Accepted Manuscript Editorial Statement “ PERSPECTIVES” on the article: The craniovertebral junction instability in adult Down syndrome patients Konstantinos Margetis, MD, PhD Edward Benzel, MD PII:
S1878-8750(14)00459-8
DOI:
10.1016/j.wneu.2014.04.075
Reference:
WNEU 2355
To appear in:
World Neurosurgery
Received Date: 10 March 2014 Accepted Date: 30 April 2014
Please cite this article as: Margetis K, Benzel E, Editorial Statement “ PERSPECTIVES” on the article: The craniovertebral junction instability in adult Down syndrome patients, World Neurosurgery (2014), doi: 10.1016/j.wneu.2014.04.075. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Editorial Statement “ PERSPECTIVES” on the article: The craniovertebral junction instability in adult Down syndrome patients
Editorial Statement “ PERSPECTIVES” Authors:
RI PT
Konstantinos Margetis MD, PhD and Edward Benzel, MD
Center for Spine Health, Department of Neurosurgery, Neurological Institute, Cleveland
AC C
EP
M AN U
TE D
Corresponding Author: Edward C. Benzel, MD Chair, Department of Neurosurgery Neurological Institute Cleveland Clinic 9500 Euclid Ave, S40 Cleveland, OH 44195 [email protected] T: 216-444-7381 F: 216-445-4527
SC
Clinic, Cleveland, Ohio, USA
ACCEPTED MANUSCRIPT John Langdon Down first described the syndrome that now bears his name in 1866. The genetic cause of Down syndrome (DS) was elucidated in 1959.(14) It is now known that DS is caused by "extra genetic material from chromosome 21", either by trisomy 21 in 95% of the cases, or Robertsonian translocations in 3-4% or mosaicism in 1-2%.(25) In the 1960s
RI PT
the association of craniovertebral instability and DS was recognized.(26,27) Dzenitis(8) described the first case of a symptomatic atlanto-axial subluxation in DS.
SC
The ligamentous laxity in DS has classically been attributed as the causative factor of
craniovertebral junction instability (CVJI) in DS.(24) Browd et al showed that DS patients
M AN U
have an abnormal flattening of the occipital condyles that contributes to the atlanto-occipital instability (AOI) in these patients.(6) Osseous abnormalities such as os odontoideum and abnormal ossification of the C1 might also contribute to the instability.(16,21) Another possible contributing factor might be the arthropathy of the DS.(13,19) The CVJI might also
TE D
be post-inflammatory, with a pathophysiological mechanism similar to the Grisel's syndrome.(11) The difficulty in history taking and the concurrent medical conditions might
EP
render some mild forms of these inflammatory conditions under-diagnosed.
AC C
The basion-dental interval (BDI) and the basion-posterior axial line interval (BAI) are the most practical radiological parameters to assess for traumatic AOI;(4) an interval of more than 12mm for either the BDI or BAI is considered abnormal.(12) The subluxation of >2mm in atlanto-occipital joint has also been proposed as a sign of AOI in the general population,(29) however in the DS, >7mm has been proposed as evidence of instability.(5) The atlanto-dens interval (ADI) and the posterior atlanto-dens interval (PADI) have been proposed as the measurement of choice in evaluating for traumatic atlanto-axial instability (AAI).(4) In DS, a lower limit of 14 mm for the PADI has been proposed(9) with an upper
ACCEPTED MANUSCRIPT limit of 3mm for the ADI.(2). Dynamic x-rays are necessary to assess the ADI and PADI as pathologic values can be observed only in flexion in some patients(2) or only in neutral or extension views.(20) Given that the hypermobility in DS might be due to ligamentous laxity in multiple joints, the overall effect might be additive in terms of reducing the space available
RI PT
for the cord and therefore the isolated measurements of mobility in the various joints might not connote the clinical significance of the observed hypermobility.(28)
SC
Parfenchuck et al(17) showed an 8.5% prevalence of atlanto-occipital hypermobility in DS patients, by using the Power's ratio; the mean age was 17.3 y (range 2-79), with 66% of the
M AN U
patients with the increased motion being symptomatic. Roy et al(22) used an ADI of 3mm or more on lateral flexion x-rays to identify adult DS patients with AAI and they found a 10.2% prevalence. There was no statistically significant difference in the distribution of patients with neurological abnormality between the groups with or without AAI (43 vs 41%
