait[1].
SMA has been classified into at least three subtypes depending on age of disease onset
and the achievement of motor milestones[2]. Type 1 SMA (severe form, or Werdnig-Hoffman disease) is characterized by an age
of onset of 0–6 months old, and the children are unable to sit unaided. In type 2
SMA (intermediate form), the clinical manifestations start between 6 and 18 months
of age, and children are unable to stand or walk unaided. Children with type 3 SMA
(mild form) manifest the disease in the second year of life or later and are able
to stand or walk unaided[2].
The SMN2 gene, a centromeric copy of the SMN1 gene, produces a truncated, highly unstable, and non-functional variant of the SMN
protein due to a pre-mRNA that undergoes an alternative splicing of exon 7[3]. Several studies have demonstrated a strong inverse correlation between the number
of SMN2 copies and SMA severity[1],[4]. Nusinersen is an antisense oligonucleotide that targets the pre-RNA of SMN2 and increases full-length SMN protein levels. Its effectiveness has been demonstrated
in two pivotal trials: one for patients with SMA type 1 and the other for SMA types
2 and 3[5],[6]. The US Food and Drug Administration (FDA) first approved nusinersen for the treatment
of SMA in 2016. The Brazilian National Health Surveillance Agency (ANVISA) approved
it in 2017[7]. Because of its inability to cross the blood-brain barrier, nusinersen is administered
intrathecally in a therapeutic regimen requiring four lumbar punctures within two
months and consecutive maintenance injections every four months thereafter[5],[6],[7],[8],[9]. This administration schedule has proven to be a challenge in patients with scoliosis
and in those with previous spinal fusion.
Scoliosis is a frequent manifestation in all forms of SMA, being secondary to progressive
weakness of the axial muscles[10],[11]. Surgical treatment is indicated in most cases, especially when the curve is greater
than 45 degrees, to control curve progression and pelvic obliquity[12],[13]. The surgical approach, often with the use of bone graft, makes the conventional
lumbar puncture by posterior interlaminar approach a challenge in these patients.
The benefit of using imaging to perform lumbar puncture for nusinersen administration
in this special population has been well demonstrated[14]. In addition, many innovative reports have addressed the use of different methods
for intrathecal nusinersen infusion in SMA patients with scoliosis or with previous
spinal surgery[15],[16],[17],[18],[19],[20],[21].
The aim of this study was to evaluate the feasibility of fluoroscopy and CT imaging,
as well as the main technical and safety differences when comparing the transforaminal
and posterior interlaminar punctures in the intrathecal administration of nusinersen
in patients with SMA and previous spinal surgery.
METHODS
From March 2018 to December 2019, we retrospectively analyzed the nusinersen injection
procedures in SMA types 2 and 3 patients who had a previous extensive posterior thoraco-lumbar
spinal fusion. A multidisciplinary team composed of a neurologist and physiotherapist
routinely followed up with patients. First, all patients underwent a computed tomography
(CT) scan before intrathecal administration. Then, patients were seen by a radiologist
with expertise in CT-guided interventions or by an anesthesiologist with expertise
in interventional procedures for pain management (procedures guided by fluoroscopy)
to choose the best approach. Patients with preserved interlaminar space ([Figure 1A]) underwent a conventional posterior interlaminar puncture, whereas those without
preserved posterior space ([Figures 1B and 1C]) underwent a transforaminal puncture. Either CT or fluoroscopy was chosen for the
procedure depending on the availability of the service and the professional experience
of the imaging-guided intervention used.
Figure 1 Prior spine computed tomography scan of two different patients. In A, preserved interlaminar
space is shown (arrows). In B and C, note the extensive bone graft and no residual
interlaminar space.
Technical success was defined by a return of cerebrospinal fluid (CSF) without need
of aspiration and complete medication delivery. Adverse events (e.g., post-lumbar
puncture syndrome, back pain and radiculopathy) and the need of sedation were recorded.
