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Cervical medullary syndrome secondary to craniocervical instability and ventral brainstem compression in hereditary hypermobility connective tissue disorders: 5-year follow-up after craniocervical reduction, fusion, and stabilization

  • The Metroplitan Neurosurgery Group
  • Metropolitan Neurosurgery Group

Abstract and Figures

A great deal of literature has drawn attention to the “complex Chiari,” wherein the presence of instability or ventral brainstem compression prompts consideration for addressing both concerns at the time of surgery. This report addresses the clinical and radiological features and surgical outcomes in a consecutive series of subjects with hereditary connective tissue disorders (HCTD) and Chiari malformation. In 2011 and 2012, 22 consecutive patients with cervical medullary syndrome and geneticist-confirmed hereditary connective tissue disorder (HCTD), with Chiari malformation (type 1 or 0) and kyphotic clivo-axial angle (CXA) enrolled in the IRB-approved study (IRB# 10-036-06: GBMC). Two subjects were excluded on the basis of previous cranio-spinal fusion or unrelated medical issues. Symptoms, patient satisfaction, and work status were assessed by a third-party questionnaire, pain by visual analog scale (0–10/10), neurologic exams by neurosurgeon, function by Karnofsky performance scale (KPS). Pre- and post-operative radiological measurements of clivo-axial angle (CXA), the Grabb-Mapstone-Oakes measurement, and Harris measurements were made independently by neuroradiologist, with pre- and post-operative imaging (MRI and CT), 10/20 with weight-bearing, flexion, and extension MRI. All subjects underwent open reduction, stabilization occiput to C2, and fusion with rib autograft. There was 100% follow-up (20/20) at 2 and 5 years. Patients were satisfied with the surgery and would do it again given the same circumstances (100%). Statistically significant improvement was seen with headache (8.2/10 pre-op to 4.5/10 post-op, p < 0.001, vertigo (92%), imbalance (82%), dysarthria (80%), dizziness (70%), memory problems (69%), walking problems (69%), function (KPS) (p < 0.001). Neurological deficits improved in all subjects. The CXA average improved from 127° to 148° (p < 0.001). The Grabb-Oakes and Harris measurements returned to normal. Fusion occurred in 100%. There were no significant differences between the 2- and 5-year period. Two patients returned to surgery for a superficial wound infections, and two required transfusion. All patients who had rib harvests had pain related that procedure (3/10), which abated by 5 years. The results support the literature, that open reduction of the kyphotic CXA to lessen ventral brainstem deformity, and fusion/stabilization to restore stability in patients with HCTD is feasible, associated with a low surgical morbidity, and results in enduring improvement in pain and function. Rib harvest resulted in pain for several years in almost all subjects.
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Cervical medullary syndrome secondary to craniocervical
instability and ventral brainstem compression in hereditary
hypermobility connective tissue disorders: 5-year follow-up
after craniocervical reduction, fusion, and stabilization
Fraser C. Henderson Sr
&C. A. Francomano
&M. Koby
&K. Tuchman
&J. Adcock
&S. Patel
Received: 10 October 2018 /Revised: 28 November 2018 / Accepted: 10 December 2018 / Publ ished online: 9 January 2 019
A great deal of literature has drawn attention to the complex Chiari,wherein the presence of instability or ventral brainstem
compression prompts consideration for addressing both concerns at the time of surgery. This report addresses the clinical and
radiological features and surgical outcomes in a consecutive series of subjects with hereditary connective tissue disorders
(HCTD) and Chiari malformation. In 2011 and 2012, 22 consecutive patients with cervical medullary syndrome and
geneticist-confirmed hereditary connective tissue disorder (HCTD), with Chiari malformation (type 1 or 0) and kyphotic
clivo-axial angle (CXA) enrolled in the IRB-approved study (IRB# 10-036-06: GBMC). Two subjects were excluded on the
basis of previous cranio-spinal fusion or unrelated medical issues. Symptoms, patient satisfaction, and work status were assessed
by a third-party questionnaire, pain by visual analog scale (010/10), neurologic exams by neurosurgeon, function by Karnofsky
performance scale (KPS). Pre- and post-operative radiological measurements of clivo-axial angle (CXA), the Grabb-Mapstone-
Oakes measurement, and Harris measurements were made independently by neuroradiologist, with pre- and post-operative
imaging (MRI and CT), 10/20 with weight-bearing, flexion, and extension MRI. All subjects underwent open reduction,
stabilization occiput to C2, and fusion with rib autograft. There was 100% follow-up (20/20) at 2 and 5 years. Patients were
satisfied with the surgery and would do it again given the same circumstances (100%). Statistically significant improvement was
seen with headache (8.2/10 pre-op to 4.5/10 post-op, p<0.001, vertigo (92%), imbalance (82%), dysarthria (80%), dizziness
(70%), memory problems (69%), walking problems (69%), function (KPS) (p<0.001). Neurological deficits improved in all
subjects. The CXA average improved from 127° to 148° (p<0.001). The Grabb-Oakes and Harris measurements returned to
normal. Fusion occurred in 100%. There were no significant differences between the 2- and 5-year period. Two patients returned
to surgery for a superficial wound infections, and two required transfusion. All patients who had rib harvests had pain related that
procedure (3/10), which abated by 5 years. The results support the literature, that open reduction of the kyphotic CXA to lessen
ventral brainstem deformity, and fusion/stabilization to restore stability in patients with HCTD is feasible, associated with a low
surgical morbidity, and results in enduring improvement in pain and function. Rib harvest resulted in pain for several years in
almost all subjects.
Keywords Ehlers-Danlos syndrome .Craniocervical instability .Clivo-axial angle .Cervical medullary syndrome
Neurosurgical Review (2019) 42:915936
Many studies have drawn attention to the presence of
craniocervical instability or basilar invagination in patients
with Chiari one and Chiari zero malformation [123]. The
need for reduction and stabilization in basilar invagination
and craniocervical instability are recognized in connective tis-
sue joint degenerative disorders, such as rheumatoid arthritis
and lupus [10,17,2436] and hereditary hypermobile and
*Fraser C. Henderson, Sr
Doctors Community Hospital, Lanham, MD, USA
The Metropolitan Neurosurgery Group, LLC, Silver Spring, MD,
Harvey Institute of Human Genetics, Greater Baltimore Medical
Center, Baltimore, MD, USA
Medical University of South Carolina, Charleston, SC, USA
#The Author(s) 2019
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developmental disorders, including osteogenesis imperfecta,
achondroplasia, Down syndrome and Ehlers-Danlos syn-
drome (EDS) [8,18,21,26,31,3750].
Emblematic of the approximately 50 heritable connective
tissue disorders characterized by joint hypermobility is Ehlers-
Danlos syndrome (EDS). Though Ehlers-Danlos syndrome
was described in 1905, its neurological and spinal manifesta-
tions have only recently been appreciated [18,41,5166].
These heritable connective tissue disorders are characterized
by tissue fragility, skin extensibility, joint hypermobility, pre-
mature disk degeneration and spinal problems, and numerous
comorbid conditions.
We report on an IRB-approved retrospective cohort study
of 20 consecutive patients with hereditary connective tissue
disorders and a kyphotic CXA, cerebellar ectopia (18/20), and
craniocervical instability or ventral brainstem compression,
who underwent reduction and stabilization. This is the first
such study to critically assess 5-year outcomes after
craniocervical reduction, stabilization, and fusion in a patient
population with hereditary connective tissue disorders.
In this study, the CXA (clivo-axial angle) was used to in-
dicate potential brainstem deformity. The CXA has drawn
increasing attention as an important radiological metric to in-
dicate the presence of neurological deficit and consideration
for craniocervical stabilization [4]. The line of reasoning that a
kyphotic CXA is associated with pathologic bending of the
brainstem (medullary kyphosis, or kink) began with Liszt,
who first recognized that clivo-axial kyphosis may result in
neurobehavioral effects. Van Gilder reported that CXA of less
than 150° were often associated with neurological deficits
[67]. Breig demonstrated the importance of mechanical ten-
sion and deformation of the brainstem [68]. Menezes de-
scribed the fulcrum effect in basilar invagination, by which
traction is applied to the caudal brainstem and rostral cervical
spinal cord. Others have demonstrated the salutary conse-
quences to the correction of the CXA [1,10,12,15,30,49,
It is important to recognize that the CXA is simply a static
representation of a dynamic phenomenon. It has been gener-
ally considered that a CXA of less than 135° represents the
threshold below which chronic repetitive injury may occur as
a result of mechanical deformation of the lower brainstem and
upper spinal cord.
The authorshypothesis was that reduction of the Clivo-
axial kyphosis and stabilization for craniocervical instability
were feasible and associated with clinical improvement in the
hereditary connective tissue disorder (HCTD) population.
Materials and methods
Subject enrollment Over a 2-year period (20112012), a co-
hort of 22 consecutive patients diagnosed with EDS, or in a
few cases, unspecified hereditary connective tissue disorders
(HCTD), were enrolled in the study and underwent occipital
to C1/C2 fusion for craniovertebral instability and flexion de-
formity. Of the original 22 consecutive subjects, two were
excluded: one had previously undergone a cranio-spinal fu-
sion, and the second declined to participate due to unrelated
medical issues. The data analysis was, therefore, conducted on
the remaining 20 subjects, all of whom were enrolled in the
IRB-approved study (IRB# 10-036-06: Greater Baltimore
Medical Center). In 18 patients, cerebellar ectopia was also
Evaluation Symptoms were assessed by a standardized ques-
tionnaire administered by third party at 2 and 5 years. Pain
was assessed by the visual analog scale for pain (010/10).
The neurologic exams were performed by the neurosurgeon.
Function and the ability to return to work were assessed with
the Karnofsky Performance Scale (Fig. 1). Radiological mea-
surements were performed by a neuroradiologist (MK) after
Pre- and post-operative radiological measurements were
made or reviewed by the neuroradiologist (MK). Subjects
underwent pre-operative and post-operative imaging with
MRI and CT of the cervical spine. Upright, weight-bearing
flexion and extension MRI of the cervical spine was obtained
in 10/20 of the subjects.
