Advertisement

Journal of Neurology

, Volume 266, Issue 1, pp 183–194 | Cite as

Intrathecal administration of nusinersen in adolescent and adult SMA type 2 and 3 patients

  • Claudia D. WursterEmail author
  • Benedikt Winter
  • Kurt Wollinsky
  • Albert C. Ludolph
  • Zeljko Uzelac
  • Simon Witzel
  • Michael Schocke
  • Ralf Schneider
  • Tugrul Kocak
Original Communication
  • 356 Downloads

Abstract

Spinal muscular atrophy is a genetic motor neuron disease that leads to progressive muscular atrophy and muscle weakness. In December 2016, the Food and Drug Administration, and in June 2017, the European Medicines Agency approved the antisense oligonucleotide nusinersen for treatment of spinal muscular atrophy. Nusinersen has to be repeatedly administered intrathecally. Due to the clinical features of SMA, the application of the ASO by lumbar puncture can be challenging in symptomatic patients considering the frequently observed scoliosis, previous spine fusion surgeries, joint contractures, and respiratory insufficiency. To evaluate safety and feasibility of the intrathecal treatment in adolescent and adult SMA type 2 and 3 patients, we analyzed 93 lumbar punctures, monitored number of lumbar puncture attempts, duration of the procedure, injection site, and needle length. Oxygen saturation during the intervention, medication for sedation and local anesthesia, adverse events related to lumbar punctures, and macroscopic analysis of CSF were recorded. Moreover, we analyzed the use of CT-scans for performing lumbar punctures and its associated radiation exposure. Performing lumbar puncture for the intrathecal administration of nusinersen in adolescent and adult patients with later-onset SMA is feasible and safe, even in patients with complex spinal anatomies and respiratory insufficiency. To guarantee the quality of the procedure, we recommend establishing an experienced interdisciplinary team consisting of neurologists and/or neuropediatricians, anesthesiologists, orthopedic surgeons, and/or neuroradiologists.

Keywords

Spinal muscular atrophy Nusinersen Lumbar puncture 

Notes

Acknowledgements

The training of our physiotherapists was sponsored by Biogen and Hoffmann-La Roche.

Compliance with ethical standards

Conflicts of interest

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. CDW has received honoraria from Biogen as an advisory board member and for lectures and as a consultant from Hoffmann-La Roche. ACL has received financial research support from AB Science, Biogen Idec, Cytokinetics, GSK, Orion Pharam, Novartis, TauRx Therapeutics Ltd., and TEVA Pharmaceuticals, and has received honoraria as a consultant from Mitsubishi, Orion Pharma, Novartis, Teva and as an advisory board member from Biogen, Treeway, and Hoffmann-La Roche. ZU has received honoraria from Biogen as a consultant. BW has received honoraria from Biogen for a lecture. SW, KW, MS, RS, and TK report no disclosures relevant to the manuscript.

Ethical standards

The study was approved by the local ethics committee and has, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

Patients or their relatives gave informed consent to participate in the study.

Research data policy

Demographic and clinical data on motor functions of the investigated patients are provided to the German Network for Motor Neuron Diseases (MND-NET).

