Nusinersen and Spinal Muscular Atrophy: Old Lessons for a New Therapy?
Oct 1, 2019
Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by the loss of motor neurons in the anterior horn of the spinal cord, resulting in proximal muscle weakness. It affects approximately 1 in 10,000 live births, and, in its extremes, results in severe early motor disability and death. Recently, nusinersen has been approved for treatment of SMA, which has resulted in a unique cohort of patients who present unique challenges both in the intrathecal administration of the drug as well as in the pesky complications of these procedures.
SMA results from degeneration of alpha motor neurons in the spinal cord due to the absence of the survival motor neuron (SMN1) gene. The lack of the protein encoded by this gene results in varying levels of hypotonicity and subsequent problems with ambulation, core strength, dexterity, and respiratory mechanics. These effects are mitigated to some extent by the presence of the SMN2 gene, which encodes a protein that is structurally similar but far less functional, due to aberrant splicing in 90 to 95% of the translated protein. The disease presents with varying severity, which is inversely related to the number of SMN2 copies present.
The most severe form, SMA type 1, typically carries one copy of SMN2. The onset of hypotonia is before 6 months of age, and patients are typically not able to sit unsupported. Due to the impact on muscles of respiration, there is profound susceptibility to respiratory insult and early progression to non-invasive respiratory support.
SMA type 2 is associated with less weakness due to additional copies of the SMN2 gene. Disease severity is variable, and symptoms typically present between seven and 18 months of age. Patients with SMA type 2 can usually sit unsupported and even acquire a standing position but do not walk independently.
SMA type 3 is rare and has patients achieving motor milestones before developing progressive proximal muscle weakness during infancy with varying severity through life.
Nusinersen (Spinraza®) is an antisense oligonucleotide treatment approved by the FDA for treatment of SMA in 2016. It works by antagonizing repressive sites near the SMN2 gene’s coding region, which in turn promotes SMN2’s production of functional SMN protein. The drug is administered intrathecally six times per year initially, and three times per year afterwards. Nusinersen was investigated in early phase 1 and 2 trials before entry into larger investigation via prospective, randomized, sham-controlled trials. In presymptomatic SMA recognized by newborn screening, an interim analysis has shown that administration of nusinersen helped stabilize or improve motor scores when compared to SMA patients not treated with nusinersen. In SMA type 1, nusinersen has been evaluated in open-label studies and a phase-3, double-blind, sham-controlled efficacy trial with demonstrated improvement in motor-milestone achievement and event-free survival.[4, 6, 7] In SMA type 2 and type 3, open-label and double-blind, sham-controlled trials have demonstrated higher motor function scores.[8, 9] The most common adverse events noted in multiple trials include upper and lower respiratory tract infection and constipation, though causality is not established. Antisense oligopeptides have been associated with thrombocytopenia, but this has not been encountered in a clinically relevant fashion.
Difficult Lumbar Punctures and Lessons Learned
The intrathecal administration of nusinersen has presented new conundrums to those caring for these patients. First, the overall fragility, immobility, and potential large body habitus of older patients can make positioning for a lumbar puncture quite difficult. Conventional wisdom holds that letting the patient guide movement and liberal use of hoists are essential to allow for safe movement to the procedure bed. Due to the tenuous respiratory status of many patients, it is often useful to coach the patient preoperatively with attention to the use of topical and local anesthetics in the hope of avoiding sedation. Of note, many older patients with SMA have undergone posterior spinal fusion. While no best practice has been established, strategies to perform nusinersen administration include surgical fenestration of the posterior spinal fusion in the lumbar area, caudal intrathecal approach, and transforaminal intrathecal approach. At Children’s Hospital Colorado, the transforaminal intrathecal approach under fluoroscopic guidance has become a standard practice in the patient with a posterior spinal fusion.
Younger patients with SMA often have undergone placement of magnetic expansion control rods or vertical expandable prosthetic titanium ribs to treat scoliosis. While spinal hardware is present in these patients, the intervertebral spaces are spared. At Children’s Hospital Colorado, we have found that using an ultrasound to mark the midline, spinous processes, and interspaces before the procedure has increased the ease of lumbar puncture in this population.
Managing Post-Dural Puncture Headaches
The intrathecal administration of nusinersen in a fragile population introduces unique challenges in the care of these patients. One example is the anecdotal but widely accepted belief that these patients experience a high rate of post-dural puncture headache (PDPH). This could be due to the underlying decreased muscle tone of patients with SMA, weakness of dural tissue after posterior spinal fusion, or other unknown factors. PDPH in the patient with SMA typically demonstrates the classical presentation: a postural headache within five days of dural puncture with associated photophobia, tinnitus, hypoacusis, and nausea. To date, there are no case reports of patients with SMA experiencing more severe sequelae, such as subarachnoid hemorrhage or dural sinus thrombosis.
At best, the care of an SMA patient with a PDPH is a system of trial and error. Medical treatment is a mainstay of therapy for PDPH in the patient with SMA, with many lessons borrowed from the obstetric population. While the evidence is often contradictory, caffeine has remained a mainstay of medical therapy in addition to oral rehydration. Cosyntropin, an adrenocorticotropic hormone analog, can be offered to patients as well, though investigations into this treatment have had mixed results.[12, 13] We typically administer 10 mcg/kg up to 1 mg as an intravenous bolus with no additional monitoring of vitals or serum sodium. On occasion, we have treated PDPH refractory to more conservative therapy with 24-hour infusions of low-dose ketamine and subsequent oral dextromethorphan. These patients seemed to respond to N-methyl-D-aspartate receptor antagonism, but this has not been systematically evaluated. The use of gabapentin, theophylline, and hydrocortisone can be considered; but evaluation of these treatments in the literature has shown mixed results.