Radiometrics were performed at the 2-year follow-up and
included the clivo-axial angle (CXA), Grabb-Mapstone-Oaks
measurement (the pBC2), and the horizontal Harris
Measurement (Basion axis interval or BAI). CXA is the mea-
surement in degrees between the line drawn along the lower
third of the clivus, and a line drawn along the posterior aspect
916 Neurosurg Rev (2019) 42:915936
Fig. 1 The Karnofsky Performance Status Scale
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Neurosurg Rev (2019) 42:915936 917
Fig. 2 aThe normal CXA. The
normal CXA is approximately
155°;, . In the case shown, the
CXA is 165 ° decreasing 10° in
flexion and increasing 10° in
extension. bThe pathological
clival axial angle (CXA) is more
kyphotic than the normal CXA.
The CXA is subtended by the
posterior axial line and a line
drawn along the surface of the
lower third of the clivus. An angle
of 135° or less is considered
potentially pathological. The
kyphotic CXA of 124° shown
here is clearly pathological and
results in a mechanical deformity
and lengthening of the brainstem
and upper spinal cord, as shown
diagrammatically in the next
image (Fig. 2c). cDiagrammatical
rendering of a kyphotic CXA. In
hereditary connective tissue
disorders, ligamentous laxity may
thus result in a kyphotic CXA in
flexion, with a concurrent
increase in strain ( )
of the axis [1,76](Fig.2a). The CXA measurements were
taken from the flexion image, when it was available (Fig. 2b,
The pBC2,orGrabb,Oakes measurement (Fig. 3)isthe
perpendicular measurement from the dura to a line drawn
from the basion to the posterior inferior aspect of C2 [7,76,
Horizontal Harris measurement or BAI is the distance from
the basion drawn perpendicularly to the posterior axial line
(PAL) (Fig. 4). A measurement greater than 12 mm represents
instability [7678]. When possible, the Harris measurement/
BAI is made from the MRI or CT in both flexion and exten-
sion to assess translation (sliding movement) between flexion
and extension.
Inclusion criteria for occipital-cervical fusion
stabilization surgery
All subjects met the following criteria:
i. Formal genetics evaluation and diagnosis with a hereditary
connective tissue disorder (CF)
ii. Signed consent
iii. Severe headache and/or neck pain greater than or equal to
7/10 by the visual analog scale for greater than 6 months.
iv. Symptoms of the cervical medullary syndrome [1,79]
v. Demonstrable neurological deficits
vi. Congruent radiological findings were in accordance with
the treatment algorithm previously set forward [70], in-
cluding kyphotic CXA (less than 135°), craniocervical
instability (the Harris/BAI measurement in flexion minus
the Harris measurement in extension > 4 mm*), or low-
lying cerebellar tonsils or Chiari malformation.
vii. Failed conservative treatment (physical therapy, activity
modification, pain medications, neck brace, and in some
circumstances, chiropractic, electrical stimulation,
*Note: The normal Harris/BAI measurement changes no
more than 1 mm between flexion and extension. The authors
allowed 3 mm for error.
Operative technique Preoperative traction reduction was not
performed.Subjects were intubated in the neck brace with a
GlideScope intubation technique to improve the view of the
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glottis and to avoid hyperextension of the neck. Sensory
evoked potentials were performed throughout the surgery. A
three-pronged Mayfield head holder was placed, and the sub-
ject positioned prone on chest rolls. The cervical spine was
carefully aligned to eliminate tilt and rotation, and then placed
in a neutral position, as confirmed by cross table fluoroscopy.
After sterile prep and drape, the incision was made from inion
to C4, but the subperiosteal exposure was limited to the occi-
put, C1and C2. Care was taken to preserve the ligaments at-
tached to the dorsal aspect of the spinous process of C2 and to
the caudal aspect of the C2 lamina.
A limited sub occipital decompression was performed with
high speed burr and Kerrison rongeur from the foramen
magnum upward 14 mm, but carried laterally to the full me-
ridian of the dura. The dura was not opened, and thus, no
expansion duroplasty was performed.
Open reduction of the craniocervical junction was per-
formed to normalize the CXA. To accomplish the open reduc-
tion, the surgeon stepped to the head of the table, applied
traction, posterior translation, and extension at the
craniocervical junction. The head holder was then locked in
place and checked with fluoroscopy (Fig. 5). Sensory and
motor-evoked potentials were continuously monitored
throughout the procedure. The reduction was accomplished
in one to four iterations, under fluoroscopic guidance, with
the goal of increasing the CXA by approximately 20° [10,
12,70] and to bring the basion over the midpoint or anterior
half of the odontoid (Fig. 6).
These subjects underwent a craniocervical fusion and sta-
bilization in order to maintain the corrected CXA and relation-
ship of the basion to the odontoid process and to stabilize the
craniocervical junction. To accomplish the stabilization, a ti-
tanium plate (Nex-Link OCT® Occipital cervical plating sys-
tem, Zimmer) was contoured slightly and affixed to the occi-
put. Titanium 3.5-mm screws were placed in the C1 lateral
masses and the C2 pedicles bilaterally. After reduction, the
screws were connected by rods to the occipital plate
[8082]. In one case, it was necessary to place screws in the
C3 lateral masses to achieve adequate stability.
To accomplish the fusion, bone surfaces were decorticated.
Two rib autografts were harvested at approximately the T7
level [83]. The rib grafts were contoured to fit from the
suboccipital bone to the upper cervical vertebrae, augmented
with demineralized bone matrix, and secured with number one
proline to prevent migration of the graft.
918 Neurosurg Rev (2019) 42:915936
Fig. 5 Traction reduction: the surgeon stands at the head of the table,
grasps the head holder, and applies 1: traction; 2: posterior translation;
3: extension, to bring the basion into correct relationship with the
Fig. 4 Horizontal Harris Measurement (HHM): a measurement of >
12 mm represents craniocervical instability. If the HHM changes by >
2 mm between flexion and extension, then craniocervical instability is
Fig. 3 The Grabb, Mapstone, Oakes measurement: a measurement of
9 mm or greater implies a high risk of ventral brainstem compression
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Both the neck and graft harvest wounds were then closed
over drains. The patients were usually mobilized 1 day after
surgery and kept in a neck brace (Miami J, or equivalent)
for 4 weeks. Physical therapy was then started.
Statement of human and animal rights All procedures per-
formed in studies involving human participants were carried
out in accordance with the ethical standards of the institutional
and/or national research committee in the United States, and
with the 1964 Helsinki declaration and its later amendments or
comparable ethical standards. Informed consent was obtained
from all individual patients and participants included in the
Nineteen subjects were female and one male, with an average
age of 24 years (range of 1253 years). All patients were
diagnosed with a hereditary connective tissue disorder
(HCTD): ten had hypermobile EDS (h-EDS), two classical
EDS, four unspecified EDS, and four hypermobility spectrum
disorder. All subjects (20/20) had a kyphotic CXA (less than
or equal to 135°) and craniocervical instability (Harris
Measurement/BAI of 4 mm or greater). Eighteen subjects
had cerebellar ectopia.
Pre-operative findings
The most prominent symptoms prior to surgery included
headache (100%), fatigue (100%), dizziness (100%), muscle
pain, vertigo, arm weakness, neck pain, balance problems,
memory problems, night awakenings, numbness and weak-
ness of the arms and legs, and gait problems (Table 1).
Patient satisfaction
There was 100% follow-up at 2 years and 5 years (Figs. 7and
8). All patients were satisfied with the surgery and would
repeat the surgery given similar circumstances, and reported
improved quality of life (Figs. 9,10, and 11). All but one
patient would recommend the surgery to a family member
(Fig. 10). Eighteen of the twenty patients reported that the
craniocervical fusion surgery had decreased their limitations;
the remaining two patients, who responded that the limitations
had not decreased with surgery, explained that there remained
limitations from other medical problems and spinal instability
elsewhere (Fig. 12).
Postoperative findings
Postoperatively at 2 years, statistically significant improve-
ments were seen in vertigo (92%), headaches (85%), imbal-
ance (82%), dysarthria (80%), dizziness (70%), memory
(69%), walking (69%), and frequent daytime urination
(42%) (Table 1). The average headache decreased from 8.1/
10 pre-op to 4.35/10 post-op (p< 0.0001). Neck pain mean
decreased in 71% of patients, from 6.45/10 to 4.05/10 post-op
(p< 0.002), and muscle pain decreased from 6/10 to 4.7/10
post-op (p<0.009) (Table 2).
Improvement, though not statistically significant, included
tremors (87%), syncope (86%), numbness of the arms and
hands (73%), upper extremity numbness (73%), lower ex-
tremity weakness (69%), back numbness (67%), swallowing
difficulty (63%), upper extremity weakness (61%), hearing
problems (61%), lower extremity numbness (55%), and
GERDS (55%) (Table 1).
Similarly, at 5 years, there remained statistically significant
improvement in dizziness (75%), walking problems (69%),
speech problems (67%), frequent daytime urination (67%),
headaches (65%), and imbalance (59%).Improvement in up-
per extremity numbness, syncope, lower extremity weakness,
back numbness, swallowing difficulty, upper extremity weak-
ness, hearing problems, and lower extremity numbness were
improved but not with statistical significance (Tables 2,3,4,
and 5).
On neurological examination, those who were weak before
surgery improved, though not completely. The ability to walk
heel-to-toe, Romberg, and sensation were all improved. There
was no significant improvement in reflexes (Table 3).
Functional outcome
Function and the ability to return to work, as assessed with the
Karnofsky Performance Scale, demonstrated a highly statical-
ly significant improvement (p<0.001). Preoperatively, 12/20
subjects were completely disabled, and 4/20 were able to care
for themselves only, but unable to go to work or school.