TE D
respectively). Pueschel and Scola(20) in a mixed adult and pediatric DS patient population found a 14.6% prevalence of AAI, defined by an ADI of 5mm or more, with 6 out of the 59 patients with AAI being symptomatic. Alvarez and Rubin(3) found in an adult DS patient
EP
population a 40% prevalence of ADI of 3mm or more and a 10% prevalence of ADI>5mm;
AC C
only 50% of the total patient population had a normal neurological examination. The CVJI causes upper motor neuron symptoms and neck pain. Symptoms of vertebral insufficiency or upper cervical radiculopathy are theoretically possible, although, to our knowledge, they have not been described so far. A fatal outcome is considered very rare, however it has been reported.(23) There is a wide spectrum of functional status in the adult DS patient population that includes patients with significant intellectual disability. The clinical evaluation of the patients in the lower end of the spectrum can be highly challenging in terms of eliciting information about craniovertebral instability symptoms. The AAP in a
ACCEPTED MANUSCRIPT review of 41 symptomatic CVJI cases in DS concluded that many patients had had symptoms of spinal cord compression long before they were finally diagnosed.(1)
The American Academy of Pediatrics (AAP) has published guidelines regarding the health
RI PT
supervision of DS patients.(7) The AAP recommends, for asymptomatic DS patients: education of their parents regarding the early recognition of CVJI symptoms, clinical
examinations looking for signs of CVJI in the well child-visits and limitations regarding the
SC
high-impact sports. In symptomatic patients, the AAP recommends cervical spine
radiography and urgent evaluation by a surgeon. In the evaluation of a symptomatic DS
M AN U
patient with CVJI, one should take into consideration some other causes of neurologic symptoms in DS that include stroke from Moyamoya disease or vaso-occlusive disease or venous sinus thrombosis, intracranial hematoma or infection and brachial plexus injury.(30)
TE D
Once a symptomatic patient is referred to a surgeon a determination between surgical or conservative treatment needs to be made. Ferguson proposed as surgical indications in AAI the progressive or acute neurologic deterioration, a PADI of 10
AC C
mm; if ADI is between 4.5 and 10mm they proposed surgery only in the presence of neurologic deficit and MRI signal change in the spinal cord; in the AOI they proposed surgery only if there is motion>2mm, neurologic deficit and MRI signal change in the cord. Brockmeyer has also proposed as surgical indication the presence of os odontoideum in AAI or the subluxation of>8 mm in AOI.(5) The initial operative results of craniovertebral stabilization were discouraging, however the advent of modern rigid instrumentation allowed for more favorable outcomes and the negation of the need for post-op HALO orthosis.(5,15)
ACCEPTED MANUSCRIPT The importance of craniovertebral instability in adult DS patient population is rising, given that the life expectancy of DS patients has been increasing and it now approaches that of the general population.(10) We need further studies to establish radiological criteria that would distinguish DS patients with increased CVJ motion into craniovertebral instability (i.e.
RI PT
increased neurological risk) or craniovertebral hypermobility groups (i.e. neurological risk similar to that of the general population). The dynamic MRI has emerged as a ‘necessary’ examination for such a study as it would allow a direct estimation of the spinal cord
SC
compression, albeit with the limitations of the supine position. Static and dynamic lateral xrays should also be included, searching for correlations with the MRI findings that would
M AN U
allow the extrapolation of instability criteria for the x-rays. Should x-ray instability criteria be established, they would make x-rays a reliable screening test. Moreover, a comprehensive evaluation of the risks of CVJI in DS should take into consideration the possibility of vertebral artery compression and subsequent insufficiency as a possible cause of neurologic
TE D
symptoms, possibly by incorporating a dynamic vascular imaging study in suspicious cases.