References

  1. 1.
    Lunn MR, Wang CH (2008) Spinal muscular atrophy. Lancet 371:2120–2133.  https://doi.org/10.1016/S0140-6736(08)60921-6 CrossRefGoogle Scholar
  2. 2.
    Lefebvre S, Bürglen L, Reboullet S et al (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155–165.  https://doi.org/10.1016/0092-8674(95)90460-3 CrossRefGoogle Scholar
  3. 3.
    Wang CH, Finkel RS, Bertini ES et al (2007) Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol.  https://doi.org/10.1177/0883073807305788 Google Scholar
  4. 4.
    Mercuri E, Finkel RS, Muntoni F et al (2018) Diagnosis and management of spinal muscular atrophy: Part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord 28:103–115.  https://doi.org/10.1016/j.nmd.2017.11.005 CrossRefGoogle Scholar
  5. 5.
    Finkel RS, Mercuri E, Meyer OH et al (2018) Diagnosis and management of spinal muscular atrophy: Part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord 28:197–207.  https://doi.org/10.1016/j.nmd.2017.11.004 CrossRefGoogle Scholar
  6. 6.
    Passini MA, Bu J, Richards AM et al (2011) Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med 3:72ra18–72ra18.  https://doi.org/10.1126/scitranslmed.3001777 CrossRefGoogle Scholar
  7. 7.
    Singh NK, Singh NN, Androphy EJ, Singh RN (2006) Splicing of a critical exon of human survival motor neuron is regulated by a unique silencer element located in the last intron. Mol Cell Biol.  https://doi.org/10.1128/MCB.26.4.1333-1346.2006 Google Scholar
  8. 8.
    Hua Y, Sahashi K, Hung G et al (2010) Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev 24:1634–1644.  https://doi.org/10.1101/gad.1941310 CrossRefGoogle Scholar
  9. 9.
    Finkel RS, Mercuri E, Darras BT et al (2017) Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 377:1723–1732.  https://doi.org/10.1056/NEJMoa1702752 CrossRefGoogle Scholar
  10. 10.
    Mercuri E, Darras BT, Chiriboga CA et al (2018) Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med.  https://doi.org/10.1056/NEJMoa1710504 Google Scholar
  11. 11.
    Bertini E, Hwu W-L, Reyna SP et al (2017) Efficacy and safety of nusinersen in infants with presymptomatic spinal muscular atrophy (SMA): interim results from the NURTURE study. Eur J Paediatr Neurol 21:e14.  https://doi.org/10.1016/j.ejpn.2017.04.1218 CrossRefGoogle Scholar
  12. 12.
    Schwentker EP, Gibson DA (1976) The orthopaedic aspects of spinal muscular atrophy. J Bone Jt Surg Ser AGoogle Scholar
  13. 13.
    McElroy MJ, Shaner AC, Crawford TO et al (2011) Growing rods for scoliosis in spinal muscular atrophy. Spine (Phila Pa 1976).  https://doi.org/10.1097/BRS.0b013e3182194937 Google Scholar
  14. 14.
    Holt JB, Dolan LA, Weinstein SL (2017) Outcomes of primary posterior spinal fusion for scoliosis in spinal muscular atrophy. J Pediatr Orthop.  https://doi.org/10.1097/BPO.0000000000001049 Google Scholar
  15. 15.
    Phillips DP, Roye DP, Farcy JP et al (1990) Surgical treatment of scoliosis in a spinal muscular atrophy population. Spine (Phila Pa 1976)Google Scholar
  16. 16.
    Kaufmann P, McDermott MP, Darras BT et al (2011) Observational study of spinal muscular atrophy type 2 and 3: functional outcomes over 1 year. Arch Neurol.  https://doi.org/10.1001/archneurol.2010.373 Google Scholar
  17. 17.
    Pechmann A, Langer T, Wider S, Kirschner J (2017) Original article single-center experience with intrathecal administration of Nusinersen in children with spinal muscular atrophy type 1. Eur J Paediatr Neurol.  https://doi.org/10.1016/j.ejpn.2017.11.001 Google Scholar
  18. 18.
    Haché M, Swoboda KJ, Sethna N et al (2016) Intrathecal injections in children with spinal muscular atrophy: Nusinersen clinical trial experience. J Child Neurol 31:899–906.  https://doi.org/10.1177/0883073815627882 CrossRefGoogle Scholar
