1. Frequencies of neurological malformations in EDS patients
Amanda Saikali
Mentored by Dr. Clair Francomano
Introduction
There may be a significant difference in the proportions of Chiari malformation type 1 (CM-1), craniocervical instability, and/or cervical instability in patients with Ehlers Danlos Syndrome hypermobility type (hEDS) than in the general public or Down syndrome patients. Similarly, a study was conducted by Milhorat et al. (2009) which explored the correlation between CM-1 and tethered cord syndrome. HEDS is a connective tissue disorder often characterized by joint hypermobility (see Figure 1) as well as skin hyperelasticity
and frailty (see Figure 2). HEDS can
lead to a number of complications
ranging in severity. A malformation that
may be seen is CM-1, a condition in which
a crowding of the brainstem, cerebellum,
and tonsils pushes the tonsils through the
foramen magnum (the opening of the
skull in which the spinal cord exits). Craniocervical instability causes compression of the cervicomedullary junction, resulting in injuries
extending from the medulla to the midcervical
cord. Cervical instability is when the cervical
spine can no longer support strong enough
weights. Each of these malformations may start
out as relatively harmless, but severe cases can
lead to profound symptoms if left undiagnosed.
Unfortunately, many patients with EDS and/or
these neurological malformations are not diagnosed until adulthood. Establishing clinical/radiological correlations could help identify these disorders faster by prompting doctors to test for the malformations associated with a diagnosis right after it is made.
Methods (cont’d)
foramen magnum. This causes the tonsils to put pressure on the spinal cord resulting in a variety of bone deformities that, when paired with hEDS, can compromise the connection between the skull and spine. To determine the presence of CM-1, a line was drawn from the inner margins of the foramen magnum to the inferior part of the tonsils (see Figure 3); if the length was 5mm or greater, the patient had CM-1. To test for craniocervical instability, a line was drawn down the base of the skull followed by a second line drawn down the back of the body to create the clivo-axial angle. A “normal” clivo-axial angle (Henderson et al., 2010) is approximately 165° when neutral, 155° when flexed, and 175° when extended (see Figure 4). If the clivo-axial angle is less than 135°, the patient has
craniocervical instability. Cervical
instability was assessed for by
measuring the curve in the cervical
spine; if there was a reverse, or
kyphotic angle, the patient had cervical
instability. Originally, the plan was to
compare the neurological
malformation frequencies discovered
in this study to their counterparts in
the general population, however after
extensive research through various
medical databases and literature, it
was discovered that there are no
known set frequencies of
craniocervical or cervical instability in
the general population, only of CM-1 (one in every thousand births). The fact that there is so little known about those disorders was a discovery in it of itself. To continue with the project, the results from a study comparing neurological malformations in male and female patients with Down syndrome conducted by El-Khouri et al. (2014) were utilized. Rather than being compared
to their frequencies
in the general
population, the
frequencies of
cervical and
craniocervical
instability were
compared to their
frequencies in
Down syndrome
patients.
Results
On the basis of two-proportion z-tests, there was convincing evidence that the proportion of CM-1 is significantly higher in hEDS patients than it is in the general public (p-value approx. 0). Cervical instability also appears significantly more frequently in hEDS patients than it does in Down syndrome patients (p-value approx. 0). However, there was no significant difference found between the frequencies of craniocervical instability in hEDS and Down syndrome patients (p-value approx. 0.75).
Figure 1: an example of joint hypermobility in an elbow
Conclusion
The prevalence of patients with CM-1 and hEDS is significantly higher than patients in the general public with CM-1. Similarly, the prevalence of patients with cervical instability as well as hEDS is significantly higher than the prevalence of cervical instability in patients with Down syndrome. With further studies, there is a chance that CM-1 and/or cervical instability could be proven to be symptoms of hEDS. Until then, the research conducted in this study means that as soon as a patient is diagnosed with hEDS, a doctor would be within his/her jurisdiction to have the patient tested for CM-1 and/or cervical instability. This would in turn allow patients to be diagnosed before their symptoms become out of hand. Earlier diagnoses would mean preventative measures could be taken to keep the neurological malformations from reaching their maximum irregularities. The patients would ultimately be in far less pain. There was an insignificant prevalence of patients with Down syndrome and hEDS.
Figure 3: the line spans the distance from left to right of the tonsils to the foramen magnum, respectively
Figure 2: an example of skin hyperelasticity with the skin of an elbow
References
El-Khouri, M., Mourao, M., Tobo, A., Rizzo, L., Fernando, C., & Riberto, M. (2014). Prevalence of Atlanto-Occipital and Atlantoaxial Instability in Adults with Down Syndrome. World Neurosurgery, 82(1-2),
Henderson, F., Wilson, W., Mott, S., Mark, A., Schmidt, K., & Berry, J. (2010). Deformative stress associated with an abnormal clivo-axial angle: A finite element analysis. Surg Neurol Int, 1(1), 30.
Milhorat, T., Bolognese, P., Nishikawa, M., Francomano, C., McDonnell, N., Roonprapunt, C., & Kula, R. (2009). Association of Chiari malformation type I and tethered cord syndrome: preliminary results of sectioning filum terminale. Surgical Neurology, 72(1),
Methods
With a population including all of Dr. Francomano’s new hEDS patients from September of 2013 to February of 2014 (55), each patient’s chart was studied for the following information: gender; date & age at the time of the visit; whether or not there was a previous diagnosis of any of the malformations or syndromes mentioned in this project, if so, which; whether or not the patient was suspected to have any of the malformations or syndromes mentioned in this project, if so, which; and whether or not the patient was recommended for imaging. The information was then recorded in a chart later used to make statistical conclusions. The patients recommended for imaging had their MRI’s pulled for measurements that would indicate the presence of neurological malformations. As earlier stated, CM-1 is a condition in which the tonsils are pushed through the
Figure 4: examples of the normal clivo-axial angle in its neutral, flexed, and extended states
165°
155°
175°
Neutral
Flexion
Extension
Acknowledgements
I would like to thank Dr. Francomano as well as Mrs. Gabriel for all of their help and guidance. Another thanks to the SMA for giving me the opportunity to participate in such an immersive project.