Neurosurg Rev (2019) 42:915936 919
Fig. 6 Intraoperative reduction: the preoperative CT (i) shows a CXA of
130°; the intra-operative fluoroscopic image after reduction (ii) shows a
CXA of 146°
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Table 1 Two-year follow-up: presence and change in frequency of symptoms/problems among participants (n= 20)
Symptom/problem % Pre-surgery % Post-surgery %With improvement
in frequency post-surgery
% With worsening of
frequency post-surgery
% With onset
Headaches 100% 95% (19/20) 85% (17/20) 0 < 0.001 0
Fatigue 100% 100% 30% (6/20) 15% (3/20) NS 0
Dizziness 100% 95% (19/20) 70% (14/20) 10% (2/20) < 0.0007 0
Muscle pain 95% (19/20) 95% (19/20) 36.8% (7/19) 10.5% (2/19) NS 0
Upper extremity weakness 90% (18/20) 85% (17/20) 61.1% (11/18) 22.2% (4/18) NS 0
Joint pain 85% (17/20) 85% (17/20) 29.4% (5/17) 11.8% (2/17) NS 0
Neck pain 85% (17/20) 90% (18/20) 70.6% (12/17) 5.9% (1/17) NS 33.3% (1/3)
Balance problems 85% (17/20) 85% (17/20) 82.4% (14/17) 5.9% (1/17) < 0.0001 0
Night awakenings 85% (17/20) 85% (17/20) 23.5% (4/17) 11.8% (2/17) NS 0
Memory problems 80% (16/20) 80% (16/20) 68.9% (11/16) 0 < 0.002 0
Walking problems 80% (16/20) 70% (14/20) 68.9% (11/16) 6.3% (1/16) < 0.002 0
Upper extremity numbness 75% (15/20) 85% (17/20) 73.3% (11/15) 6.7% (1/15) NS 40% (2/5)
Hands and feet turning cold 75% (15/20) 70% (14/20) 26.75% (4/15) 6.7% (1/15) NS 0
Lower extremity numbness 75% (15/20) 70% (14/20) 60% (9/15) 13.3% (2/15) NS 0
Visual problems 75% (15/20) 80% (16/20) 53.3% (8/15) 13.3% (2/15) NS 20% (1/5)
Lower extremity weakness 65% (13/20) 70% (14/20) 69.2% (9/13) 15.4% (2/13) NS 14.3% (1/7)
Vertigo 65% (13/20) 50% (10/20) 92.3% (12/13) 0 < 0.0006 0
Hearing problems 65% (13/20) 65% (13/20) 61.5% (8/13) 15.4% (2/13) NS (0.053) 14.3% (1/7)
Speech problems 60% (12/20) 55% (11/20) 80% (8/12) 8.3% (1/12) <0.03 0
Frequent daytime urination (> every 2 h) 60% (12/20) 45% (9/20) 41.7% (5/12) 0 <0.02 0
GERD 55% (11/20) 55% (11/20) 36.4% (4/11) 0 NS 11.1% (1/9)
Swallowing/choking problems 55% (11/20) 55% (11/20) 63.4% (7/11) 18.2% (2/11) NS 22.2% (2/9)
Nocturia (> twice a night) 55% (11/20) 55% (11/20) 27.3% (3/11) 9.1% (1/11) NS 11.1% (1/9)
IBS 50% (10/20) 50% (10/20) 30% (3/10) 0 NS 0
Tremors 40% (8/20) 40% (8/20) 87.5% (7/8) 0 NS 0
Fainting 35% (7/20) 25% (5/20) 85.7% (6/7) 0 NS 14.3% (1/7)
Numbness in back 30% (6/20) 40% (8/20) 66.7% (4/6) 0 NS 14.3% (2/14)
Sleep apnea 25% (5/20) 25% (5/20) 20% (1/5) 0 NS 0
For those participants who had presence of symptom/problem prior to surgery
Comparing frequencies of symptom/problem pre vs. post-surgery, a significant pvalue indicates less frequent symptom/problem post-surgery
For those participants who did not have the presence of symptom/problem prior to surgery
920 Neurosurg Rev (2019) 42:915936
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Postoperatively, 3/20 showed no change and 3/20 wors-
ened on the Karnofsky scale. However, 14/20 subjects
improved in their Karnofsky score: 5/20 had improved
in work/school status, and an additional two subjects were
seeking part time work or about to begin school, for a
total of 7/20. Many patients were able to return to caring
for their families and enjoying life to some extent; overall,
10/20 had a Karnofsky of 80 or higher (Fig. 7,Tab l e 6).
Karnofsky scores were reassessed post-operatively at
5 years. There remained statistically significant improve-
ment (p< 0.003). Eleven of 20 patients remained in work
or school; 17/20 had improvement in Karnofsky
compared to pre-op, 1/20 had no change and 2/20 had
worsened (Fig. 7).
There was no significant difference found between the 2-
year and 5-year Karnofsky (p<0.43) (Fig. 7).Comparedto
the 2-year score, the 5-year post-op Karnofsky evaluation had
improved in 8/20, showed no change in 6/20, and worsened in
Radiological outcomes
Open reduction was successful in normalizing the CXA in
every subject. Preoperatively, radiological examination
Fig. 7 Comparison of Karnofsky
scores before surgery and at 2 and
5 years post-surgery
Neurosurg Rev (2019) 42:915936 921
10 20 30 40 50 60 70 80 90 100
Percentage of Subjects
Karnofsky Score
Before Surgery
2 Years After Surgery
5 years After Surgery
Fig. 8 Comparison of CXA measurements pre vs. post-surgery
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demonstrated abnormal CXA (less than or equal to 135°) in
20/20 subjects, with an average CXA of 127° (Fig. 8). Post-
operatively at 2 years, the average CXAwas 148° (p<0.001).
Preoperatively, the Grabb, Mapstone, Oakes measurement
was made in 18 subjects; the methodology yielded a measure-
ment greater than 9 mm in 9/18 subjects, constituting a high-
risk category for ventral brainstem compression [7].
Postoperatively at 2 years, all subjects (20/20) were within
the normal range (less than 9 mm).
Preoperatively, the horizontal Harris measurement demon-
strated craniocervical instability in 5/6 patients; in these pa-
tients, there was pathological translation varying from a mean
of 4 to 9 mm. Translation in the Harris measurement was the
difference between that measured on flexion and that mea-
sured on extension in the upright MRI [7678]. Post-opera-
tively, as a consequence of the reduction and stabilization, the
translation by horizontal Harris measurement was less than or
equal to 1 mm in 12 out of 14 subjects and equal to 2 mm in 2
out of 14 subjects (Table 4).
Eleven of twenty had Chiari malformation (descent of the
cerebellar tonsils of 5 mm or more below McRaes Line), of
whom, five had undergone a prior suboccipital decompres-
sion; one had a Chiari Zero; six subjects had low-lying
cerebellar tonsils (cerebellar ectopia, where the descent of
the cerebellar tonsils did not reach the 5 mm threshold).
The fusion rate as determined by postoperative CT scan
was 100%.
Complications of surgery
There were no deaths or major peri-operative morbidities.
Two subjects underwent transfusion intraoperatively. Two
subjects had superficial infections, of which one returned to
the operating room for closure of the rib wound dehiscence.
Mild to moderate pain (3/10) at the rib harvest site was com-
mon at 2 years, substantially abating at 5 years.
Despite the loss of 20 to 30° of flexion and extension at the
craniocervical junction, and 35° of rotation to each side at C1
C2, range of motion was not a concern for any of these sub-
jects. One to four years after the craniocervical fusion, some
subjects developed pain over the suboccipital instrumentation
(the screw saddles) due to tissue thinning, and requested
hardware removal (8/20 subjects).
922 Neurosurg Rev (2019) 42:915936
Agree Somewhat
Disagree Strongly
% of Subjects
If I had a family member or close friend in a
similar situaon, I would feel comfortable
recommending the craniovertebral fusion
Fig. 10 Opinion regarding recommending surgery
Agree Somewhat
Disagree Strongly
% of Subjects
In looking back I would sll choose to have the
craniovertebral fusion surgery
Fig. 9 Opinion regarding choice of surgery
Agree Somewhat
Disagree Strongly
% of Subjects
Having this surgery improved my symptoms and
decreased my limitaons.
Fig. 12 Opinion regarding symptoms and limitations
Agree Somewhat
Disagree Strongly
% of Subjects
My quality of life was improved by having the
craniovertebral fusion surgery
Fig. 11 Opinion regarding improvement of quality of life
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This is the first 5-year study to retrospectively examine
the outcome of craniocervical fusion in patients with a
hereditary connective tissue disorder and craniovertebral
instability. The study reviews responses of a cohort of 20
subjects disabled with pain and neurologic deficit, who
had failed non-operative regimens, who presented with
kyphotic clivo-axial angle (CXA less than 135°) and bas-
ilar invagination, or instability at the craniocervical junc-
tion (CCI) in the setting of a hereditary connective tissue
disorder, such as Ehlers-Danlos syndrome. Eighteen of the
twenty subjects had low-lying cerebellar tonsils, including
Chiari malformation, type I or type 0.
Ehlers-Danlos syndrome
Emblematic of the approximately 50 hereditary connective
tissue disorders are the Ehlers-Danlos syndromes (EDS), a
heterogeneous group of heritable, connective tissue disorders
characterized by joint hypermobility, skin extensibility, and
tissue fragility. The 2017 classification [84] recognizes 13
Table 2 Two- and five-year
follow-up: comparison of pain
levels (010 scale) among
participants pre- vs. post-surgery
Area of pain Pre-
2 year post-surgery pvalue 5 year post-surgery pvalue
Headaches 8.10 4.35 <0.0001 5.75 < 0.00002
Neck 6.45 4.05 <0.002 4.7 NS (< .091)
Joints 5.30 4.60 NS 3.70 <0.018
Muscles 5.95 4.70 < 0.009 4.45 NS (< .069)
Table 3 Two-year follow-up: comparison of neurological findings among participants pre vs. post-surgery
Normal before
Normal after
Improvement after
No change in abnormal
Worsening after
Deltoids 15/19 (78.9%) 18/19 (94.7%) 4/4 (100%) 0 1/15 (6.7%)
Biceps 15/19 (78.9%) 18/19 (94.7%) 4/4 (100%) 0 1/15 (6.7%)
Triceps 12/19 (63.2%) 17/19 (89.5%) 7/7 (100%) 0 2/12 (16.7%)
Grips 13/19 (68.4%) 17/19 (89.5%) 6/6 (100%) 0 2/13 (15.4%)
Quads 11/19 (57.9%) 16/19 (84.2%) 7/8 (87.5%) 1/8 (12.5%) 2/11 (18.2%)
Hamstrings 12/19 (63.2%) 15/19 (78.9%) 6/7 (85.7%) 1/7 (14.3%) 2/12 (16.7%)
Iliopsoas 10/19 (52.6%) 16/19 (84.2%) 9/9 (100%) 0 2/10 (20.0%)
Biceps 12/18 (66.7%) 14/18 (77.8%) 4/6 (66.7%) 2/6 (33.3%) 2/12 (16.7%)
Triceps 13/18 (72.2%) 12/18 (66.7%) 2/5 (40.0%) 3/5 (60.0%) 3/13 (23.1%)
Patella 10/18 (55.5%) 12/18 (66.7%) 5/8 (62.5%) 3/8 (37.5%) 3/10 (30.0%)
Achilles 12/18 (66.7%) 12/18 (66.7%) 4/6 (66.7%) 2/6 (33.3%) 3/12 (25.0%)
Heel to toe 10/15 (66.7%) 13/15 (86.7%) 4/5 (80.0%) 1/5 (20.0%) 1/10 (10.0%)
Finger to nose 14/14 (100.0%) 14/14 (100.0%) NA NA 0
Rapid alternating
13/13 (100.0%) 12/13 (92.3%) NA NA 1/13 (7.7%)
Romberg 13/16 (81.3%) 14/16 (87.5%) 2/3 (66.7%) 1/3 (33.3%) 1/13 (7.7%)
Sensation to vibration 10/10 (100%) 10/10 (100%) 0 NA 0
Sensation to pinprick 7/16 (43.8%) 9/16 (56.25%) 5/9 (55.6%) 4/9 (44.4%) 3/7 (42.9%)
Absence of tremor 19/19 (100%) 16/19 (84.2%) NA NA 3/19 (15.8%)
Some participants did not have completed documentation for certain pre-op findings
Participants who had abnormal finding prior to surgery
Participants who had normal finding prior to surgery and developed abnormal findings s/p surgery
Neurosurg Rev (2019) 42:915936 923
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subtypes, which for the most part are due to mutation of
genes that encode fibrillary collagens or the enzymes in-
volved in post-translational modification of collagen.
