Spinal involvement in Morquio A

1. Spinal involvement in Morquio A

2. Atlantoaxial system: anatomy and pathology • Articulation of C1 (atlas) with C2 (axis) is complex, comprising several joints • Median atlantoaxial joint • Two lateral atlantoaxial joints • These joints are held in place and supported by several ligaments • Major stabilizing ligaments are the transverse and alar ligaments • Incompetent ligaments and/or dens hypoplasia may cause excessive independent movement between the C1 anterior arch and the dens to result in atlantoaxialsubluxation and instability • During flexion, spinal cord compression at the C1-C2 level results from indentation by the C1 posterior arch and posterior tilting of the dens • Upward translation of the dens may also result from transverse ligament failure • Vertical subluxation can lead to compression of the medulla, paralysis and death Competent transverse and alar ligaments maintain the integrity of the C1-C2 articulation by limiting posterior translation of the dens (odontoid process) Solanki et al, J Inherit MetabDis, 2013

3. Spinal involvement is a major cause of morbidity and mortality in Morquio A Syndrome • Spectrum of spinal involvement: • Bony anomalies • Cervical spine subluxation and instability • Spinal canal stenosis • Spinal cord compression • Spinal problems predispose patients to myelopathy, paralysis, and premature death Top image courtesy of Michael Beck, MD, and Christina Lampe, MD Bottom image courtesy of Christina Lampe, MD Solanki et al, J Inherit MetabDis, 2013; Montano et al, J Inherit MetabDis, 2007; Tomatsu et al, CurrPharmBiotechnol, 2011

4. Spinal involvement is common in Morquio A n = 325 Morquio A subjects (mean age = 14.5 years) Data based on medical history reviews MorCAP baseline data Harmatz et al, Mol Genet Metab, 2013

5. Bony anomalies: Dysostosis multiplex • Dens hypoplasia • Platyspondyly • Anterior beaking • Posterior scalloping • Thoracolumbar kyphosis Solanki et al, J Inherit Metab Dis, 2013

6. Cervical spine subluxation and instability • Etiology: • dens hypoplasia • ligamentous laxity • Atlantoaxial (C1-C2) subluxation: • ADI > 5 mm or PADI < 14 mm • Instability is present when ADI difference between flexion/extension views > 2 mm • Risk of cord compression and neurological compromise especially in presence of cervical spinal canal stenosis Solanki et al, J Inherit Metab Dis, 2013

7. Spinal canal stenosis • Etiology • Diffuse stenosis: • Generalized thickening of the posterior longitudinal ligament and the ligamentumflavum due to GAG accumulation • Most likely to result in compression at C4-C7 and T10-L1 • Focal stenosis: • CCJ: thickening of the membranatectoria and apical and occipito-atlantal ligaments • C1-C2: thickening of the peri-odontoid tissue and transverse atlantoaxial ligament + C1 posterior arch • C3-C7: bulging discs • Thoracolumbar and upper thoracic spine: kyphosis Solanki et al, J Inherit MetabDis, 2013

8. Spinal cord compression • Etiology: • Thickened ligaments • Cervical instability • Cartilaginous and ligamentous hypertrophy at the C1-C2 joint • Spinal canal stenosis • Disc protrusion • Kyphosis • Spinal canal stenosis or a combination of stenosis and instability may be predictive of spinal cord compression • Spinal stenosis with concomitant loss of CSF flow on MRI signifies spinal cord compression • Untreated cord compression can lead to cord damage and myelopathy Solanki et al, J Inherit MetabDis, 2013

9. Early recognition and diagnosis of spinal problems can minimize morbidity and mortality Diagnostic and monitoring tools: • Neurological examination • Imaging • Radiography • Computed tomography (CT) • Magnetic resonance imaging (MRI) • Other diagnostic examinations • Functional testing (e.g. 6 minute walk test) • Sleep studies • Urodynamics Image courtesy of Kenneth Martin, MD Solanki et al, J Inherit MetabDis, 2013

10. Neurological examination can identify patients at early stages of spinal cord compression • Presenting symptoms include loss of endurance, diminished walking distance, gait instability, leg weakness, paresthesia (legs and/or arms) • Hyperreflexia, raised muscle tone, pyramidal tract signs (ankle clonus, Babinski sign) and proprioceptive deficits may be observed upon examination • Limitations: • Morquio A patients may be difficult to assess neurologically due to lower limb joint involvement • neurological signs and symptoms may underestimate the severity of spinal cord compression seen on MRI • determination of the responsible level is challenging in patients with multi-segmental myelopathy Solanki et al, J Inherit MetabDis, 2013