When medical management of a PDPH is unsuccessful, invasive therapies such as epidural blood patches should be considered. In this population, an epidural blood patch is performed in the standard fashion and can have excellent results. Often, however, these patients have undergone posterior spinal fusion, which can make an epidural blood patch difficult or impossible. The consultant anesthesiologist is often asked if a blood patch can be performed on a patient in whom a window has been created in the posterior spinal fusion bone scar. This has not been detailed in the literature and likely presents two problems. First, the dura underlying the bone scar in a posterior spinal fusion tends to be quite thin. This has the potential to make such dura particularly susceptible to inadvertent puncture. Second, it is unclear if the injection into this area could result in impingement of spinal nerves with resultant injury.
So, what are the alternatives? Transnasal sphenopalatine block has been shown to reduce symptoms in patients with SMA through case reports and retrospective reviews.[15-17] This block is typically performed with 4% lidocaine applied to a cotton-tipped applicator. The local anesthetic is advanced through the nose to the posterior pharynx and left for approximately 20 minutes. This procedure has been tolerated, in our experience, by patients as young as seven years old. Another alternative is the greater occipital nerve block, which is performed either by landmark or with ultrasound guidance.[18-20]
In summary, the patient with SMA undergoing intrathecal injection of nusinersen can be a tricky clinical scenario. These frail patients who have often undergone spinal instrumentation present unique challenges, and, unfortunately, there is limited guidance from current literature. That being said, lessons learned from limited experience are the foundation upon which knowledge and wisdom are built, so stay tuned for more data to emerge!
- Finkel R, Kuntz N, Mercuri E, et al. Efficacy and safety of nusinersen in infants with spinal muscular atrophy (SMA): Final results from the phase 3 ENDEAR study. European Journal of Paediatric Neurology. 2017;21:e14-15.
- Gavrilov DK, Shi X, Das K, Gilliam TC, Wang CH. Differential SMN2 expression associated with SMA severity. Nat Genet. 1998;20(3):230-1.
- D’Amico A, Mercui E, Tiziano FD, Bertini E. Spinal muscular atrophy. Orphanet J Rare Dis. 2011;6(1):71.
- Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723-32.
- Neil EE, Bisaccia EK. Nusinersen: A novel antisense oligonucleotide for the treatment of spinal muscular atrophy. J Pediatr Pharmacol Ther. 2019;24(3):194-203.
- Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study. The Lancet. 2016;388(10063):3017-26.
- Chiriboga CA, Swoboda KJ, Darras BT, et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology. 2016;86(10):890-7.
- Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. 2018;378(7):625-35.
- Darras BT, Chiriboga CA, Iannaccone ST, et al. Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies. Neurology. 2019;92(21):e2492-506.
- Hoy SM. Nusinersen: First global approval. Drugs. 2017;77(4):473-9.
- Bielsky AR, Fuhr PG, Parsons JA, Yaster M. A retrospective cohort study of children with spinal muscular atrophy type 2 receiving anesthesia for intrathecal administration of nusinersen. Pediatric Anesthesia. 2018;51(10063):157.
- Basurto Ona X, Osoria D, Bonfill Cosp X. Drug therapy for treating post-dural puncture headache. Cochrane Database Syst Rev. 2015;28(7):CD007887.
- Hanling SR, Lagrew JW, Colmenar DH, Quiko AS, Drastol CA. Intravenous cosyntropin versus epidural blood patch for treatment of postdural puncture headache. Pain Med. 2016;17(7):1337-42.
- Peralta F, Devroe S. Any news on the postdural puncture headache front? Best Pract Res Clin Anaesthesiol. 2017;31(1):35-47.
- Cohen S, Ramos D, Grubb W, Mellender S, Mohiuddin A, Chiricolo A. Sphenopalatine ganglion block: A safer alternative to epidural blood patch for postdural puncture headache. Reg Anesth Pain Med. 2014;39(6):563.
- Cohen S, Levin D, Mellener S, et al. Topical sphenopalatine ganglion block compared with epidural blood patch for postdural puncture headache management in postpartum patients: A retrospective review. Reg Anesth Pain Med. 2018;43(8):880-4.
- Nair AS. Bilateral transnasal sphenopalatine block for treating postdural puncture headache. Korean J Anesthesiol. 2018;71(1):73-4.
- Uyar Turkyilmaz E, Eryilmaz NC, Guzey NA, Moraloglu O. Bilateral greater occipital nerve block for treatment of post-dural puncture headache after caesarean operations. Rev Bras Anesthesiol. 2016;66(5):445-50.
- Nirag G, Kelkar A, Girotra V. Greater occipital nerve block for postdural puncture headache (PDPH): A prospective audit of a modified guideline for the management of PDPH and review of the literature. J Clin Anesth. 2014;26(7):539-44.
- Niraj G. Greater occipital nerve treatment in the management of chronic headache secondary to accidental dural puncture: A case report. Headache. 2018;58(7):1118-9.