Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience

Manon Haché, Kathryn J Swoboda, Navil Sethna, Alan Farrow-Gillespie, Alexander Khandji, Shuting Xia, Kathie M Bishop, Manon Haché, Kathryn J Swoboda, Navil Sethna, Alan Farrow-Gillespie, Alexander Khandji, Shuting Xia, Kathie M Bishop

Abstract

Nusinersen (ISIS-SMNRx 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 = 9), back pain (n = 9), and post-lumbar puncture syndrome (n = 8). 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.

Trial registration: ClinicalTrials.gov NCT01494701 NCT01780246.

Keywords: antisense oligonucleotide; drug delivery; lumbar puncture; spinal muscular atrophy.

Conflict of interest statement

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 Pharmaceuticals, 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.

© The Author(s) 2016.

Figures

Figure 1.
Figure 1.
Time of onset of headache, back pain, and post–lumbar puncture syndrome. Most common lumbar puncture–associated adverse events (N = 73) and their time of onset are shown. aTime of onset for 2 cases of back pain were not reported.

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.
    1. Miller TM, Pestronk A, David W, et al. An antisense oligonucleotide 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.
    1. National Institute for Health and Care Excellence. Multiple sclerosis. Management of multiple sclerosis in primary and secondary care. NICE Guidance. Published November 2003.
    1. Crawford TO, Pardo CA. The neurobiology of childhood spinal muscular atrophy. Neurobiol Dis. 1996;3:97–110.
    1. Lefebvre S, Burglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80:155–165.
    1. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371:2120–2133.
    1. Russman BS. Spinal muscular atrophy: clinical classification and disease heterogeneity. J Child Neurol. 2007;22:946–51.
    1. 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.
    1. Hua Y, Vickers TA, Okunola HL, Bennett CF, Krainer AR. Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects Ital splicing in transgenic mice. Am J Hum Genet. 2008;82:834–848.
    1. Bonadio W. Pediatric lumbar puncture and cerebrospinal fluid analysis. J Emerg Med. 2014;46:141–150.
    1. 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.
    1. 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.
    1. Kiechl-Kohlendorfer U, Unsinn KM, Schlenck B, Trawöger R, Gassner I. Cerebrospinal fluid leakage after lumbar puncture in neonates: incidence and sonographic appearance. AJR Am J Roentgenol. 2003;181:231–234.
    1. Chiriboga C SK, Darras BT, Iannaccone ST, et al. Results from a phase 1 study of nusinersen (ISIS-SMNRX) in children with spinal muscular atrophy. Neurology. 2016;86(10):890–7.
    1. Kokki H, Heikkinen M, Turunen M, Vanamo K, Hendolin H. Needle design does not affect the success rate of spinal anaesthesia or the incidence of postpuncture complications in children. Acta Anaesthesiol Scand. 2000;44:210–213.
    1. Koch BL, Moosbrugger EA, Egelhoff JC. Symptomatic spinal epidural collections after lumbar puncture in children. AJNR Am J Neuroradiol. 2007;28:1811–1816.
    1. 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.
    1. Gordon N. Spontaneous intracranial hypotension. Dev Med Child Neurol. 2009;51:932–935.
    1. Amini A, Liu JK, Kan P, Brockmeyer DL. Cerebrospinal fluid dissecting into spinal epidural space after lumbar puncture causing cauda equina syndrome: review of literature and illustrative case. Childs Nerv Syst. 2006;22:1639–1641.
    1. Ahmed SV, Jayawarna C, Jude E. Post lumbar puncture headache: diagnosis and management. Postgrad Med J. 2006;82:713–716.
    1. Turnbull DK, Shepherd DB. Post-dural puncture headache: pathogenesis, prevention and treatment. Br J Anaesth. 2003;91:718–729.
    1. Apiliogullari S, Duman A, Gok F, Akillioglu I. Spinal needle design and size affect the incidence of postdural puncture headache in children. Paediatr Anaesth. 2010;20:177–182.
    1. Sharma SK, Gambling DR, Joshi GP, Sidawi JE, Herrera ER. Comparison of 26-gauge Atraucan and 25-gauge Whitacre needles: insertion characteristics and complications. Can J Anaesth. 1995;42:706–710.
    1. Thomas SR, Jamieson DR, Muir KW. Randomised controlled trial of atraumatic versus standard needles for diagnostic lumbar puncture. BMJ. 2000;321:986–990.
    1. Kokki H, Hendolin H, Turunen M. Postdural puncture headache and transient neurologic symptoms in children after spinal anaesthesia using cutting and pencil point paediatric spinal needles. Acta Anaesthesiol Scand. 1998;42:1076–1082.
    1. Basurto Ona X, Martínez García L, Solà I, Bonfill Cosp X. Drug therapy for treating post-dural puncture headache. Cochrane Database Syst Rev. 2011;8:CD007887.
    1. Janssens E, Aerssens P, Alliët P, Gillis P, Raes M. Post-dural puncture headaches in children. A literature review. Eur J Pediatr. 2003;162:117–121.
    1. Kokki M, Sjövall S, Kokki H. Epidural blood patches are effective for postdural puncture headache in pediatrics—a 10-year experience. Paediatr Anaesth. 2012;22:1205–1210.
    1. Boonmak P, Boonmak S. Epidural blood patching for preventing and treating post-dural puncture headache. Cochrane Database Syst Rev. 2010;1:CD001791.
    1. Öncel S, Günlemez 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.
    1. Abo A, Chen L, Johnston P, Santucci K. Positioning for lumbar puncture in children evaluated by bedside ultrasound. Pediatrics. 2010;125:e1149–e1153.
    1. 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.
    1. Molina A, Fons J. Factors associated with lumbar puncture success. Pediatrics. 2006;118:842–844.
    1. Kil HK, Cho JE, Kim WO, Koo BN, Han SW, Kim JY. Prepuncture ultrasound-measured distance: an accurate reflection of epidural depth in infants and small children. Reg Anesth Pain Med. 2007;32:102–106.
    1. Kim S, Adler DK. Ultrasound-assisted lumbar puncture in pediatric emergency medicine. J Emerg Med. 2014;47:59–64.
    1. 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.
    1. Ljungman G, Gordh T, Sörensen S, Kreuger A. Lumbar puncture in pediatric oncology: conscious sedation vs. general anesthesia. Med Pediatr Oncol. 2001;36:372–379.
    1. Pinheiro JM, Furdon S, Ochoa LF. Role of local anesthesia during lumbar puncture in neonates. Pediatrics. 1993;91:379–382.
    1. Anghelescu DL, Burgoyne LL, Faughnan LG, Hankins GM, Smeltzer MP, Pui CH. Prospective randomized crossover evaluation of three anesthetic regimens for painful procedures in children with cancer. J Pediatr. 2013;162:137–141.
    1. Psaty BM, Platt R, Altman RB. Neurotoxicity of generic anesthesia agents in infants and children: an orphan research question in search of a sponsor. JAMA. 2015;313:1515–1516.

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