11. Imaging is critical for risk assessment and diagnosis of spinal cord compression • Goals of imaging: • Detect treatable spinal cord compression • Stratify risk to spinal cord prior to permanent loss of function • Assist in surgical planning • Assess efficacy of surgical and medical treatment • Systematic and careful imaging involves: • Plain radiography, including instability imaging • MRI of the spinal cord • CT may be required Clinical and neurological findings should be correlated with imaging studies Images courtesy of Kenneth Martin, MD Solanki et al, J Inherit MetabDis, 2013

12. Radiography Solanki et al, J Inherit Metab Dis, 2013

13. CT Solanki et al, J Inherit MetabDis, 2013

14. MRI Solanki et al, J Inherit MetabDis, 2013

15. MRI is the single most useful tool for assessing spinal cord compression • MRI sequences: • T1 • T2 • Cisternography • CSF Flow • Diffusion • Spectroscopy • MR venography Myelomalaciais diagnosed by an increase in T2 signal coupled with volume loss in regions of cord compression Solanki et al, J Inherit Metab Dis, 2013

16. Natural history of cord compression - Threshold for critical cord compression - Solanki et al, Mol Genet Metab, 2012

17. Regular assessments are recommended for improved patient outcomes Solanki et al, J Inherit MetabDis, 2013

18. Surgical interventions • Indications include: • Neurological deficits + instability • Cord compression with signal change on MRI • Cervical spine: • Posterior fusion for C1-C2 subluxation and instability, often with posterior occipito-cervical fixation • If subluxation is irreducible and cord compression is present, decompression + fusion is indicated • Prophylatic fusion recommended by some • Thoracolumbarkyphosis: • Decompression, segmental instrumentation and fusion • Anterior discectomy and fusion strongly recommended to augment posterior fusion in cases of rigid kyphosis Ain et al, Spine, 2006 White, Curr Orthop Prac, 2012 Solanki et al, J Inherit MetabDis, 2013; White, CurrOrthopPrac, 2012; Ain et al, Spine (Phila PA 1976), 2006; Ransford et al, J Bone Joint Surg Br, 1996; Lipson, J Bone Joint Surg Am, 1977

19. Surgical outcomes • Short-term post-operative outcomes generally good • Possible post-surgical complications: • Late instability below fusion site may necessitate multiple fusions • Halo pin tract infection → Long-term monitoring is important • Long-term outcomes beyond 5 years are less known – few studies Morquio patient 26 years post-surgery: complete resolution of quadriparesis achieved and neurological function maintained 26 years after C1-C2 decompression and stabilization White, J Bone Joint Surg Am, 2009 Solanki et al, J Inherit Metab Dis, 2013; White, J Bone Joint Surg Am, 2009; Ain et al, Spine (Phila PA 1976), 2006; Dalvie et al, J Pediatr Orthop B, 2001; Holte et al, Neuro-Orthopedics,1994; Houten et al, Pediatr Neurosurg, 2011; Lipson, J Bone Joint Surg Am, 1977; Ransford et al, J Bone Joint Surg Br, 1996; Stevens et al, J Bone Joint Surg Br 1991; Svensson and Aaro, Act Orthop Scand, 1988.

20. Airway and anesthetic management of Morquio A patients presenting for surgery is challenging • Morquio A patients are at high risk of anesthesia-related morbidity and mortality due to: • Cervical instability and myelopathy • Compromised respiratory function • Upper and lower airway obstruction • Restrictive lung disease • Cardiac abnormalities • Any elective surgery requires: • Thorough pre-operative ENT, pulmonary and cardiac evaluations • Pre-operative radiological evaluation of the cervical spine • Skilled personnel in airway management • Spectrum of airway management equipment • Morquio A patients should be managed by experienced anesthesiologists at centers familiar with MPS disorders Theroux et al, PaediatrAnaesth, 2012; Solanki et al, J Inherit MetabDis, 2013; Walker et al, J Inherit MetabDis, 2013; McLaughlin et al, BMC Anesthesiol, 2010; Morgan et al, PaediatrAnaesth, 2002; Shinhar et al, Arch Otolaryngol Head Neck Surg, 2004; Belani et al, J PedSurg, 1993; Walker et al, Anaesthesia, 1994