Herein, El-Khouri et al investigate the CVJI in adult DS patients and give us a fresh look on
EP
the AOI in DS by using the BAI/BDI measurements and the Wiesel-Rothman line. These two
AC C
measurements used in conjunction appear to complement each other towards an increased sensitivity in the detection of AOI. They also assessed the same patient population for AAI by using the ADI with a cut-off of 3mm. The 17.5% prevalence of AOI and 11.2% of AAI are similar to the values reported in literature. Two out of the 80 total patients were symptomatic, both in the group with radiographic AAI or AOI. Interestingly, 2 (2.5%) patients had concurrent AAI and AOI. 11.2% of the patients could not be radiologically classified, showing the difficulty of obtaining satisfactory plain radiographs in this patient population. Given the high prevalence of CVJI in the adult DS patient population and the fact
ACCEPTED MANUSCRIPT that both symptomatic patients were in the CVJI group, the authors recommend imaging evaluation of the adult DS patients involved in risky activities. Should the CVJI be identified in these patients, the authors propose as an option to recommend the avoidance of contact
AC C
EP
TE D
M AN U
SC
RI PT
sports or similar high-risk activities and perform regular radiological evaluations.
ACCEPTED MANUSCRIPT References
1.
Atlantoaxial instability in Down syndrome: subject review. American Academy of Pediatrics Committee on Sports Medicine and Fitness. Pediatrics 96:151-154, 1995 Ali FE, Al-Bustan MA, Al-Busairi WA, Al-Mulla FA, Esbaita EY: Cervical spine
RI PT
2.
abnormalities associated with Down syndrome. Int Orthop 30:284-289, 2006 3.
Alvarez N, Rubin L: Atlantoaxial instability in adults with Down syndrome: a clinical
4.
SC
and radiological survey. Appl Res Ment Retard 7:67-78, 1986
Bono CM, Vaccaro AR, Fehlings M, Fisher C, Dvorak M, Ludwig S, et al:
M AN U
Measurement techniques for upper cervical spine injuries: consensus statement of the Spine Trauma Study Group. Spine (Phila Pa 1976) 32:593-600, 2007 5.
Brockmeyer D: Down syndrome and craniovertebral instability. Topic review and treatment recommendations. Pediatr Neurosurg 31:71-77, 1999 Browd SR, McIntyre JS, Brockmeyer D: Failed age-dependent maturation of the
TE D
6.
occipital condyle in patients with congenital occipitoatlantal instability and Down syndrome: a preliminary analysis. J Neurosurg Pediatr 2:359-364, 2008 Bull MJ, Committee on G: Health supervision for children with Down syndrome.
EP
7.
8.
AC C
Pediatrics 128:393-406, 2011 Dzenitis AJ: Spontaneous atlanto-axial dislocation in a mongoloid child with spinal cord compression. Case report. J Neurosurg 25:458-460, 1966 9.
Ferguson RL, Putney ME, Allen BL, Jr.: Comparison of neurologic deficits with atlanto-dens intervals in patients with Down syndrome. J Spinal Disord 10:246-252, 1997
ACCEPTED MANUSCRIPT 10.
Glasson EJ, Sullivan SG, Hussain R, Petterson BA, Montgomery PD, Bittles AH: The changing survival profile of people with Down's syndrome: implications for genetic counselling. Clin Genet 62:390-393, 2002
11.
Harley EH, Collins MD: Neurologic sequelae secondary to atlantoaxial instability in
RI PT
Down syndrome. Implications in otolaryngologic surgery. Arch Otolaryngol Head Neck Surg 120:159-165, 1994 12.