CT-guided lumbar puncture
CT-guided access was performed with the patient in lateral decubitus. The procedure
was performed in conventional or multislice tomography with local anesthesia. Sedation
or general anesthesia is required only in non-collaborative patients, which did not
occur in our case series. The procedure duration was approximately 15 minutes and
was performed by an interventional radiologist (R.B.S.P.) with tomography-guided intervention
expertise.
In transforaminal access, the upper foraminal third (“safety triangle”, cranial to
the exiting nerve root) is approached using a 22G spinal needle ([Figure 2]) to avoid neural or vascular injuries between the L2 to S1 levels.
Figure 2 Computed tomography scan for both interlaminar posterior puncture (A and B) and transforaminal
lumbar puncture (C and D). In A, note the needle (arrow) in the posterior aspect of
lamina. In B, the needle is located inside the dural sac (arrow). In C, the needle
(arrow) and the soft tissues around are visible. In D, the needle is located in the
posterior aspect of foramen (arrow).
Fluoroscopy-guided lumbar puncture
In fluoroscopy-guided lumbar puncture, the patient is positioned in lateral decubitus
in a lumbar flexion posture. The fluoroscopy C-arm should be in the anterior-posterior
position relative to the patient, with slight craniocaudal oblique angulation if necessary.
The entry point between two laminae on the midline was marked and anesthetized. The
puncture needle (Quincke 20-22G) was then inserted at the same point and directed
parallel to the incidence of fluoroscopy rays, in a technique called “tunnel vision”
(the parallel-ray needle is shown as a point) in radioscopy. The needle should be
directed 0.5–1.0 cm at a time, and its position is checked by radioscopic images and
its direction corrected. When loss of resistance is noticed after crossing the yellow
ligament and perforating the dura, it is possible to check for CSF reflux. If further
confirmation is desired, it is possible to make a fluoroscopic lateral image and check
the depth of the needle ([Figure 3]). Fluoroscopy-guided procedures were performed by a neurologist (R.H.M.) and an
anesthesiologist (H.S.F.) with expertise in interventional procedures.
Figure 3 Sequence for transforaminal fluoroscopic-guided spinal injection. (A) Initial image
on oblique incidence, (B) surface mark, (C) tunnel vision needle advance (arrow),
(D) confirmation of needle depth in lateral view, and (E) fluid reflux, as confirmation
of spinal puncture.
The transforaminal approach is similar to the technique used for transforaminal epidural
steroid injection[22]. The C-arm is rotated 30 to 40 degrees lateral oblique to allow direction of the
needle toward the superolateral aspect of the intervertebral foramen ([Figure 3]). The intervertebral foramen is identified, and the surface entry point is marked
and anesthetized. Using the “tunnel vision” needling technique, a 20–22G 90–120 mm
Quincke needle is advanced, aiming toward the superior third of the foramina (cranial
to the exiting nerve root), as shown in [Figure 3]. After loss of resistance in needle advance, position confirmation with lateral
view and fluid reflux is checked, followed by collection of 5 mL of CSF and medication
injection ([Figures 3D and 3E]).
RESULTS
Nine SMA patients (six women) underwent 57 lumbar punctures for nusinersen injection
([Table 1]). The patients’ ages ranged from 14 to 50 years (mean age=30.2 years old) at the
first injection. Six patients were diagnosed as having type 2 SMA and three as having
type 3 SMA ([Table 1]), and they were all wheelchair users.
Table 1
Spinal muscular atrophy patients with previous spinal surgery who underwent treatment
with nusinersen.