  19. 19.
    Weaver JJ, Natarajan N, Shaw DWW et al (2018) Transforaminal intrathecal delivery of nusinersen using cone-beam computed tomography for children with spinal muscular atrophy and extensive surgical instrumentation: early results of technical success and safety. Pediatr Radiol.  https://doi.org/10.1007/s00247-017-4031-6 Google Scholar
  20. 20.
    Geraci AP, Black K, Jin M et al (2018) Transforaminal lumbar puncture for intrathecal nusinersen administration. Muscle Nerve.  https://doi.org/10.1002/mus.26082 Google Scholar
  21. 21.
    Nascene DR, Ozutemiz C, Estby H et al (2018) Transforaminal lumbar puncture: an alternative technique in patients with challenging access. Am J Neuroradiol.  https://doi.org/10.3174/ajnr.A5596 Google Scholar
  22. 22.
    Veerapandiyan A, Pal R, D’Ambrosio S et al (2018) Cervical puncture to deliver nusinersen in patients with spinal muscular atrophy. Neurology.  https://doi.org/10.1212/WNL.0000000000006006 Google Scholar
  23. 23.
    Mousa MA, Aria DJ, Schaefer CM et al (2018) A comprehensive institutional overview of intrathecal nusinersen injections for spinal muscular atrophyGoogle Scholar
  24. 24.
    O’Hagen JM, Glanzman AM, McDermott MP et al (2007) An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients. Neuromuscul Disord.  https://doi.org/10.1016/j.nmd.2007.05.009 Google Scholar
  25. 25.
    Glanzman AM, O’Hagen J, McDermott M et al (2011) Validation of the expanded hammersmith functional motor scale in spinal muscular atrophy type II and III. J Child Neurol.  https://doi.org/10.1177/0883073811420294 Google Scholar
  26. 26.
    Chiriboga CA, Swoboda KJ, Darras BT et al (2016) Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology 86:890–897.  https://doi.org/10.1212/WNL.0000000000002445 CrossRefGoogle Scholar
  27. 27.
    Dussourd L, Martinon B, Candille C et al (2017) Ultrasonography helps emergency physician identify the best lumbar puncture site under the conus medullaris. Scand J Trauma Resusc Emerg MedGoogle Scholar
  28. 28.
    Pierce DB, Shivaram G, Koo KSH et al (2018) Ultrasound-guided lumbar puncture in pediatric patients: technical success and safety. Pediatr Radiol.  https://doi.org/10.1007/s00247-018-4091-2 Google Scholar
  29. 29.
    Cauley KA (2015) Fluoroscopically guided lumbar puncture. Am J Roentgenol.  https://doi.org/10.2214/AJR.14.14028 Google Scholar
  30. 30.
    Loebe FM (1988) History and significance of suboccipital puncture. Psychiatr Neurol Med Psychol (Leipz) 40:617–620Google Scholar
  31. 31.
    Knosp E, Richling B, Horaczek A (1984) Laterale C1/C2-Punktion: Darstellung der Technik und Ergebnisse der ersten 100 Patienten. Acta Chir Austr 16:81–84.  https://doi.org/10.1007/BF02656232 CrossRefGoogle Scholar
  32. 32.
    Cahill PJ, Marvil S, Cuddihy L et al (2010) Autofusion in the immature spine treated with growing rods. Spine (Phila Pa 1976).  https://doi.org/10.1097/BRS.0b013e3181e21b50 Google Scholar
  33. 33.
    Andreisek G, Jenni M, Klingler D et al (2013) Access routes and reported decision criteria for lumbar epidural drug injections: a systematic literature review. Skelet Radiol.  https://doi.org/10.1007/s00256-013-1713-5 Google Scholar
  34. 34.
    Huda W, Ogden KM, Khorasani MR (2008) Converting dose-length product to effective dose at CT. Radiology.  https://doi.org/10.1148/radiol.2483071964 Google Scholar
  35. 35.
    Chang AL, Schoenfeld AH, Brook AL, Miller TS (2013) Radiation dose for 345 CT-guided interlaminar lumbar epidural steroid injections. Am J Neuroradiol.  https://doi.org/10.3174/ajnr.A3540 Google Scholar
  36. 36.