Harris JH, Jr., Carson GC, Wagner LK, Kerr N: Radiologic diagnosis of traumatic
SC
occipitovertebral dissociation: 2. Comparison of three methods of detecting
Roentgenol 162:887-892, 1994 13.
M AN U
occipitovertebral relationships on lateral radiographs of supine subjects. AJR Am J
Juj H, Emery H: The arthropathy of Down syndrome: an underdiagnosed and underrecognized condition. J Pediatr 154:234-238, 2009
14.
Lejeune J, Gautier M, Turpin R: [Study of somatic chromosomes from 9 mongoloid
15.
TE D
children]. C R Hebd Seances Acad Sci 248:1721-1722, 1959 Menezes AH: Specific entities affecting the craniocervical region: Down's syndrome. Childs Nerv Syst 24:1165-1168, 2008 Nader-Sepahi A, Casey AT, Hayward R, Crockard HA, Thompson D: Symptomatic
EP
16.
17.
AC C
atlantoaxial instability in Down syndrome. J Neurosurg 103:231-237, 2005 Parfenchuck TA, Bertrand SL, Powers MJ, Drvaric DM, Pueschel SM, Roberts JM: Posterior occipitoatlantal hypermobility in Down syndrome: an analysis of 199 patients. J Pediatr Orthop 14:304-308, 1994 18.
Pizzutillo PD, Herman MJ: Cervical spine issues in Down syndrome. J Pediatr Orthop 25:253-259, 2005
ACCEPTED MANUSCRIPT 19.
Pueschel SM, Herndon JH, Gelch MM, Senft KE, Scola FH, Goldberg MJ: Symptomatic atlantoaxial subluxation in persons with Down syndrome. J Pediatr Orthop 4:682-688, 1984
20.
Pueschel SM, Scola FH: Atlantoaxial instability in individuals with Down syndrome:
21.
RI PT
epidemiologic, radiographic, and clinical studies. Pediatrics 80:555-560, 1987
Pueschel SM, Scola FH, Tupper TB, Pezzullo JC: Skeletal anomalies of the upper cervical spine in children with Down syndrome. J Pediatr Orthop 10:607-611, 1990 Roy M, Baxter M, Roy A: Atlantoaxial instability in Down syndrome--guidelines for
SC
22.
screening and detection. J R Soc Med 83:433-435, 1990
Saad KF: A lethal case of atlantoaxial dislocation in a 56-year-old woman with
M AN U
23.
Down's syndrome. J Intellect Disabil Res 39 ( Pt 5):447-449, 1995 24.
Semine AA, Ertel AN, Goldberg MJ, Bull MJ: Cervical-spine instability in children with Down syndrome (trisomy 21). J Bone Joint Surg Am 60:649-652, 1978 Sheets KB, Crissman BG, Feist CD, Sell SL, Johnson LR, Donahue KC, et al:
TE D
25.
Practice guidelines for communicating a prenatal or postnatal diagnosis of Down syndrome: recommendations of the national society of genetic counselors. J Genet
Spitzer R, Rabinowitch JY, Wybar KC: A Study of the Abnormalities of the Skull,
AC C
26.
EP
Couns 20:432-441, 2011
Teeth and Lenses in Mongolism. Can Med Assoc J 84:567-572, 1961 27.
Tishler J, Martel W: Dislocation of the Atlas in Mongolism: Preliminary Report. Radiology 84:904-906, 1965
28.
Uno K, Kataoka O, Shiba R: Occipitoatlantal and occipitoaxial hypermobility in Down syndrome. Spine (Phila Pa 1976) 21:1430-1434, 1996
29.
