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CC BY-NC-ND 4.0 · Arq Neuropsiquiatr 2021; 79(02): 127-132
DOI: 10.1590/0004-282X-ANP-2020-0200
Article

Managing intrathecal administration of nusinersen in adolescents and adults with 5q-spinal muscular atrophy and previous spinal surgery

Manejo da administração intratecal de nusinersena em adolescentes e adultos com atrofia muscular espinhal 5q e cirurgia prévia de coluna
Rodrigo de Holanda Mendonça 
1   Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, São Paulo SP, Brazil.
,
Hermann dos Santos Fernandes 
2   Universidade de São Paulo, Faculdade de Medicina, Departamento de Anestesiologia, São Paulo SP, Brazil.
,
Rafael Barbéro Schimmelpfeng Pinto 
3   Fleury Medicina Saúde, Radiologia Intervencionista, São Paulo SP, Brazil.
,
Ciro Matsui  Júnior
1   Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, São Paulo SP, Brazil.
,
Graziela Jorge Polido 
1   Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, São Paulo SP, Brazil.
,
André Macedo Serafim da Silva 
1   Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, São Paulo SP, Brazil.
,
Luis Fernando Grossklauss 
4   Universidade Federal de São Paulo, Departamento de Neurologia, Divisão Neuromusculares, São Paulo SP, Brazil.
,
Umbertina Conti Reed 
1   Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, São Paulo SP, Brazil.
,
Edmar Zanoteli 
1   Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, São Paulo SP, Brazil.
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ABSTRACT

Background: Spinal muscular atrophy (SMA) is a neurodegenerative disease of lower motor neurons associated with frequent occurrence of spinal deformity. Nusinersen is an antisense oligonucleotide that increases SMN protein level and is administrated by frequent intrathecal lumbar injections. Thus, spinal deformities and previous spinal surgery are important challenges for drug delivery in SMA. Objective: To report imaging methods used for Nusinersen injection in SMA patients. Methods: Nusinersen injection procedures in SMA types 2 and 3 patients who had previous spinal surgery were analyzed retrospectively to describe the imaging and puncture procedures, as well as the occurrence of complications. Results: Nine SMA patients (14 to 50 years old) underwent 57 lumbar punctures for nusinersen injection. Six patients had no interlaminar space available; in five of them, a transforaminal approach was used, and another one underwent a surgery to open a posterior bone window for the injections. Transforaminal puncture was performed using CT scan in three cases and fluoroscopy in the other two, with a similar success rate. One patient in the transforaminal group had post-procedure radiculitis, and another one had vagal reaction (hypotension). In three cases, with preserved interlaminar space, injections were performed by posterior interlaminar puncture, and only one adverse event was reported (post-puncture headache). Conclusion: In SMA patients with previous spinal surgery, the use of imaging-guided intervention is necessary for administering intrathecal nusinersen. Transforaminal technique is indicated in patients for whom the interlaminar space is not available, and injections should always be guided by either CT or fluoroscopy.

RESUMO

Introdução: A atrofia muscular espinal (AME) é uma desordem neurodegenerativa dos motoneurônios inferiores frequentemente associada à ocorrência de deformidade da coluna vertebral. Nusinersena é um oligonucleotídeo antisense que aumenta os níveis da proteína SMN, sendo administrado através de injeções lombares intratecais frequentes. Assim, deformidades da coluna vertebral e abordagem cirúrgica prévia são desafios importantes para a administração de medicamentos na AME. Objetivo: descrever os métodos de imagens utilizados para administração do Nusinersena nos pacientes com AME. Métodos: Os procedimentos de administração de nusinersena em pacientes com AME dos tipos 2 e 3 submetidos à cirurgia prévia da coluna foram analisados retrospectivamente para descrever os métodos de imagem e punção, e a ocorrência de complicações. Resultados: Nove pacientes com AME (14 a 50 anos) foram submetidos a 57 punções lombares para administração de nusinersena. Seis pacientes tinham enxerto ósseo ou nenhum espaço interlaminar disponível; em cinco deles foi utilizada uma abordagem transforaminal, e outra paciente foi submetida à abertura cirúrgica de janela óssea para as injeções. A punção transforaminal foi realizada usando tomografia computadorizada (TC) em três casos e fluoroscopia nos outros dois, com taxa de sucesso semelhante. Um paciente no grupo de abordagem transforaminal apresentou radiculite pós-procedimento e outro apresentou reação vagal (hipotensão). Em três casos, com espaço interlaminar preservado, foram realizadas técnica de punção interlaminar posterior e apenas um evento adverso foi relatado (cefaleia pós-punção). Conclusão: Em pacientes com AME e cirurgia prévia, o uso de intervenção guiada por imagem é necessário para a administração de nusinersena. A técnica transforaminal é indicada nos casos onde o espaço interlaminar não está disponível, devendo ser guiada por TC ou técnicas de imagem fluoroscópica.