Hypermobile type EDS (h-EDS) is diagnosed on the basis
of clinical findings [85], while molecular testing is avail-
able to confirm most other forms of EDS [84,8688]. The
neurological and spinal manifestations of h-EDS and the
classic form of EDS have been reviewed [41,89,90].
Table 4 Two-year follow-up:
comparison of CXA, Grabb,
Mapstone Oakes and horizontal
Harris measurements pre vs. post-
Patient CXA pre-
CXA post-
Grabb-Oakes pre-
HHM pre-
HHM post-
1 131 150 8 6
2 135 151 7.5 8
3130 146 0.1
4 131 141 8.5 7.4 1
5 115 143 12 5.2 9.2 0.1
6 124 142 12 7.4 1
7 120 152 8.8 5 9.1 1
8128 146 10 7.7
9 130 149 10 8 4.3
10 124 149 9.9 5.4 1
11 132 143 8 7.4 3.2 1.4
12 128 156 7.6 4.6 2
13 130 162 0
14 130 146 9 6.6 2.9 2
15 115 150 8.8 7 0
16 130 146 7.9 6.7 1
17 131 152 7.9 6 0.4
18 128 140 9.6 7
19 126 146 9.5 7.6 1
20 131 143 9.5 7.1 1
Clivo-axial angle abnormal (135); abnormal preop 20/20; post-op 0/20
Grabb-Oakes abnormal > 9, n=9/18
Horizontal Harris measurement: a difference of greater than 2 mm between flexion and extension is an abnormal
translation. Abnormal n=5/6(pre-op),n=0/14(post-op)
Table 5 Five-year post-op presence and change in frequency of statistically significant symptoms/problems among participants (n=20)
Symptom/problem % Pre-surgery % Post-surgery % With improvement
in frequency
% With worsening
of frequency
Headaches 100% 100% 65% (13/20) 0 <0.0001 0
Dizziness 100% 85%(17/20) 75%(15/20) 15%(3/20) <0.02 0
Balance problems 85% (17/20) 75%(15/20) 58.8%(10/17) 11.8%(2/17) <0.008 0
Memory problems 80% (16/20) 80%(16/20) 25%(4/16) 12.5%(2/16) NS (< .1) 0
Walk i n g pro blem s 80% (16/20) 50% (10/20) 68.8% (11/16) 6.3%(1/16) <0.003 25%(1/4)
Vertigo 65% (13/20) 55%(11/20) 84.6%(11/13) 0 NS(.074) 28.6%(2/7)
Speech problems 60% (12/20) 35%(7/20) 66.7% (8/12) 0 <0.006 0
Frequent daytime urination (> every 2 h) 60% (12/20) 35%(7/20) 66.7% (8/12) 0 <0.04 25%(2/8)
For those participants who had presence of symptom/problem prior to surgery
Comparing frequencies of symptom/problem pre vs. post-surgery, a significant pvalue indicates less frequent symptom/problem post-surgery
For those participants who did not have the presence of symptom/problem prior to surgery
924 Neurosurg Rev (2019) 42:915936
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Table 6 Two- and five-year patient Karnofsky scores and current functioning levels
Age at
Gender Karnofsky
2 years post-
5 years post-
Present illnesses/contributing factors
1 18 F 50 80 80 In school, doing research 2015 hardware removal and fusion augmentation
2 11 F 30 50 70 Online school, part time EDS issues-chronic pain, difficulty walking (WC for long dist), t-spine pinching, l-spine popping and
sliding, both spasming, further surgical procedures between 2012 and 2014 including untethering of
spinal cord, ACDF C3-C5 and C5-C6, LP and hardware revision C2-C3
3 17 F 80 90 90 In school/ waitressing MVA 45 months ago with C7 fx, shoulder pain
4 17 F 40 80 60 Not in school EDS issues, intracranial HTN, GI issues, recently failed lumbar shunt, (score goes to 80 when shunt is
working), Had previous Chiai Decompression and duroplasty in 8/10 and 5/11; 4 shunt revisions
20132015, Also had ACDF C4-C5 and fusion T6-T11 in 2015; fusion revision T8-L4 12/6/16,
fusion C2-T1 12/27/16, had immune reaction to bone dust with vascular swelling, volunteers at
moms school when able.
5 20 F 50 80 70 Not in school or working Had decompression in 5/09; EDS issues-dystonias/ dislocations, fatigue, pain all over/ back and leg
pain, more dislocations and subluxations, slippeddiskinback~5×/week, fiancé helps with
shopping, driving > 30 min, can do most ADLs needs help with heavier tasks
6 20 F 50 40 40 Fully disabled/bed bound EDS issues- severe dislocations, inc. ICP, cervical medullary syndrome, POTS, dysautonomias, J-tube,
gastroparesis, clotting disorder, 5 clots incl. R internal jugular, migraines, intractable aura, GERD,
constipation, dec. cog function, Patient had tethered cord procedure 11/2011, has moderate cognitive
impairment, in house nursing/palliative care
7 43 F 60 70 80 Part time job Fatigue, pain, arms/leg joints- is able to care for son
8 34 F 50 50 70 disabled Had 2004 suboccipital decompression and previous TC procedure, EDS issues- IIH, Adrenal insuf,
OA, MCAD, scoliosis, interstitial cystitis, 2013 tethered cord procedure, had hardware removal with
augmentation of fusion 2015 with improved POTS, headaches are better but continue to keep her
from working, she believestheymayberelatedtoIIH
9 17 F 60 80 90 Full time job Still has blackout/dysautonomia issues and severe pain 1-2x yearly, had 2014 hardware revision,
routine PT helps her function at higher level
10 28 F 50 60 70 disabled Pituitary adenoma, failed hip surgery, possible eagle syndrome, tremors, adrenal insufficiency,
acromegaly, daily H/A, dislocations, 4/14 hardware removal/fusion augmentation; fusion C2-T1
arthrex ligament augment 1/10/17, can do self care
11 18 F 80 60 90 Full time Student Symptoms improved after stopping diazepam, had 2014 hardware removal with augmentation fusion,
credits surgery and PT/life balance
12 17 F 30 90 80 Working part time Headaches, joint pain elbows, knees, urinary problems, had MVA in July now 22 weeks pregnant
(2/22), can do house work and self care
13 12 F 80 90 90 Student Getting straight As, taking dance classes. Has 34 classes a semester, has found that school plus work
is too much in that it increases fatigue/headaches and other symptoms
14 36 F 60 70 70 Disabled Pressure, LP shunt placement 2013, revision 10/15, tethered cord procedure in 2012, hardware revision
in 2013, ACDF C3-C4 2014, fusion C4-T1 2015. PANDAS, POTS, ICH, June surgery/does self
care but needs help with heavier chores, shopping, driving more than locally-no highway driving,
has headache, instability, shoulder blade pain, 10/16 fusion C2-T1
15 19 M 70 90 80 Student, part time Pain and neuropsych symptoms, 2010 TC and LP shunt Takin 1 class at community college, lives at
Neurosurg Rev (2019) 42:915936 925
Current work/school sta-
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Ligamentous laxity at the craniocervical junction
EDS is fundamentally a disorder of collagen and other struc-
tural components of connective tissue, characterized by in-
competent ligaments, joints, and spine. Ligaments are the ma-
jor occiputC1 stabilizing structures [4]. In the presence of
ligamentous laxity or disruption, the CCJ is incompetent in
the execution of multiaxial movements [91,92].
Craniocervical instability (CCI) is thus a manifestation of lig-
amentous laxity in EDS [18,53,61,62,93,94].
Most atlanto-occipital joint movement occurs in flexion-
extension, and axial rotation is normally limited; greater than
5° rotation at the occipito-atlantal joint is abnormal [95]. The
lateral atlanto-occipital ligament prevents excess rotation be-
tween occiput and atlas; incompetence of the lateral atlanto-
occipito ligament results in increased contralateral rotation by
3 to 5°. The tectorial membrane and nuchal ligament, com-
posed parallel bundles of collagen, restrict hyperflexion,
maintain posture, and help to restore normal position [96]. In
the population of patients with hypermobility connective tis-
sue disorders, incompetent ligamentous connections from the
skull to the spine may progress to CCI.
Neurological deficit has been attributed
to ligamentous laxity at the craniocervical junction
Neurological injury is common in many other connective tis-
sue disorders, such as rheumatoid arthritis, Down syndrome,
and hereditary disorders such asosteogenesis imperfecta [10,
17,18,21,2528,3035,37,42,4446,48,49]. Non-
disruptive stretch injury of the neuroaxis has been attributed
to hypermobility of the craniocervical junction in infants and
children, in whom the axonal lesions tend to be localized to
the dorsal brainstem, lower medulla, in particular the
corticospinal tracts at craniocervical junction [97]. Similar
histopathological findings of nerve injury were seen in the
lower brainstem and spinal cord, in adults [30,71,98100].