White AA, 3rd, Panjabi MM: The clinical biomechanics of the occipitoatlantoaxial complex. Orthop Clin North Am 9:867-878, 1978
ACCEPTED MANUSCRIPT Worley G, Shbarou R, Heffner AN, Belsito KM, Capone GT, Kishnani PS: New onset focal weakness in children with Down syndrome. Am J Med Genet A
EP
TE D
M AN U
SC
RI PT
128A:15-18, 2004
AC C
30.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1878-8750(14)00459-8
DOI:
10.1016/j.wneu.2014.04.075
Reference:
WNEU 2355
To appear in:
World Neurosurgery
Received Date: 10 March 2014 Accepted Date: 30 April 2014
Please cite this article as: Margetis K, Benzel E, Editorial Statement “ PERSPECTIVES” on the article: The craniovertebral junction instability in adult Down syndrome patients, World Neurosurgery (2014), doi: 10.1016/j.wneu.2014.04.075. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Editorial Statement “ PERSPECTIVES” on the article: The craniovertebral junction instability in adult Down syndrome patients
Editorial Statement “ PERSPECTIVES” Authors:
RI PT
Konstantinos Margetis MD, PhD and Edward Benzel, MD
Center for Spine Health, Department of Neurosurgery, Neurological Institute, Cleveland
AC C
EP
M AN U
TE D
Corresponding Author: Edward C. Benzel, MD Chair, Department of Neurosurgery Neurological Institute Cleveland Clinic 9500 Euclid Ave, S40 Cleveland, OH 44195 [email protected] T: 216-444-7381 F: 216-445-4527
SC
Clinic, Cleveland, Ohio, USA
ACCEPTED MANUSCRIPT John Langdon Down first described the syndrome that now bears his name in 1866. The genetic cause of Down syndrome (DS) was elucidated in 1959.(14) It is now known that DS is caused by "extra genetic material from chromosome 21", either by trisomy 21 in 95% of the cases, or Robertsonian translocations in 3-4% or mosaicism in 1-2%.(25) In the 1960s
RI PT
the association of craniovertebral instability and DS was recognized.(26,27) Dzenitis(8) described the first case of a symptomatic atlanto-axial subluxation in DS.
SC
The ligamentous laxity in DS has classically been attributed as the causative factor of
craniovertebral junction instability (CVJI) in DS.(24) Browd et al showed that DS patients
M AN U
have an abnormal flattening of the occipital condyles that contributes to the atlanto-occipital instability (AOI) in these patients.(6) Osseous abnormalities such as os odontoideum and abnormal ossification of the C1 might also contribute to the instability.(16,21) Another possible contributing factor might be the arthropathy of the DS.(13,19) The CVJI might also
TE D
be post-inflammatory, with a pathophysiological mechanism similar to the Grisel's syndrome.(11) The difficulty in history taking and the concurrent medical conditions might
EP
render some mild forms of these inflammatory conditions under-diagnosed.
AC C
The basion-dental interval (BDI) and the basion-posterior axial line interval (BAI) are the most practical radiological parameters to assess for traumatic AOI;(4) an interval of more than 12mm for either the BDI or BAI is considered abnormal.(12) The subluxation of >2mm in atlanto-occipital joint has also been proposed as a sign of AOI in the general population,(29) however in the DS, >7mm has been proposed as evidence of instability.(5) The atlanto-dens interval (ADI) and the posterior atlanto-dens interval (PADI) have been proposed as the measurement of choice in evaluating for traumatic atlanto-axial instability (AAI).(4) In DS, a lower limit of 14 mm for the PADI has been proposed(9) with an upper
ACCEPTED MANUSCRIPT limit of 3mm for the ADI.(2). Dynamic x-rays are necessary to assess the ADI and PADI as pathologic values can be observed only in flexion in some patients(2) or only in neutral or extension views.(20) Given that the hypermobility in DS might be due to ligamentous laxity in multiple joints, the overall effect might be additive in terms of reducing the space available
RI PT
for the cord and therefore the isolated measurements of mobility in the various joints might not connote the clinical significance of the observed hypermobility.(28)
SC
Parfenchuck et al(17) showed an 8.5% prevalence of atlanto-occipital hypermobility in DS patients, by using the Power's ratio; the mean age was 17.3 y (range 2-79), with 66% of the
M AN U