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

Authors’ contribution:

RHM and HSF: conceptualized the paper, collected data, analyzed data and wrote the initial draft. RBSP, CMJ, GJP, AMSS, LFG and UCR: collected data and reviewed the manuscript for important intellectual content. EZ: conceptualized the paper, wrote and reviewed the manuscript for intellectual content, supervised the study.




Publication History

Received: 07 May 2020

Accepted: 05 July 2020

Article published online:
04 July 2023

© 2021. Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995 Jan;80(1):155-65. https://doi.org/10.1016/0092-8674(95)90460-3
  • 2 Munsat TL, Davies KE. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscul Disord. 1992;2(5-6):423-8. https://doi.org/10.1016/s0960-8966(06)80015-5
  • 3 Cartegni L, Krainer AR. Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat Genet. 2002 Apr;30(4):377-84. https://doi.org/10.1038/ng854
  • 4 Mendonça RH, Matsui C Jr, Polido GJ, Silva AMS, Kulikowski L, Torchio Dias A, et al. Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy. Neurol Genet. 2020 Sep;6(5):e505. https://doi.org/10.1212/NXG.20200200202002000505
  • 5 Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017 Nov;377(18):1723-32. https://doi.org/10.1056/NEJMoa1702752
  • 6 Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. 2018 Feb;378(7):625-35. https://doi.org/10.1056/NEJMoa1710504
  • 7 Reed UC, Zanoteli E. Therapeutic advances in 5q-linked spinal muscular atrophy. Arq Neuro-Psiquiatr. 2018 Apr;76(4):265-72. https://doi.org/10.1590/0004-282x20180011
  • 8 Mendonça RH, Polido GJ, Matsui C, Silva AMS, Solla DJF, Reed UC, et al. Real-world data from nusinersen treatment for patients with later-onset spinal muscular atrophy: a single center experience. J Neuromuscul Dis. 2021;8(1):101-8. https://doi.org/10.3233/JND-200551
  • 9 Mendonça RH, Polido GJ, Matsui C, Solla DJF, Reed UC, Zanoteli E. Clinical Outcomes in Patients with Spinal Muscular Atrophy Type 1 Treated with Nusinersen. J Neuromuscul Dis. 2021 Jan. [Epub ahead of print]. https://doi.org/10.3233/JND-200533
  • 10 Rodillo E, Marini ML, Heckmatt JZ, Dubowitz V. Scoliosis in spinal muscular atrophy: review of 63 cases. J Child Neurol. 1989 Apr;4(2):118-23. https://doi.org/10.1177/088307388900400208
  • 11 Fujak A, Raab W, Schuh A, Richter S, Forst R, Forst J. Natural course of scoliosis in proximal spinal muscular atrophy type II and IIIa: descriptive clinical study with retrospective data collection of 126 patients. BMC Musculoskelet Disord. 2013 Oct;14:283. https://doi.org/10.1186/1471-2474-14-283
  • 12 Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, et al. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018 Feb;28(2):103-15. https://doi.org/10.1016/j.nmd.2017.11.005
  • 13 Roso V, Bitu S de O, Zanoteli E, Beteta JT, Castro RC, Fernandes AC. Surgical treatment of scoliosis in spinal muscular atrophy. Arq Neuro-Psiquiatr. 2003 Sep;61(3A):631-8. https://doi.org/10.1590/s0004-282x2003000400020
  • 14 Stolte B, Totzeck A, Kizina K, Bolz S, Pietruck L, Mönninghoff C, et al. Feasibility and safety of intrathecal treatment with nusinersen in adult patients with spinal muscular atrophy. Ther Adv Neurol Disord. 2018 Oct;11:1756286418803246. https://doi.org/10.1177/1756286418803246
