Cone-beam computed tomography guided nusinersen administrations in adult spinal muscular atrophy patients with challenging access: a single- center experience

Antisense-oligonucleotide nusinersen (Spinraza, Biogen Netherlands, Netherlands) was the first approved intrathecal drug for treatment of 5q spinal muscular atrophy (SMA) experienced as safe and clinically beneficial for lifelong treatment of infants and children.^1,2 Growing evidence indicate safety and efficacy even in some subgroups of adult patients.^{3 4 5}

Intrathecal administrations of nusinersen require lumbar puncture. In the natural progression of SMA, particularly in type 2 and 3, patients may develop severe scoliosis.⁶ In the most severe, type 1 SMA the patients rarely survive to adulthood, where as in type 4 being the mildest, involvement of the spine is rare.⁶ Debilitating scoliosis which requires surgery may not develop up to the onset of puberty and during childhood a conventional lumbar puncture is usually feasible.⁶ In older patients factors such as altered spine anatomy, obliterated interlaminar space and obesity are commonly present and preclude the conventional lumbar puncture.^{6 7 8} Consequentially, the need for reproducible and safe image-guided method for intrathecal administrations in adult patients has been accentuated.⁹

Several studies described successful techniques for administration of nusinersen in patients with challenging access. In these patients, successful interlaminar (IL) or transforaminal (TF) lumbar accesses have been performed under CT-, fluoroscopic- or ultrasound-guidance.^{7, 10 11 12 13 14} However, the possibility of spine deformity progression and the need for repetitive injections require a method with satisfactory deep soft tissue resolution and following the “as low as reasonable achievable” radiation principle.^10,15,16 The cone-beam CT (CBCT) allows volumetric display of the area of interest, pre-procedural planning and real time needle guidance which results in accurate anatomic navigation.¹⁷ So far, only three studies described the use of CBCT for intrathecal delivery of nusinersen in children and adults.^11,18,19 However, up to our knowledge there are no larger studies on CBCT guided intrathecal nusinersen delivery that would present data only on adult SMA patients.

The purpose of this prospective study was to present a single-center experience on implementation of lumbar spine CBCT-guided intrathecal nusinersen delivery in consecutive adult SMA patients with challenging access to investigate the technical success, feasibility, and safety.

We report our experience on implementation of lumbar spine CBCT-guided intrathecal nusinersen delivery in consecutive adult SMA patients with challenging access. Evidence gained support good technical success, safety, and feasibility of CBCT-guided intrathecal nusinersen delivery.

The patient selection in our study was multidisciplinary, prospective, and based on inclusion criteria which considered the anatomy of the adult SMA patients. Additionally, to criteria regarding scoliosis and history of corrective surgery, we also acknowledged the patients’ general constitution. This problem was so far addressed in only one study in a patient with BMI of 28, in which the intrathecal administration was performed under CT-guidance.¹⁰

Only few studies have reported their experience in CBCT-guided intrathecal administrations of nusinersen.^11,18,19 An early study utilized CBCT for needle positioning in three TF procedures in children.¹⁸ The authors reported later switch to fluoroscopy guidance as the performing physicians gained confidence with the intrathecal deliveries.¹⁸ A later study analyzed lumbar punctures with TF approach in seven adult patients.¹⁹ The latest study by Weaver et al. presented the largest group of 28 patients for CBCT-guided intrathecal nusinersen delivery.¹¹ In these studies the CBCT-guided lumbar intrathecal delivery was performed in both children and adult patients, whereas our study focused only on adult patients.^11,18,19 In our study CBCT-guided procedures were predominantly performed by the TF approach, a similar experience previously described by Weaver et al.¹¹ IL approach was not possible either due to severe scoliosis or no visible interlaminar space on CT after the posterior fusion instrumentation. Therefore, our data is in line with previous study, which acknowledges that a growing population of SMA patients requires alternative to the IL approach.¹⁸

Technical success of the CBCT-guided administrations was achieved in all patients. Only in few procedures secondary success was noted. This is in accordance with the study by Weaver et al. which reported high primary success rate for TF approach performed by both CBCT and fluoroscopy.¹¹ Similarly, high technical success is reported in studies utilizing CT as image-guidance.^7,12,20,23 However, while we specifically determined the technical success according to successful approach to the intrathecal space, other studies defined technical successes ambiguously; namely a primary success in most of the studies was not defined.^7,12,20,23 Two CT-guided studies reported a high (95% and 96.2%) single puncture attempt, which was comparable to our primary technical success.^12,23

In contrast to other CBCT studies, only mild peri-procedural AEs were reported in ours. Weaver et al. reported 4% occurrence of mild AEs such as radicular pain and headaches as well as 0.5% of severe AE such as meningitis.¹¹ Shokuhfar et al. recorded one case (10%) of bilateral radiculopathy.¹⁹ Although no severe AEs were noted in our study, the aforementioned studies raise attention to the potential risks one must take into consideration before the procedure. In the study we also report AEs from the patients that underwent conventional lumbar punctures. In comparison to patients after the conventional lumbar puncture, patients after the CBCT-guided punctures reported lower intensity and duration of low back pain. This finding is contrary to the findings by Carrera-Garcia et al.⁸ A possible explanation might be the high proportion of primary technical success which minimized the trauma to the spinal meninges and the peridural membrane which are abundant in nociceptors and other sensory receptors.²⁴

Direct comparison with other CBCT-guided studies regarding radiation was not possible due to differences in reported units.^11,19 In comparison to our study, three CT-guided studies performed predominantly on adult patients reported lower ED of around 2.5 mSv, whereas Spiliopolus et al. reported higher average ED of 12.7 mSv.^3,7,23,25 Plausible rationale for these findings may be differences in population characteristics. Patients with posterior spinal instrumentation are expected to receive higher radiation exposure than the patients without fusion instrumentation.^25,26 Contrary to this observation our data did not reveal any ED differences regarding spine instrumentation. However, the EDs for the two obese patients proved to be higher in comparison to the other patients.

There was a decline in the average ED over the course of the study time, a finding that is in line with other studies.^12,26 The following factors need to be accounted for the initial high ED. The highest contributing factor to the initial high ED was patients’ repositioning with CBCT reacquisition. The patients were repositioned as they either found the initial position uncomfortable or the target region was insufficiently depicted on acquired CBCT or the most comfortable patients’ position did not allow optimal CBCT acquisition. Physicians’ experience to adjust for specific anatomical considerations was also important in ED reduction. Thus, good cooperation between radiographers and performing physicians plays a key role in radiation exposure reduction. It is important to understand that each adult SMA patient is specific with differences in anatomical considerations, thus patient-tailored approach needs to be implemented.

There are few limitations that need to be noted. One might argue that this is only a single-center study. A multi-center comparison is not realizable since we are the only institution performing these procedures in our country. Furthermore, it would be difficult to standardize protocol in between organizations due to specifics of such a group. Here we report consecutive patients with standard protocol, which provides important insight in clinical work. Additionally, only partial comparison between other studies with CBCT-guidance was possible since there were differences in patient characteristics and methodology.^11,18,19

This single-center prospective study supported the use of CBCT-guided lumbar intrathecal administrations of nusinersen in an adult SMA population with challenging access as feasible, technically successful, and safe image guided method.