patients with the increased motion being symptomatic. Roy et al(22) used an ADI of 3mm or more on lateral flexion x-rays to identify adult DS patients with AAI and they found a 10.2% prevalence. There was no statistically significant difference in the distribution of patients with neurological abnormality between the groups with or without AAI (43 vs 41%
TE D
respectively). Pueschel and Scola(20) in a mixed adult and pediatric DS patient population found a 14.6% prevalence of AAI, defined by an ADI of 5mm or more, with 6 out of the 59 patients with AAI being symptomatic. Alvarez and Rubin(3) found in an adult DS patient
EP
population a 40% prevalence of ADI of 3mm or more and a 10% prevalence of ADI>5mm;
AC C
only 50% of the total patient population had a normal neurological examination. The CVJI causes upper motor neuron symptoms and neck pain. Symptoms of vertebral insufficiency or upper cervical radiculopathy are theoretically possible, although, to our knowledge, they have not been described so far. A fatal outcome is considered very rare, however it has been reported.(23) There is a wide spectrum of functional status in the adult DS patient population that includes patients with significant intellectual disability. The clinical evaluation of the patients in the lower end of the spectrum can be highly challenging in terms of eliciting information about craniovertebral instability symptoms. The AAP in a
ACCEPTED MANUSCRIPT review of 41 symptomatic CVJI cases in DS concluded that many patients had had symptoms of spinal cord compression long before they were finally diagnosed.(1)
The American Academy of Pediatrics (AAP) has published guidelines regarding the health
RI PT
supervision of DS patients.(7) The AAP recommends, for asymptomatic DS patients: education of their parents regarding the early recognition of CVJI symptoms, clinical
examinations looking for signs of CVJI in the well child-visits and limitations regarding the
SC
high-impact sports. In symptomatic patients, the AAP recommends cervical spine
radiography and urgent evaluation by a surgeon. In the evaluation of a symptomatic DS
M AN U
patient with CVJI, one should take into consideration some other causes of neurologic symptoms in DS that include stroke from Moyamoya disease or vaso-occlusive disease or venous sinus thrombosis, intracranial hematoma or infection and brachial plexus injury.(30)
TE D
Once a symptomatic patient is referred to a surgeon a determination between surgical or conservative treatment needs to be made. Ferguson proposed as surgical indications in AAI the progressive or acute neurologic deterioration, a PADI of 10
AC C
mm; if ADI is between 4.5 and 10mm they proposed surgery only in the presence of neurologic deficit and MRI signal change in the spinal cord; in the AOI they proposed surgery only if there is motion>2mm, neurologic deficit and MRI signal change in the cord. Brockmeyer has also proposed as surgical indication the presence of os odontoideum in AAI or the subluxation of>8 mm in AOI.(5) The initial operative results of craniovertebral stabilization were discouraging, however the advent of modern rigid instrumentation allowed for more favorable outcomes and the negation of the need for post-op HALO orthosis.(5,15)
ACCEPTED MANUSCRIPT The importance of craniovertebral instability in adult DS patient population is rising, given that the life expectancy of DS patients has been increasing and it now approaches that of the general population.(10) We need further studies to establish radiological criteria that would distinguish DS patients with increased CVJ motion into craniovertebral instability (i.e.
RI PT
increased neurological risk) or craniovertebral hypermobility groups (i.e. neurological risk similar to that of the general population). The dynamic MRI has emerged as a ‘necessary’ examination for such a study as it would allow a direct estimation of the spinal cord
SC
compression, albeit with the limitations of the supine position. Static and dynamic lateral xrays should also be included, searching for correlations with the MRI findings that would
M AN U
allow the extrapolation of instability criteria for the x-rays. Should x-ray instability criteria be established, they would make x-rays a reliable screening test. Moreover, a comprehensive evaluation of the risks of CVJI in DS should take into consideration the possibility of vertebral artery compression and subsequent insufficiency as a possible cause of neurologic
TE D
symptoms, possibly by incorporating a dynamic vascular imaging study in suspicious cases.