In the EDS population, motor delay, developmental coor-
dination disorder, headaches secondary to spinal compression,
clumsiness, and the relatively high rate of dyslexia and
dyspraxia have been recognized as a consequence of the ef-
fects of ligamentous laxity upon the central nervous system
[18,51,5360,62,66]. Interdigitation of the posterior-
atlanto-occipital membrane with the pain-sensitive spinal
dural layer has also been implicated in the genesis of headache
The cervical medullary syndrome
The cervical medullary syndrome, also known as
craniocervical syndrome(ICD-9-CM Diagnosis Code
723.2; ICD-10-CM Diagnosis Code M53.0), comprises those
symptoms commonly attributed to lower brainstem and upper
Tab l e 6 (continued)
Age at
Gender Karnofsky
2 years post-
5 years post-
Present illnesses/contributing factors
16 18 F 80 80 90 Working from home/part
time work
Had Chiari decompression procedures 3x in 2010,2012 hardware revision and 2015 fusion augment/
chronic H/A thinks she will need pain management for full time work, 3/7/17 TC
17 26 F 50 50 70 Disabled Pain and fatigue from EDS, unrelated to surgeries, can function ~ 90120 min QD, dysautonomias,
hypothyroidism, Raynauds, on ssdi, uses adaptive equipment
18 31 F 60 50 50 Disabled Had ACDF C5-C6 6/2016, before that had severe H/A, trouble walking, joint pain, hip problems, neck
pain further down upper back/arms/shoulders. Needs assistance with prepping food and bathing
19 53 F 60 90 80 Retired, thinks she could
work part time
Superior mesenteric artery syndrome nutcracker syndrome, L renal vein compression, pneumonia,
vascular digestive issues, had SMA transposition (12 yr. recovery), was posted for hardware
revision with augment fusion occ-c1/c2 in April 17, surgery has not happened as of May 17. Does
20 17 F 60 80 60 New born, unable to
Had a decompression in 10/07, TC in 8/09; EDS issues- Lumbar shunt,, inc. ICP, c-spine pain, PT
helps, 27 wks pregnant as of 9/16- needs help with different ADLs based on pain/energy, has lumbar
shunt pressure issues that have to wait to be addressed postnatally, walks ~ 20 min, WC after that,
PT helps, 2014 LP and hardware removal, augmentation of fusion, has 10wk old as of 2/22, needs
help with basic housework
926 Neurosurg Rev (2019) 42:915936
Current work/school sta-
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cervical spinal cord pathology, usually in the presence of a
complex Chiari(Chiari malformation with basilar invagina-
tion or craniocervical instability) [1,35,77,79].
In the present study, all subjects presented with headache,
fatigue and dizziness, and most reported, in descending order
of frequency: weakness, neck pain, imbalance, night awaken-
ings, memory difficulties, walking problems, sensory chang-
es, visual problems, vertigo, altered hearing, speech impedi-
ments, micturition issues and dysphagia, and syncopal epi-
sodes. In aggregate, these symptoms are reasonably described
as the Cervical Medullary Syndrome[1,77].
While there is an overlap of clinical findings, the clinical
presentation of the pure Chiari malformation differs from the
complex Chiari malformation. Chiari I malformations are
characterized primarily by the suboccipital cough headache
exacerbated by Valsalva, cough or straining-dizziness, ele-
ments of cerebellar dysfunction, lower cranial nerve deficits,
and gait problems [102]. On the other hand, the Complex
Chiariwith ventral brainstem compression or craniocervical
instability present with other genetic conditionssuch as
HOX D3 homeotic transformation, Klippel Feil malforma-
tion, hereditary connective tissue disorders [102104]and
is characterized by pyramidal changes, with weakness,
hyperreflexia, pathological reflexes, paresthesias, and sphinc-
ter problems, in addition to headache, neck pain, dizziness,
vertigo, dyspnea, dysphonia, altered vision and hearing, syn-
cope, gait changes, and altered sleep architecture [5,7,10,30,
70,71,105107]. Dysautonomia has also been attributed to
basilar impression [108].
Radiological metrics in the diagnosis of basilar
invagination and CCI
Three radiologic metrics used in this study, the Clivo-axial
angle (CXA), the horizontal Harris Measurement [78], and
the Grabb, Mapstone, Oakes measurement [7,78]havebeen
adopted as common data elements (CDEs) by the NIH/
NINDS, and characterized useful in identifying possible CCI
and basilar invagination [1,76,77]. The CXA of less than
135° is considered potentially pathological [10,12,18,30,
7075,79,109]. Salutary consequences have been attributed
to the correction of the CXA [10,12,69,70,107].
The Grabb, Mapstone, Oakes measurement of 9 mmor
more suggests high risk of ventral brainstem compression,
requiring consideration for craniospinal reduction or transoral
decompression, and fusion stabilization [7,77,79].
The horizontal Harris measurement (or BAI) was useful in
demonstrating craniocervical instability. Normally, the basion
pivots on a point above the odontoid, and there is no measur-
able translatory movement between flexion and extension. A
change in the horizontal Harris measurement of 2 mm or
more, as measured in flexion and extension images, represents
pathological translation between the basion and odontoid [1,
Non-operative management of patients
with craniocervical instability due to hereditary
connective tissue disorder
Patients should be given a specific diagnosis to validate their
concerns, and allay their fears. Rigorous instruction should
follow to avoid aggravating activitiesimpact sports and
prolonged sitting or driving, the importance of frequent rest
periods, physical therapyfor strengthening, sagittal balance,
posture and cardiorespiratory fitness, and judicious use of ap-
propriate bracing, to be accompanied by isometric exercises.
When possible, treatment of co-morbid conditions should be
Craniocervical fusion should be considered the last option,
to be engaged when non-operative treatment has failed.
Indications for surgery
Posterior occipito-cervical fusion is indicated in patients who
present with basilar invagination, instability or abnormal bio-
mechanics, and cervical medullary syndrome [13,21,25,112,
Therefore, at the time of decompression of a Chiari malfor-
mation, the finding of basilar invagination or craniocervical
instability should prompt consideration of fusion and stabili-
zation [2,3,11,18,19,2123,116,117].
In this study, indications for surgery included disabling
headache or neck pain, symptoms constituting the cervical
medullary syndrome with demonstrable neurological findings,
congruent radiological findings, a determination on the part of
the patient that they were unable to continue in the normal
activities of daily living, and failed non-operative treatment.
Headache should not be attributed a priori to craniocervical
instability. In the hereditary connective tissue disorders, head-
ache may have many origins: cervicogenic, vessel dissection,
or venous occlusive disease or thrombosis, intracranial hyper-
tension or hypotension, temporomandibular joint syndrome,
inflammatory and infectious disorders, neuralgia and migrain-
ous conditions, postural orthostatic tachycardia syndrome
(POTS), or mast cell activation syndrome (MCAS) [41,118,
Radiological metrics are useful guidelines, but not indica-
tions, per se, for surgery. The radiological indications were
congruent with the treatment algorithm previously established
[70]. Abnormal radiological metrics may exist in patients with
no neurological symptoms.
A number of subjects with CCI were also found to have
atlantoaxial instability, a radiological and clinical finding that
did add weight to the decision to proceed to surgery.
Occipitocervical fusion is indicated in some circumstances
Neurosurg Rev (2019) 42:915936 927
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for atlantoaxial instability alone, or for complex cervical de-
formities [21,27].
A patient with hereditary disorder is at risk for multilevel
instability issues; any injury or period of disability may result
in exacerbation of instability [120]. The complexity of these
patients warrants a rigorous selection process. Selection of
candidates for surgery should follow standard guidelines and
indications for instability, the diagnosis of which often re-
quires dynamic imaging [13,14,70]. Occipitocervical fusion
should be considered the last treatment option in this patient
population [41].
Surgical open reduction
The reduction should be executed in a thoughtful and deliber-
ate manner to avoid incorrect or painful malalignment, star
gazingfrom excessive extension or conversely a downward
gaze. If the cranium is inadequately extended, the oropharyn-
geal space may be decreased, and the patient may exhibit
severe dysphagia or potentially life-threatening dyspnea
[121]. To maintain appropriate oropharyngeal space, the sur-
geons extended the cervical spine to maintain 2 cm between
the anterior spinal line and the posterior edge of the mandible,
as seen on lateral fluoroscopy. In most cases, the basion was
translated posteriorly to lie above the midpoint of the
odontoid. The kyphotic angulation of the brainstem over the
odontoid process, as measured by the CXA, was normalized
by extension of the cranium at the craniocervical junction,
thereby decreasing the fulcrum effect of the odontoid [49],
and the mechanical stress on the brainstem [10,12,30,41,
109,122]. We attempted to achieve a mild cervical lordosis.
Reduction, fusion/stabilization appears to improve
pain and neurological deficit
There was 100% follow-up at 2-year and 5-year follow-up.
Except for the neurological exam, the clinical data was col-
lected by a third party, and de-identified. All patients were
satisfied with the surgery, would repeat the surgery given the
same circumstances, and reported improved quality of life. All
but one patient would recommend the surgery to a family
member. Eighteen of the twenty patients reported that the
craniocervical fusion surgery decreased their limitations; two
reported continued limitations from other medical problems
and spinal instability elsewhere.
Postoperatively, at the 2-year follow-up, patients demon-
strated a statistically significant improvement in in frequency
and severity of headache, speech, memory, vertigo, dizziness,
gait, balance, and urinary frequency. There were also improve-
ments in most patients with tremors, syncope, imbalance,
hearing problems, dysarthria, swallowing difficulty, numb-
ness of the upper and lower extremities and back, neck pain
and upper extremity weakness.
At 5 years, there remained statistically significant improve-
ment in headaches, dizziness and imbalance, gait, speech
problems, and frequent daytime urination.Though not statis-
tically significant, there was also continued improvement in
upper extremity, back and lower numbness, syncope, upper
and lower extremity weakness, swallowing difficulty, and
hearing problems.
At the 2-year period, the improvement of the Karnofsky
performance score was statistically significant and remained
significantly improved over the 5-year follow-up period, with
the majority of subjects returning to employment, school, or
work in the home. This improvement was supported by the
observed improvement in neurological deficits; weakness,
heel-to-toe walking, Romberg and sensation.
Co-morbid conditions in this population that
confounded the outcome
At 5 years, 8/20 patients reported disability from co-morbid
conditions. In keeping with the literature, most patients pre-
sented with postural orthostatic tachycardia syndrome and
other manifestations of dysautonomia; many patients received
diagnoses of abnormalities of CSF hydrodynamics with intra-
cranial hypertension or hypotension, abnormalities of intracra-
nial venous drainage due to sinus stenosis or jugular vein
stenosis. Migraine headaches and temporomandibular joint
dysfunction were very common. A majority of patients had
vitamin and trace element deficiencies. Many patients demon-
strated cervical instability with cervicogenic headaches.