|
Pt
|
SMA type
|
Age/sex
|
Age at spinal fusion
|
Interlaminar space available
|
Imaging for LP
|
TFA or PIA/level of puncture
|
Total of LP
|
Sedation
|
AE
|
|
1
|
2
|
23y, F
|
8y
|
No
|
FL
|
PILP*/ L4-L5
|
8
|
Yes, MDZ
|
Post-puncture headache
|
|
2
|
2
|
50y, M
|
20y
|
Yes
|
CT
|
PILP/ L3-L4
|
7
|
No
|
No
|
|
3
|
2
|
19y, M
|
12y
|
No
|
FL
|
TFLP/L3-L4
|
7
|
Yes, MDZ
|
No
|
|
4
|
3
|
29y, F
|
13y
|
Yes
|
FL
|
PILP/L3-L4
|
6
|
No
|
No
|
|
5
|
2
|
14y, F
|
10y
|
Yes
|
FL
|
PILP/L3-L4
|
6
|
No
|
No
|
|
6
|
2
|
36y, F
|
23y
|
No
|
CT
|
TFLP/L4-L5
|
6
|
No
|
Vagal reaction with hypotension
|
|
7
|
2
|
26y, M
|
13y
|
No
|
CT
|
TFLP/ L4-L5
|
6
|
No
|
No
|
|
8
|
3
|
37y, F
|
18y
|
No
|
FL
|
TFLP/L3-L4
|
6
|
No
|
Radiculopathy
|
|
9
|
3
|
38y, F
|
17y
|
No
|
CT
|
TFLP/L3-L4
|
5
|
No
|
No
|
SMA: spinal muscular atrophy; Age: age at first infusion; y: years; F: female; M:
male; FL: fluoroscopy; CT: computed tomography; TFLP: transforaminal lumbar puncture;
PILP: posterior interlaminar lumbar puncture; MDZ: midazolam; AE: adverse events.
*Patient 1 was initially submitted to a spinal surgical opening of a bone window for
interlaminar posterior access.
After performing a CT scan, six patients had a CT spine showing bone graft or no interlaminar
space available, and in five of them the lumbar puncture was done using a transforaminal
approach. One additional patient (patient 1) underwent a surgery to open a posterior
bone window before the infusion; the procedure caused longer hospitalization, postoperative
pain, need for opioids, and slight functional worsening. In this last case, the following
infusions were done by a posterior access guided by fluoroscopy. Transforaminal puncture
was performed using CT scan in three cases, and fluoroscopy was used in the two remaining
patients, with a 100% success rate in both approaches.
As shown in [Table 1], in three cases, the injection was performed by posterior interlaminar puncture
after the CT spine had demonstrated that the interlaminar space was preserved. In
these cases, fluoroscopy was the technique most frequently used to guide the punctures.
Fluoroscopy and CT scan both showed 100% success rates.
The rate of adverse events in the 57 procedures was 5.2% ([Table 1]), being 6.6% in the transforaminal approach group (n=30) and 3.7% in the posterior
interlaminar puncture group (n=27). In the CT-guided puncture group (n=24), only one
adverse event occurred (4.1%), whereas in the fluoroscopy-guided puncture group (n=33),
two adverse events (6%) were reported. In the transforaminal puncture group, one episode
of radiculopathy was reported, with radicular and positional pain, but which reverted
in three days after the use of analgesics. Two patients required mild sedation with
midazolam due to needle phobia, without further complication.
DISCUSSION
In this study, we present nine patients with SMA who had previous spine surgery and
who underwent repeated lumbar punctures for nusinersen treatment. Fifty-seven procedures
were performed with a very low rate of adverse events. In six patients, a CT spine
showed bone graft or no interlaminar space available, and in five of them the lumbar
puncture was done using a transforaminal approach. Five out of nine patients had fluoroscopic
procedures, and similar success and adverse event rates were seen compared to CT-guided
punctures.
As previously suggested, a posterior interlaminar puncture is possible when a CT scan
detects an available interlaminar space, otherwise a transforaminal approach is indicated[15],[16],[18],[20],[21]. Some studies have already shown success with transforaminal puncture in patients
with SMA[15],[16],[17],[18],[19],[20],[21]. Using cone-beam CT guidance with two-axis fluoroscopic navigational overlay, Weaver
et al. showed the safety and efficacy of transforaminal intrathecal delivery of nusinersen
in four children with SMA[15]. Geraci et al. described the transforaminal approach for intrathecal nusinersen
delivery in five adult SMA patients, for a total of 17 doses, and reported no major
complications[16]. Nascene et al. reported no adverse events in a cohort of seven adult SMA patients
submitted to a transforaminal approach using CT or fluoroscopy guidance[17]. Bortolani et al. treated twelve teenage and adult SMA patients who had previous
spinal surgery or severe spinal deformity with nusinersen[19]. The authors used the transforaminal approach (seven patients) or the interlaminar
approach (five patients) under CT guidance. In 47 injections, the procedure had a
97.8% success rate, with 5% of the interlaminar approach group experiencing adverse
events and 15% in the transforaminal group. In the latter group, a patient suffered
a serious adverse event, which was a subarachnoid hemorrhage that required hospitalization.
