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 atlantoaxial subluxation 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 Metab Dis, 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 Metab Dis, 2013; Montano et al, J Inherit Metab Dis, 2007; Tomatsu et al, Curr Pharm Biotechnol, 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 ligamentum flavum due to GAG accumulation
Most likely to result in compression at C4-C7 and T10-L1
Focal stenosis:
CCJ: thickening of the membrana tectoria 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 Metab Dis, 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 Metab Dis, 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 Metab Dis, 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 Metab Dis, 2013

11. Images courtesy of Kenneth Martin, MD
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 Metab Dis, 2013

12. Radiography Strengths Limitations Assess bone malformation
Assess spinal canal stenosis
Assess malalignment
Flexion-extension instability
Rapid
Inexpensive
Poor soft tissue discrimination
Limited by overlapping structures
Ionizing radiation
Limited to ossified structures
Solanki et al, J Inherit Metab Dis, 2013

13. CT Strengths Limitations Rapid (may obviate need for anesthesia)
Multiplanar imaging of bony structures
Alternative method for assessing flexion-extension instability in difficult cases (recommend low radiation dose protocol)
Can assess some soft tissue components of canal stenosis and cord compression with appropriate filtering
Preoperative planning
Suboptimal for visualizing soft tissues and the spinal cord
Ionizing radiation
More expensive and less accessible than plain film radiography
Solanki et al, J Inherit Metab Dis, 2013

14. MRI Strengths Limitations Multiplanar imaging
Ideal for soft tissue imaging
Preferred method for assessing spinal cord compression and myelomalacia
Flexion-extension imaging directly visualizes spinal cord
Demonstrate venous collaterals
Non-ionizing radiation
Long imaging times
May require anesthesia
Metal and motion artifacts
Limited access
Expensive
Solanki et al, J Inherit Metab Dis, 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
Myelomalacia is 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
Normal Cord Function
- Canal stenosis without contact or compression
- CSF effacement and cord contact
- Cord compression with normal T2, diffusivity and spectroscopy
- Threshold for critical cord compression -
Cord dysfunction, possibly reversible
- Cord compression with normal T2, but altered diffusivity and spectroscopy
Cord dysfunction, probably arrestable, may not be reversible
- Cord compression with abnormal T2, indicating myelomalacia or edema
Solanki et al, Mol Genet Metab, 2012

17. Regular assessments are recommended for improved patient outcomes
At diagnosis
Frequency
Neurological exam
Yes
6 months
Plain radiography cervical spine (AP, lateral neutral and flexion-extension)
2-3 years
Plain radiography spine (AP, lateral thoracolumbar)
2-3 years if evidence of kyphosis or scoliosis
MRI neutral position, whole spine
1 year
Flexion-extension of cervical spine by MRI
1-3 years
CT neutral region of interest
Preoperative planning
Solanki et al, J Inherit Metab Dis, 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
Thoracolumbar kyphosis:
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 Metab Dis, 2013; White, Curr Orthop Prac, 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. Belani et al, J Ped Surg, 1993; Walker et al, Anaesthesia, 1994
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, Paediatr Anaesth, 2012; Solanki et al, J Inherit Metab Dis, 2013; Walker et al, J Inherit Metab Dis, 2013;
McLaughlin et al, BMC Anesthesiol, 2010; Morgan et al, Paediatr Anaesth, 2002; Shinhar et al, Arch Otolaryngol Head Neck Surg, 2004;
Belani et al, J Ped Surg, 1993; Walker et al, Anaesthesia, 1994