Gastroparesis, superior mesenteric artery syndrome, mast cell
activation syndrome occurred and endocrine disorders.
Several patients were diagnosed with movement disorders,
Tarlov cysts, kypho-scoliosis, tethered cord syndrome, neuro-
muscular disorders, anxiety, and depression [18,41,
A multi-disciplinary team, familiar with the many co-
morbidities and the generalized ligament laxity throughout
the spinal column, is necessary to address the many issues in
order to improve the well-being of the patient with a heredi-
tary connective tissue disorder.
Complications of surgery
There were no deaths or major peri-operative morbidities.
There were two patients who underwent transfusion intraop-
eratively, two with superficial infections of whom one
returned to the operating room for closure of the rib wound
dehiscence. Mild to moderate pain at the rib harvest site was
common at 2 years, substantially abating at 5 years. Spinal
instability is a potential complication of rib harvest, but was
not reported in this group.
The absence of screw malposition and vertebral artery in-
jury [29,130] is attributed in part to improvement in
928 Neurosurg Rev (2019) 42:915936
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instrumentation, preoperative CT to examine the anatomy, and
intra-operative fluoro-CT to assess the construct real-time.
No patient complained of decreased neck range of motion
after surgery. Despite the loss of approximately 20° to 30° of
flexion and extension at the craniocervical junction, and 35°
of rotation to each side at C1C2, range of motion was not a
concern for any of these patients.
One to four years after the craniocervical fusion, some pa-
tients developed pain over the suboccipital instrumentation
(the screw saddles) due to tissue thinning, and requested
hardware removal (8/20 subjects). The authors have, there-
fore, adopted lower profile craniocervical instrumentation. A
smaller profile generally requires a smaller size and smoother
outer contour of the instrumentation. The instrumentation
should be configured to allow placement as low as possible
over the cranium, to increase the thickness of the tissue over-
lying the instrumentation.
Concerns about adjacent segment degeneration
The presence of premature disk degeneration and ligamentous
laxity with excessive spinal range of motion that characterizes
hereditary connective tissue disorders, makes this population
vulnerable to both axial and appendicular joint pathology. In
most, there had been some degree of instability in the mid-
cervical levels before the craniocervical fusion, and many of
these subsequently underwent further cervical spine surgery
(Table 7). It was surprising, however, that the adjacent seg-
ment, C23, was rarely the site of isolated segment instability
after the craniocervical fusion.
Goel has suggested that ligamentous instability at the
craniocervical junction decreases neuromuscular control,
leading to further central nervous system injury in a reverber-
ating process that is further exacerbated by the presence of
malnutrition and loss of conditioning [120].
Therefore, the putative benefits of craniocervical fusion
improvement of neuromuscular controlshould be weighed
against the possibility of adjacent segment degeneration and
increased proclivity to further spine surgery.
The many co-morbid conditions, the frequent osteopenia,
and small bone structure of this population render the appear-
ance of high surgical risk. Yet, surgical outcomes have been
surprisingly gratifying, perhaps because this population is
younger, and in some respects healthier than those in pub-
lished studies of craniocervical fusion for rheumatoid arthritis,
cancer, trauma, infection, and the elderly [21,29,32].
Is kyphosis of the CXA a consideration
in the determination to perform a fusion
The clivo-axial angle (CXA) has a normal range of 145° to
165°. Flexion of the neck usually decreases the CXA by 10°,
and extension of the neck increases the CXA by approximate-
ly 10°.
Nagashima reported an angle of less than 130° may pro-
duce brainstem compression [62,73]. Van Gilder reported that
a CXA of less than 150° was associated with neurological
changes [67]. Kim, Rekate, Klopfenstein, and Sonntag report-
ed that a kyphotic CXA (less than 135°) was a cause of failed
Chiari decompression; subsequent open reduction to normal-
ize the CXA resulted insubstantial improvement in 9/10 of the
subjects, prompting the authors to describe the kyphotic CXA
as a form of non-traditional basilar invagination[12].
Table 7 Additional surgical procedures
Before CVF After CVF Pvalue
All surgeries 30% (6/30) range 03, avg. 0.5 60%(12/20) range 09, avg. 1.7 <0.04
Chiari decompression 25% (5/20)
TCR 15% (3/20) 25%(5/20) NS
LP shunt 5% (1/20) 15% (3/20) NS
Hardware removal with fusion augment 0 40%(8/20) <0.002
Fusion at other level 0 25% (5/20) <0.04
ACDF 0 20%(4/20)
C2-T1 fusion 0 15%(3/20) NS
Thoracic Fusion 0 10%(2/20) NS
Hardware revision, other level 0 10% (2/20) NS
Shunt revision 0 10% (2/20)
Lumbar puncture 0 10% (2/20) NS
Patients with repeatedprocedures: one had two and another three Chiari decompressions, one had ACDF twice atdifferent levels, onepatient had shunt
revision two and another four times. For fusion at other levels, two patients had three procedures, and another had two
Neurosurg Rev (2019) 42:915936 929
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Morishita suggested that a clivo-axial angle of less than 135°
is a risk factor for spinal cord compression [131]. Kubota, in a
retrospective series of foramen magnum decompression for
Chiari and syringomyelia, reported that the syrinxes failed to
abate in those patients in whom the CXA was less than 130°
Brockmeyer, in a retrospective pediatric series of Chiari
decompressions, reported that 20% of patients were returned
to surgery for reduction and stabilization for kyphotic CXA,
craniocervical instability, or the presence of a Chiari 1.5 [4], a
finding echoed by Klekamp and others in the adult population
[6,7,9,13,19,21,132,133]. The medulla becomes kinked as
the CXA becomes more kyphotic; increasing kyphosis of
clivo-axial angle creates a fulcrum by which the odontoid
deforms the brainstem [49,132,134]. A more complete trea-
tise on the importance of the CXA has been presented else-
where [70]. In this study, the mean preoperative CXA of 129°
was increased to 148° by open reduction of the kyphosis,
which correlated with patient improvement. However, the ob-
served improvement may have been the result of
craniocervical stabilization.
A kyphotic CXA is associated with bending and strain of
the lower brainstem and upper spinal cord, and a prelude
to neurological deficit [9,22,32,68,135]. Stretching a
neuron nerve decreases neural firing rate and amplitude
[136]. The predominant substrate for deformity-induced
injury is the axon: electron micrographs show clumping,
loss of microtubules and neurofilaments, loss of axon
transport and accumulations of axoplasmic material iden-
tified as the retraction ball,orretraction bulb, analogous
to diffuse axonal injury (DAI) in the brain [137142].
Axon retraction bulbs result from stretch/deformation in-
jury and injury in animal models [98,100,143,144], in
the cortico-spinal tracts of the brainstem in infants with
shaken baby syndrome, adults with spinal cord injuries,
and in basilar invagination [30,109,143,145,146]. At
the molecular level, stretching of nervous tissue deforms
Na+ channels, causing increased membrane depolariza-
tion and a consequent deleterious influx of Ca++ [147].
The epigenetic effects of mechanical strain are manifest in
the observation of increased expression of N-methyl-d-
aspartate in the stretched neuron, altered mitochondrial
function, and apoptosis [148150].
The clinical improvement observed in this cohort is the
presumed consequence of reduction of mechanical deformity
of the nervous system and elimination or mitigation of
microtrauma from craniocervical instability [10,16,49,
107], consistent with the experimental models of axons sub-
jected to strain [149,151154].
Treatment of other forms of degenerative and hereditary con-
nective tissue disorders is firmly established in the literature.
However, treatment of the EDS patient has been problematic
for several reasons. First, though EDS was first described in
1901, the recognition of spinal and neurological manifesta-
tions has been only recent [56,62,18,41,51,5355,5761,
66]. Because this information is new, there is a dearth of ev-
idence upon which to base the management of these genetic
Second, EDS is considered an invisible disorder.EDS
patients are characterized by youthful skin, and the appear-
ance of good health, belying their severe pain and disability.
Third, the legion of disparate symptoms due to ligamentous
weakness of the joints and spine, and the many co-morbid
conditions that accompany EDS, result, understandably, in
dismissal by healthcare providers because of the large number
of seemingly disparate symptoms.
The authors advocate that the indications for craniocervical
fusion should be no different than for the non-EDS popula-
tion, with the caveat that conditions of ligamentous laxity
often require dynamic imaging to demonstrate the pathology
[1,13,14,27,77,112,155]. Occiput to C2 bone fusion, as
opposed to atlantoaxial fusion in conjunction with fixation,
has been discussed [3,38,69,82,115,155]. A comparison
of various methodologies for bone fusion has also been
discussed [83].
The economic significance of hypermobility
connective tissue disorders
Treatment of the EDS population is problematic because of
the diverse spectrum of disease severity and presentation for
whom, in the majority of cases, there is no genetic testing
available. In the experience and belief of most EDS care pro-
viders, EDS patients suffer through scores of visits to special-
ists over a mean of 10 years before the diagnosis of EDS is
made, during which time they consume vast medical re-
sources through emergency room visits, and unscheduled, of-
ten prolonged, admissions to hospital.
The epidemiology of EDS is not known; however, there is
little phenotypic difference between patients with h-EDS and
the very large population previously diagnosed with joint hy-
permobility disorder (now referred to as hypermobility spec-
trum disorder) sharing the same early degeneration of the
spine and joints, and the same co-morbid conditions
[156158]. Therefore, the authors believe that earlier recogni-
tion of these hereditary disorders would substantially reduce
costly specialty visits, improve care of this patient population.
Early recognition, prudent management, and non-operative
therapy may be adequate to stabilize the patient and obviate
need of surgery in many cases.
930 Neurosurg Rev (2019) 42:915936
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Neurosurg Rev (2019) 42:915936 931
In this cohort, 55% of subjects have returned to work and
are paying taxes, or attending school full or part-time with the
prospect of future employment, or serving society through
caring for their families.
Limitations of the study
This IRB study is a single-center, non-controlled analysis
of a small cohort of subjects, referred by medical pro-
viders from a broad geographical area (USA and
Canada). The study was conceived prior to any surgery,
but the subjects were not enrolled until after surgery.
Therefore, this should be considered a retrospective study.
The outcomes data is to some extent obfuscated by the
presence of previous Chiari surgery (five), multiple co-
morbid conditions common to EDS, and multiple surger-
ies within the 5-year follow-up period (12/20). The com-
plexity of the co-morbid conditions and other surgeries
are prohibitive to more complex statistical methods.