    Bauhs JA, Vrieze TJ, Primak AN et al (2008) CT dosimetry: comparison of measurement techniques and devices. RadioGraphics.  https://doi.org/10.1148/rg.281075024 Google Scholar
  37. 37.
    Leng S, Christner JA, Carlson SK et al (2011) Radiation dose levels for interventional CT procedures. Am J Roentgenol.  https://doi.org/10.2214/AJR.10.5057 Google Scholar
  38. 38.
    Lazarus MS, Forman RB, Brook AL, Miller TS (2017) Radiation dose and procedure time for 994 CT-guided spine pain control procedures. Pain PhysicianGoogle Scholar
  39. 39.
    Pearce MS, Salotti JA, Little MP et al (2012) Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet.  https://doi.org/10.1016/S0140-6736(12)60815-0 Google Scholar
  40. 40.
    Thomas SR, Jamieson DR, Muir KW et al (2000) Randomised controlled trial of atraumatic versus standard needles for diagnostic lumbar puncture. BMJ.  https://doi.org/10.1136/bmj.321.7267.986 Google Scholar
  41. 41.
    Turnbull DK, Shepherd DB (2003) Post-dural puncture headache: pathogenesis, prevention and treatment. Br J Anaesth 91:718–729.  https://doi.org/10.1093/bja/aeg231 CrossRefGoogle Scholar
  42. 42.
    Tourtellotte WW, Henderson WG, Tucker RP et al (1972) A randomized, double-blind clinical trial comparing the 22 versus 26 gauge needle in the production of the post-lumbar puncture syndrome in normal individuals. Headache J Head Face Pain.  https://doi.org/10.1111/j.1526-4610.1972.hed1202073.x Google Scholar
  43. 43.
    Campbell DC, Douglas MJ, Pavy TJG et al (1993) Comparison of the 25-gauge Whitacre with the 24-gauge Sprotte spinal needle for elective Caesarean section: cost implications. Can J Anaesth.  https://doi.org/10.1007/BF03009601 Google Scholar
  44. 44.
    Ross AW, Greenhalgh C, McGlade DP et al (1993) The sprotte needle and post dural puncture headache following Caesarean section. Anaesth Intensive CareGoogle Scholar
  45. 45.
    Lowery S, Oliver A (2008) 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.  https://doi.org/10.1111/j.1460-9592.2008.02414.x Google Scholar
  46. 46.
    Janssens E, Aerssens P, Alliët P et al (2003) Post-dural puncture headaches in children. A literature review. Eur J Pediatr.  https://doi.org/10.1007/s00431-002-1122-6 Google Scholar
  47. 47.
    Ebinger F, Kosel C, Pietz J, Rating D (2004) Headache and backache after lumbar puncture in children and adolescents: a prospective study. Pediatrics.  https://doi.org/10.1542/peds.113.6.1588 Google Scholar
  48. 48.
    Zhou H, Meng J, Marrosu E et al (2015) Repeated low doses of morpholino antisense oligomer: an intermediate mouse model of spinal muscular atrophy to explore the window of therapeutic response. Hum Mol Genet 24:6265–6277.  https://doi.org/10.1093/hmg/ddv329 CrossRefGoogle Scholar
  49. 49.
    The Lancet Neurology (2017) Treating rare disorders: time to act on unfair prices. Lancet Neurol 16:761CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Claudia D. Wurster
    • 1
    Email author
  • Benedikt Winter
    • 2
  • Kurt Wollinsky
    • 3
  • Albert C. Ludolph
    • 1
  • Zeljko Uzelac
    • 1
  • Simon Witzel
    • 1
  • Michael Schocke
    • 4
  • Ralf Schneider
    • 4
  • Tugrul Kocak
    • 5
  1. 1.Department of NeurologyRKU-University and Rehabilitation Clinics, Ulm UniversityUlmGermany
  2. 2.Department of PediatricsUlm UniversityUlmGermany
  3. 3.Department of AnesthesiologyRKU-University and Rehabilitation Clinics, Ulm UniversityUlmGermany
  4. 4.Department of NeuroradiologyRKU-University and Rehabilitation Clinics, Ulm UniversityUlmGermany
  5. 5.Department of Orthopedic SurgeryRKU-University and Rehabilitation Clinics, Ulm UniversityUlmGermany

Personalised recommendations