Herein, El-Khouri et al investigate the CVJI in adult DS patients and give us a fresh look on
EP
the AOI in DS by using the BAI/BDI measurements and the Wiesel-Rothman line. These two
AC C
measurements used in conjunction appear to complement each other towards an increased sensitivity in the detection of AOI. They also assessed the same patient population for AAI by using the ADI with a cut-off of 3mm. The 17.5% prevalence of AOI and 11.2% of AAI are similar to the values reported in literature. Two out of the 80 total patients were symptomatic, both in the group with radiographic AAI or AOI. Interestingly, 2 (2.5%) patients had concurrent AAI and AOI. 11.2% of the patients could not be radiologically classified, showing the difficulty of obtaining satisfactory plain radiographs in this patient population. Given the high prevalence of CVJI in the adult DS patient population and the fact
ACCEPTED MANUSCRIPT that both symptomatic patients were in the CVJI group, the authors recommend imaging evaluation of the adult DS patients involved in risky activities. Should the CVJI be identified in these patients, the authors propose as an option to recommend the avoidance of contact
AC C
EP
TE D
M AN U
SC
RI PT
sports or similar high-risk activities and perform regular radiological evaluations.
ACCEPTED MANUSCRIPT References
1.
Atlantoaxial instability in Down syndrome: subject review. American Academy of Pediatrics Committee on Sports Medicine and Fitness. Pediatrics 96:151-154, 1995 Ali FE, Al-Bustan MA, Al-Busairi WA, Al-Mulla FA, Esbaita EY: Cervical spine
RI PT
2.
abnormalities associated with Down syndrome. Int Orthop 30:284-289, 2006 3.
Alvarez N, Rubin L: Atlantoaxial instability in adults with Down syndrome: a clinical
4.
SC
and radiological survey. Appl Res Ment Retard 7:67-78, 1986
Bono CM, Vaccaro AR, Fehlings M, Fisher C, Dvorak M, Ludwig S, et al:
M AN U
Measurement techniques for upper cervical spine injuries: consensus statement of the Spine Trauma Study Group. Spine (Phila Pa 1976) 32:593-600, 2007 5.
Brockmeyer D: Down syndrome and craniovertebral instability. Topic review and treatment recommendations. Pediatr Neurosurg 31:71-77, 1999 Browd SR, McIntyre JS, Brockmeyer D: Failed age-dependent maturation of the
TE D
6.
occipital condyle in patients with congenital occipitoatlantal instability and Down syndrome: a preliminary analysis. J Neurosurg Pediatr 2:359-364, 2008 Bull MJ, Committee on G: Health supervision for children with Down syndrome.
EP
7.
8.
AC C
Pediatrics 128:393-406, 2011 Dzenitis AJ: Spontaneous atlanto-axial dislocation in a mongoloid child with spinal cord compression. Case report. J Neurosurg 25:458-460, 1966 9.
Ferguson RL, Putney ME, Allen BL, Jr.: Comparison of neurologic deficits with atlanto-dens intervals in patients with Down syndrome. J Spinal Disord 10:246-252, 1997
ACCEPTED MANUSCRIPT 10.
Glasson EJ, Sullivan SG, Hussain R, Petterson BA, Montgomery PD, Bittles AH: The changing survival profile of people with Down's syndrome: implications for genetic counselling. Clin Genet 62:390-393, 2002
11.
Harley EH, Collins MD: Neurologic sequelae secondary to atlantoaxial instability in
RI PT
Down syndrome. Implications in otolaryngologic surgery. Arch Otolaryngol Head Neck Surg 120:159-165, 1994 12.