The authors considered the transforaminal approach an effective option for nusinersen
administration in highly selected patients, but potential serious complications should
be considered[19]. More recently, Cordts et al. reported 53 CT-guided lumbar punctures of 11 adult
non-ambulatory SMA type 2 and 3 patients with 100% of success with post-lumbar puncture
syndrome occurring in 9.4% of the punctures[21]. In eight lumbar punctures from four patients with complete osseous fusion, the
authors proceeded with alternative routes of nusinersen injections including transforaminal
punctures and translaminar drilling[21]. In addition, in patients submitted to the transforaminal approach, the authors
reported a high rate of complications; a root irritation syndrome in two patients
(one had CSF signs of a subarachnoid hemorrhage) and a severe headache and lumbar
back pain in another one[21]. In our study, radiculopathy was also reported in the transforaminal group. We noted
a slightly higher rate of adverse events in the transforaminal approach compared to
the interlaminar group, but no serious adverse events were reported.
Labianca and Weinstein performed a laminotomy at the L3–L4 level for the intrathecal
injection of nusinersen in five SMA patients[23]. The procedure was carried out during the scoliosis surgery, or for those who underwent
posterior spinal fusion earlier, a second procedure was necessary to perform the laminotomy.
A similar approach was used in one of our patients, in which the interlaminar space
was not available for the puncture. However, this procedure is much more complicated,
and in our case, we noticed longer hospitalization, postoperative pain, need for opioids,
and slight functional worsening. Thus, we advise that the use of a transforaminal
approach guided by imaging should be tried first, before the indication of the laminotomy.
Our study showed that transforaminal or posterior interlaminar punctures guided by
fluoroscopy or CT imaging is feasible, with similar rates of complication and success,
regardless of the imaging method used. The main advantages in fluoroscopy-guided transforaminal
spinal puncture are availability of the equipment (fluoroscopic C-arms are more often
available than CT scan machines) and lower cost, and the main disadvantage is the
low-resolution image, especially for soft tissues[22]. CT-guided intrathecal punctures are a safe and effective option, especially in
patients with arthrodesis and scoliosis, with or without posterior bone graft. Its
main advantages include a single puncture from a single contact with the dura-mater,
which favors lower incidence of post-puncture headache, lower pain during the procedure,
greater comfort, and a reduced need for sedation or general anesthesia. This option
also allows visualization of the needle bezel inside the dural sac, an aspect that
guarantees proper needle positioning even in cases where there is no return of CSF,
as well as better visualization of soft tissues[17]. However, none of the mentioned imaging techniques accurately visualizes vascular
structures, such as radicular arteries, which can lead to bleeding and even serious
adverse events such as subarachnoid hemorrhage after transforaminal puncture[19].
Average exposure to radiation with CT guidance is comparable to a standard abdominal/pelvic
tomographic examination (9.95 mSV)[24],[25]. The study's use of targeted CT programming contributes to low doses of absorbed
radiation; as in intrathecal punctures, a few tomographic sections are performed (about
30 sections) instead of a complete spinal study (about 500 sections)[26].
Our study has some limitations, such as the small number of subjects included. In
addition, it is a retrospective study carried out in different institutions, in which
there was no prior planning and standardization of the applied techniques, and thus,
the comparison between them was limited.
In adults and adolescents with SMA and previous spine surgery, the use of imaging-guided
intervention is necessary for administering intrathecal nusinersen. The transforaminal
technique is a safe procedure indicated in cases where the interlaminar space is not
available, and it should always be guided by either CT or fluoroscopic imaging. Both
imaging-guided interventions seem equally effective. Although fluoroscopy is more
readily available, the CT-guided procedure offers better visualization of bone structures
and soft tissues and should be preferred when available.
