Spinal involvement in Morquio A

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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