Harris JH, Jr., Carson GC, Wagner LK, Kerr N: Radiologic diagnosis of traumatic
SC
occipitovertebral dissociation: 2. Comparison of three methods of detecting
Roentgenol 162:887-892, 1994 13.
M AN U
occipitovertebral relationships on lateral radiographs of supine subjects. AJR Am J
Juj H, Emery H: The arthropathy of Down syndrome: an underdiagnosed and underrecognized condition. J Pediatr 154:234-238, 2009
14.
Lejeune J, Gautier M, Turpin R: [Study of somatic chromosomes from 9 mongoloid
15.
TE D
children]. C R Hebd Seances Acad Sci 248:1721-1722, 1959 Menezes AH: Specific entities affecting the craniocervical region: Down's syndrome. Childs Nerv Syst 24:1165-1168, 2008 Nader-Sepahi A, Casey AT, Hayward R, Crockard HA, Thompson D: Symptomatic
EP
16.
17.
AC C
atlantoaxial instability in Down syndrome. J Neurosurg 103:231-237, 2005 Parfenchuck TA, Bertrand SL, Powers MJ, Drvaric DM, Pueschel SM, Roberts JM: Posterior occipitoatlantal hypermobility in Down syndrome: an analysis of 199 patients. J Pediatr Orthop 14:304-308, 1994 18.
Pizzutillo PD, Herman MJ: Cervical spine issues in Down syndrome. J Pediatr Orthop 25:253-259, 2005
ACCEPTED MANUSCRIPT 19.
Pueschel SM, Herndon JH, Gelch MM, Senft KE, Scola FH, Goldberg MJ: Symptomatic atlantoaxial subluxation in persons with Down syndrome. J Pediatr Orthop 4:682-688, 1984
20.
Pueschel SM, Scola FH: Atlantoaxial instability in individuals with Down syndrome:
21.
RI PT
epidemiologic, radiographic, and clinical studies. Pediatrics 80:555-560, 1987
Pueschel SM, Scola FH, Tupper TB, Pezzullo JC: Skeletal anomalies of the upper cervical spine in children with Down syndrome. J Pediatr Orthop 10:607-611, 1990 Roy M, Baxter M, Roy A: Atlantoaxial instability in Down syndrome--guidelines for
SC
22.
screening and detection. J R Soc Med 83:433-435, 1990
Saad KF: A lethal case of atlantoaxial dislocation in a 56-year-old woman with
M AN U
23.
Down's syndrome. J Intellect Disabil Res 39 ( Pt 5):447-449, 1995 24.
Semine AA, Ertel AN, Goldberg MJ, Bull MJ: Cervical-spine instability in children with Down syndrome (trisomy 21). J Bone Joint Surg Am 60:649-652, 1978 Sheets KB, Crissman BG, Feist CD, Sell SL, Johnson LR, Donahue KC, et al:
TE D
25.
Practice guidelines for communicating a prenatal or postnatal diagnosis of Down syndrome: recommendations of the national society of genetic counselors. J Genet
Spitzer R, Rabinowitch JY, Wybar KC: A Study of the Abnormalities of the Skull,
AC C
26.
EP
Couns 20:432-441, 2011
Teeth and Lenses in Mongolism. Can Med Assoc J 84:567-572, 1961 27.
Tishler J, Martel W: Dislocation of the Atlas in Mongolism: Preliminary Report. Radiology 84:904-906, 1965
28.
Uno K, Kataoka O, Shiba R: Occipitoatlantal and occipitoaxial hypermobility in Down syndrome. Spine (Phila Pa 1976) 21:1430-1434, 1996
29.
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ACCEPTED MANUSCRIPT Worley G, Shbarou R, Heffner AN, Belsito KM, Capone GT, Kishnani PS: New onset focal weakness in children with Down syndrome. Am J Med Genet A
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