  • 15 Weaver JJ, Natarajan N, Shaw DWW, Apkon SD, Koo KSH, Shivaram GM, et al. 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. 2018 Mar;48(3):392-7. https://doi.org/10.1007/s00247-017-4031-6
  • 16 Geraci AP, Black K, Jin M, Rimler S, Evans A. Transforaminal lumbar puncture for intrathecal nusinersen administration. Muscle Nerve. 2018 Jan. https://doi.org/10.1002/mus.26082
  • 17 Nascene DR, Ozutemiz XC, Estby XH, McKinney AM, Rykken JB. Transforaminal lumbar puncture: an alternative technique in patients with challenging access. AJNR Am J Neuroradiol. 2018 May;39(5):986-91. https://doi.org/10.3174/ajnr.A5596
  • 18 Wurster CD, Winter B, Wollinsky K, Ludolph AC, Uzelac Z, Witzel S, et al. Intrathecal administration of nusinersen in adolescent and adult SMA type 2 and 3 patients. J Neurol. 2019 Jan;266(1):183-94. https://doi.org/10.1007/s00415-018-9124-0
  • 19 Bortolani S, Stura G, Ventilii G, Vercelli L, Rolle E, Ricci F, et al. Intrathecal administration of nusinersen in adult and adolescent patients with spinal muscular atrophy and scoliosis: transforaminal versus conventional approach. Neuromuscul Disord. 2019 Oct;29(10):742-6. https://doi.org/10.1016/j.nmd.2019.08.007
  • 20 Jacobson JP, Cristiano BC, Hoss DR. Simple Fluoroscopy-Guided Transforaminal Lumbar Puncture: Safety and Effectiveness of a Coaxial Curved- Needle Technique in Patients with Spinal Muscular Atrophy and Complex Spines. AJNR Am J Neuroradiol. 2020 Jan;41(1):183-8. https://doi.org/10.3174/ajnr.A6351
  • 21 Cordts I, Lingor P, Friedrich B, Pernpeintner V, Zimmer C, Deschauer M, et al. Intrathecal nusinersen administration in adult spinal muscular atrophy patients with complex spinal anatomy. Ther Adv Neurol Disord. 2020 Jan;13:1756286419887616. https://doi.org/10.1177/1756286419887616
  • 22 Stolzenberg D, Ahn JJ, Kurd M. Fluoroscopically guided lumbar transforaminal epidural steroid injection: procedural technique. Clin Spine Surg. 2018 Aug;31(7):297-9. https://doi.org/10.1097/BSD.20200200202002000627
  • 23 Labianca L, Weinstein SL. Scoliosis and spinal muscular atrophy in the new world of medical therapy: providing lumbar access for intrathecal treatment in patients previously treated or undergoing spinal instrumentation and fusion. J Pediatr Orthop B. 2019 Jul;28(4):393-6. https://doi.org/10.1097/BPB.20200200202002000632
  • 24 Dietrich TJ, Peterson CK, Zeimpekis KG, Bensler S, Sutter R, Pfirrmann CWA. Fluoroscopy-guided versus CT-guided lumbar steroid injections: comparison of radiation exposure and outcomes. Radiology. 2019 Mar;290(3):752-9. https://doi.org/10.1148/radiol.2018181224
  • 25 Kizina K, Stolte B, Totzeck A, Bolz S, Fleischer M, Mönninghoff C, et al. Clinical implication of dosimetry of computed tomography- and fluoroscopy-guided intrathecal therapy with nusinersen in adult patients with spinal muscular atrophy. Front Neurol. 2019 Nov;10:1166. https://doi.org/10.3389/fneur.2019.01166
  • 26 Oldenburg D, Guberina N, Stolte B, Kizina K, Stenzel E, Radbruch A, et al. Radiation exposure of image-guided intrathecal administration of nusinersen to adult patients with spinal muscular atrophy. Neuroradiology. 2019 May;61(5):565-74. https://doi.org/10.1007/s00234-019-02189-x