These patients appeared to be the most seriously affected
patients within the spectrum of hereditary connective tis-
sue disorders.
Not every patient had cerebellar ectopia (18/20). Subjects
may have inaccurately reported the severity of their preoper-
ative symptoms upon questioning at the 2-year follow-up and
may have exaggerated the degree of improvement. However,
accuracy of reporting was improved through the employment
of two independent researchers, who performed the subjects
interviews at 2 and 5 years. Some subjects may have seen
surgery as means validation of their suffering. There was no
control for a placebo effect [159].
This study supports the hypothesis that craniocervical reduc-
tion, stabilization, and fusion are feasible and associated with
clinical improvement in patients in the HCTD population with
Chiari malformation or cerebellar ectopia, kyphotic clivo-
axial angle, ventral brainstem compression, and/or
craniocervical instability. The neurological and functional im-
provements associated with craniocervical fusion/stabilization
appear to be clinically significant and durable. That said,
craniocervical fusion should be considered as a last resort after
a reasonable course of non-operative treatments.
Acknowledgements To Betsy G. Henderson for help with layout and
editing, and to the patients who have informed this study.
Compliance with ethical standards
Funding This study was solely funded by the Metropolitan
Neurosurgery Group, LLC.
Conflict of interest One of the senior authors (FCH Sr.) was first author
of a patent for a craniocervical stabilization device, which is currently
being developed by LifeSpine, Inc. (Huntley, IL) and related patents
discussing finite element analysis (spinal cord stress injury analysis) of
the central nervous system, mathematical prediction of neurobehavioral
change, and related devices pertinent to disorders of the craniocervical
junction. The same author (FCH Sr) has donated his royalties for the
craniocervical device to the Chiari Syringomyelia Foundation (CSF).
Ethical approval The study was conducted under the auspices of the
Greater Baltimore Medical Center (IRB# 10-036-06: GBMC). This study
followed all requirements of the 1964 Helsinki declaration and its later
amendments or comparable ethical standards.
Informed consent Every patient signed an informed consent form to
participate in the study.
Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://, which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appro-
priate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
PublishersNote Springer Nature remains neutral with regard to jurisdic-
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1. Batzdorf U HF, Rigamonti D. et al (2016) Consensus statement in
proceedings of CSF colloquium 2014. In: Batzdorf U (ed) Co-
morbidities that complicate the treatment and outcomes of Chiari
malformation. Chiari Syringomyelia Foundation, Inc., Lulu, p 3
2. Bekelis K, Duhaime AC, Missios S, Belden C, Simmons N (2010)
Placement of occipital condyle screws for occipitocervical fixation
in a pediatric patient with occipitocervical instability after decom-
pression for Chiari malformation. J Neurosurg Pediatr 6:171176.
3. Bollo RJ, Riva-Cambrin J, Brockmeyer MM, Brockmeyer DL
(2012) Complex Chiari malformations in children: an analysis of
preoperative risk factors for occipitocervical fusion. J Neurosurg
Pediatr 10:134141.
4. Brockmeyer DL (2011) The complex Chiari: issues and manage-
ment strategies. Neurol Sci 32(Suppl 3):S345S347. https://doi.
5. Caetano de Barros M, Farias W, Ataide L, Lins S (1968) Basilar
impression and Arnold-Chiari malformation. A study of 66 cases.
J Neurol Neurosurg Psychiatry 31:596605
6. Felbaum D, Spitz S, Sandhu FA (2015) Correction of clivoaxial
angle deformity in the setting of suboccipital craniectomy: techni-
cal note. J Neurosurg Spine 23:815.
7. Grabb PA, Mapstone TB, Oakes WJ (1999) Ventral brain stem
compression in pediatric and young adult patients with Chiari I
malformations. Neurosurgery 44:520527 discussion 527-528
8. Henderson FC (2016) Cranio-cervical Instability in Patients with
Hypermobility Connective Disorders. J Spine
9. Henderson FC, Wilson WA, Benzel EC (2010) Pathophysiology
of cervical myelopathy: biomechanics and deformative stress. In:
Benzel EC (ed), Spine surgery: Techniques, complication avoid-
ance, and management, vol 1, 1st edn. Elsevier: Churchill
Livingstone, p 188195
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
932 Neurosurg Rev (2019) 42:915936
10. Henderson FC, Wilson WA, Mott S, Mark A, Schmidt K, Berry
JK, Vaccaro A, Benzel E (2010) Deformative stress associated
with an abnormal clivo-axial angle: a finite element analysis.
Surg Neurol Int 1:30.
11. Joseph V, Rajshekhar V (2003) Resolution of syringomyelia and
basilar invagination after traction. Case illustration. J Neurosurg
12. Kim LJ, Rekate HL, Klopfenstein JD, Sonntag VK (2004)
Treatment of basilar invagination associated with Chiari I
malformations in the pediatric population: cervical reduction and
posterior occipitocervical fusion. J Neurosurg 101:189195.
13. Klekamp J (2012) Neurological deterioration after foramen mag-
num decompression for Chiari malformation type I: old or new
pathology? J Neurosurg Pediatr 10:538547.
14. Klekamp J (2015) Chiari I malformation with and without basilar
invagination: a comparative study. Neurosurg Focus 38:E12.
15. Kubota M, Yamauchi T, Saeki N Surgical Results of Foramen
Magnum Decompression for Chiari Type 1 Malformation associ-
ated with Syringomyelia: A Retrospective Study on
Neuroradiological Characters influencing Shrinkage of Syringes
Y12004. - Spinal Surg M1 - Journal Article:- 81
16. Menezes AH (2012) Craniovertebral junction abnormalities with
hindbrain herniation and syringomyelia: regression of syringomy-
elia after removal of ventral craniovertebral junction compression.
J Neurosurg 116:301309.
17. Menezes AH, VanGilder JC, Clark CR, el-Khoury G (1985)
Odontoid upward migration in rheumatoid arthritis. An analysis
of 45 patients with "cranial settling". J Neurosurg 63:500509.
18. Milhorat TH, Bolognese PA, Nishikawa M, McDonnell NB,
Francomano CA (2007) Syndrome of occipitoatlantoaxial hyper-
mobility, cranial settling, and chiari malformation type I in pa-
tients with hereditary disorders of connective tissue. J Neurosurg
Spine 7:601609.
19. Nishikawa M, Ohata K, Baba M, Terakawa Y, Hara M (2004)
Chiari I malformation associated with ventral compression and
instability: one-stage posterior decompression and fusion with a
new instrumentation technique. Neurosurgery 54:14301434 dis-
cussion 1434-1435
20. Nishikawa M, Sakamoto H, Hakuba A, Nakanishi N, Inoue Y
(1997) Pathogenesis of Chiari malformation: a morphometric
study of the posterior cranial fossa. J Neurosurg 86:4047.
21. Singh SK, Rickards L, Apfelbaum RI, Hurlbert RJ, Maiman D,
Fehlings MG (2003) Occipitocervical reconstruction with the
Ohio medical instruments loop: results of a multicenter evaluation
in 30 cases. J Neurosurg 98:239246
22. Smith JS, Shaffrey CI, Abel MF, Menezes AH (2010) Basilar
invagination. Neurosurgery 66:3947.
23. Tubbs RS, Beckman J, Naftel RP, Chern JJ, Wellons JC 3rd,
Rozzelle CJ, Blount JP, Oakes WJ (2011) Institutional experience
with 500 cases of surgically treated pediatric Chiari malformation
type I. J Neurosurg Pediatr 7:248256.
24. Braca J, Hornyak M, Murali R (2005) Hemifacial spasm in a
patient with Marfan syndrome and Chiari I malformation. Case
report. J Neurosurg 103:552554.
25. Crockard HA, Stevens JM (1995) Craniovertebral junction anom-
alies in inherited disorders: part of the syndrome or caused by the
disorder? Eur J Pediatr 154:504512
26. Gabriel KR, Mason DE, Carango P (1990) Occipito-atlantal trans-
lation in Down's syndrome. Spine 15:9971002
27. Fehlings MG, Cooper P, Errico TJ Rheumatoid arthritis of the
cervical spine, Neurosurgical topics: Degenerative disease of the
cervical spine Y11992. - AANS M1 - Journal Article:- 125139
28. Grob D, Schutz U, Plotz G (1999) Occipitocervical fusion in pa-
tients with rheumatoid arthritis. Clin Orthop Relat Res 366:4653
29. Grob D, Dvorak J, Panjabi MM, Antinnes JA (1994) The role of
plate and screw fixation in occipitocervical fusion in rheumatoid
arthritis. Spine 19:25452551
30. Henderson FC, Geddes JF, Crockard HA (1993) Neuropathology
of the brainstem and spinal cord in end stage rheumatoid arthritis:
implications for treatment. Ann Rheum Dis 52:629637
31. Ibrahim AG, Crockard HA (2007) Basilar impression and osteo-
genesis imperfecta: a 21-year retrospective review of outcomes in
20 patients. J Neurosurg Spine 7:594600.
32. Menezes AH, VanGilder JC (1988) Transoral-transpharyngeal ap-
proach to the anterior craniocervical junction. Ten-year experience
with 72 patients. J Neurosurg 69:895903.
33. Nockels RP, Shaffrey CI, Kanter AS, Azeem S, York JE (2007)
Occipitocervical fusion with rigid internal fixation: long-term fol-
low-up data in 69 patients. J Neurosurg Spine 7:117123. https://
34. Sandhu FA, Pait TG, Benzel E, Henderson FC (2003)
Occipitocervical fusion for rheumatoid arthritis using the inside-
outside stabilization technique. Spine 28:414419. https://doi.
35. Zygmunt SC, Christensson D, Saveland H, Rydholm U, Alund M
(1995) Occipito-cervical fixation in rheumatoid arthritisan anal-
ysis of surgical risk factors in 163 patients. Acta Neurochir 135:
36. Yoshizumi TMH, Ikenishi Y et al (2014) Occipitocervical fusion
with relief of odontoid invagination: atlantoaxial distraction meth-
od using cylindrical titanium cage for basilar invaginationcase
report. Neurosurg Rev 37:519525
37. Bick S, Dunn R (2010) Occipito-cervical fusion: review of surgi-
cal indications, techniques and clinical outcomes. SA Orthop J 3:
38. Brockmeyer D (1999) Down syndrome and craniovertebral insta-
bility. Topic review and treatment recommendations. Pediatr
Neurosurg 31:7177.
39. Gordon N (2000) The neurological complications of achondropla-
sia. Brain Dev 22:37
40. Harkey HL, Crockard HA, Stevens JM, Smith R, Ransford AO
(1990) The operative management of basilar impression in osteo-
genesis imperfecta. Neurosurgery 27:782786 discussion 786
41. Henderson FC Sr, Austin C, Benzel E, Bolognese P, Ellenbogen
R, Francomano CA, Ireton C, Klinge P, Koby M, Long D, Patel S,
Singman EL, Voermans NC (2017) Neurological and spinal man-
ifestations of the Ehlers-Danlos syndromes. Am J Med Genet C:
Semin Med Genet 175:195211.
42. Jain VK, Mittal P, Banerji D, Behari S, Acharya R, Chhabra DK
(1996) Posterior occipitoaxial fusion for atlantoaxial dislocation
associated with occipitalized atlas. J Neurosurg 84:559564.
43. Keiper GL Jr, Koch B, Crone KR (1999) Achondroplasia and
cervicomedullary compression: prospective evaluation and surgi-
cal treatment. Pediatr Neurosurg 31:7883.
44. Kosnik-Infinger L, Glazier SS, Frankel BM (2014) Occipital con-
dyle to cervical spine fixation in the pediatric population. J
Neurosurg Pediatr 13:4553.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Neurosurg Rev (2019) 42:915936 933
45. Menezes AH (2008) Specific entities affecting the craniocervical
region: osteogenesis imperfecta and related
osteochondrodysplasias: medical and surgical management of
basilar impression. Childs Nerv. Syst. 24:11691172. https://doi.
46. Menezes AH, Ryken TC (1992) Craniovertebral abnormalities in
Down's syndrome. Pediatr Neurosurg 18:2433
47. National Down Syndrome C the position statement. In:
BContinuing the Revolution^,1991
48. Noske DP, van Royen BJ, Bron JL, Vandertop WP (2006) Basilar
impression in osteogenesis imperfecta: can it be treated with halo
traction and posterior fusion? Acta Neurochir 148:13011305;
discussion 1305.
49. Sawin PD, Menezes AH (1997) Basilar invagination in osteogen-
esis imperfecta and related osteochondrodysplasias: medical and
surgical management. J Neurosurg 86:950960.
50. Tredwell SJ, Newman DE, Lockitch G (1990) Instability of the
upper cervical spine in down syndrome. J Pediatr Orthop 10:602
51. Adib N, Davies K, Grahame R, Woo P, Murray KJ (2005) Joint
hypermobility syndrome in childhood. A not so benign multisys-
tem disorder? Rheumatology (Oxford, England) 44:744750.
52. Castori M, Camerota F, Celletti C, Danese C, Santilli V, Saraceni
VM, Grammatico P (2010) Natural history and manifestations of
the hypermobility type Ehlers-Danlos syndrome: a pilot study on
21 patients. Am J Med Genet A 152a:556564.
53. De Paepe A, Malfait F (2012) The Ehlers-Danlos syndrome, a
disorder with many faces. Clin Genet 82:111.
54. Di Palma F, Cronin AH (2005) Ehlers-Danlos syndrome: correla-
tion with headache disorders in a young woman. J Headache Pain
55. Easton V, Bale P, Bacon H, Jerman E, Armon K, Macgregor AJ
(2014) The relationship between benign joint hypermobility syn-
drome and developmental coordination disorders in children.
Arthritis Rheumatol 124
56. el-Shaker M, Watts HG (1991) Acute brachial plexus neuropathy
secondary to halo-gravity traction in a patient with Ehlers-Danlos
syndrome. Spine 16:385386
57. Galan E, Kousseff BG (1995) Peripheral neuropathy in Ehlers-
Danlos syndrome. Pediatr Neurol 12:242245
58. Halko GJ, Cobb R, Abeles M (1995) Patients with type IV Ehlers-
Danlos syndrome may be predisposed to atlantoaxial subluxation.
J Rheumatol 22:21522155
59. Jelsma LD, Geuze RH, Klerks MH, Niemeijer AS, Smits-
Engelsman BC (2013) The relationship between joint mobility
and motor performance inchildren with and without the diagnosis
of developmental coordination disorder. BMC Pediatr 13:35.
60. Kirby A, Davies R (2007) Developmental coordination disorder
and joint hypermobility syndromeoverlapping disorders?
Implications for research and clinical practice. Child Care Health
Dev 33:513519.
61. Milhorat TH, Nishikawa M, Kula RW, Dlugacz YD (2010)
Mechanisms of cerebellar tonsil herniation in patients with
Chiari malformations as guide to clinical management. Acta
Neurochir 152:11171127.
62. Nagashima C, Tsuji R, Kubota S, Tajima K (1981) [Atlanto-axial,
Atlanto-occipital dislocations, developmental cervical canal steno-
sis in the Ehlers-Danlos syndrome (author's transl)]. No shinkei
geka. Neurol Surg 9:601608
63. Palmeri S, Mari F, Meloni I, Malandrini A, Ariani F, Villanova M,
Pompilio A, Schwarze U, Byers PH, Renieri A (2003)
Neurological presentation of Ehlers-Danlos syndrome type IV in
afamily with parental mosaicism. Clin Genet 63:510515
64. Rombaut L, De Paepe A, Malfait F, Cools A, Calders P (2010)
Joint position sense and vibratory perception sense in patients with
Ehlers-Danlos syndrome type III (hypermobility type). Clin
Rheumatol 29:289295.
65. Voermans NC, Drost G, van Kampen A, Gabreels-Festen AA,
Lammens M, Hamel BC, Schalkwijk J, van Engelen BG (2006)
Recurrent neuropathy associated with Ehlers-Danlos syndrome. J
Neurol 253:670671.
66. Voermans NC, van Alfen N, Pillen S, Lammens M, Schalkwijk J,
Zwarts MJ, van Rooij IA, Hamel BC, van Engelen BG (2009)
Neuromuscular involvement in various types of Ehlers-Danlos
syndrome. Ann Neurol 65:687697.
67. VanGilder JC, Menezes AH, Dolan KD (1987) The
craniovertebral junction and its abnormalities. Futura Publishing
68. Breig A (1978) Effects of pincer and clamping actions on the
spinal cord Adverse Mechanical Tension in the Central Nervous
69. Goel A (2004) Treatment of basilar invagination by atlantoaxial
joint distraction and direct lateral mass fixation. J Neurosurg Spine
70. Henderson FC Sr, Henderson FC Jr, WAt W, Mark AS, Koby M
(2018) Utility of the clivo-axial angle in assessing brainstem de-
formity: pilot study and literature review. Neurosurg Rev 41:149
71. Howard RS, Henderson F, Hirsch NP, Stevens JM, Kendall BE,
Crockard HA (1994) Respiratory abnormalities due to
craniovertebral junction compression in rheumatoid disease. Ann
Rheum Dis 53:134136
72. Menezes A, Ryken T, Brockmeyer D Abnormalities of the
craniocervical junction Y12001. - Pediatric Neurosurgery:
Surgery of the Developing Nervous System:- 400422
73. Nagashima C, Kubota S (1983) Craniocervical abnormalities.
Modern diagnosis and a comprehensive surgical approach.
Neurosurg Rev 6:187197
74. Scoville WB, Sherman IJ (1951) Platybasia, report of 10 cases
with comments on familial tendency, a special diagnostic sign,
and the end results of operation. Ann Surg 133:496502
75. Smoker WR (1994) Craniovertebral junction: normal anatomy,
craniometry, and congenital anomalies. Radiographics 14:255
76. Elements NCD (2016) Clinical research common data Elements
(CDEs): radiological metrics standardization for Craniocervical
instability. National Institute of Neurological Disorders and
Stroke common data element project - approach and methods.
Clin Trials 9(33):322329
77. Batzdorf U B E, Henderson F. et al (2013) Consensus Statement In
Proceedings of CSF Colloquium 2013. In: U B (ed) Basilar
Impression & Hypermobility at the Craniocervical Junction.
Chiari Syringomyelia Foundation, Lulu,
78. Harris JH Jr, Carson GC, Wagner LK (1994) Radiologic diagnosis
of traumatic occipitovertebral dissociation: 1. Normal
occipitovertebral relationships on lateral radiographs of supine
subjects. AJR Am J Roentgenol 162:881886.
79. Elements NCD Clinical Research Common Data Elements
(CDEs): Radiological Metrics Standardization for Craniocervical
Instability Y12016
80. Aryan HE, Newman CB, Nottmeier EW, Acosta FL Jr, Wang VY,
Ames CP (2008) Stabilization of the atlantoaxial complex via C-1
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
934 Neurosurg Rev (2019) 42:915936
lateral mass and C-2 pedicle screw fixation in a multicenter clin-
ical experience in 102 patients: modification of the harms and
Goel techniques. J Neurosurg Spine 8:222229.
81. Dickman CA, Sonntag VK (1998) Posterior C1-C2 transarticular
screw fixation for atlantoaxial arthrodesis. Neurosurgery 43:275
280 discussion 280-271
82. Goel A, Bhatjiwale M, Desai K (1998) Basilar invagination: a
study based on 190 surgically treated patients. J Neurosurg 88:
83. Sawin PD, Traynelis VC, Menezes AH (1998) A comparative
analysis of fusion rates and donor-site morbidity for autogeneic
rib and iliac crest bone grafts in posterior cervical fusions. J
Neurosurg 88:255265.
84. Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black
J, Bloom L, Bown JM et al (2017) The 2017 international classi-
fication of the EhlersDanlos syndromes. Am J Med Genet 175:
85. Tinkle B, Castori M, Berglund B, Cohen H, Grahame R, Kazkaz
H, Levy H (2017) Hypermobile EhlersDanlos syndrome (a.k.a.
EhlersDanlos syndrome type III and EhlersDanlos syndrome
hypermobility type): clinical description and natural history. Am
J Med Genet 175C:4869.
86. Byers PH (2001) Folding defects in fibrillar collagens. Philos
Trans R Soc.B 356:151158.
87. Malfait F, Coucke P, Symoens S, Loeys B, Nuytinck L, De Paepe
A (2005) The molecular basis of classic Ehlers-Danlos syndrome:
a comprehensive study of biochemical and molecular findings in
48 unrelated patients. Hum Mutat 25:2837
88. Steinmann B, Royce PM, Superti-Furga A The Ehlers-Danlos
Syndrome Y12003. - Connective Tissue and Its Heritable
Disorders: Molecular, Genetic, and Medical Aspects:- 431
89. Castori M, Voermans NC (2014) Neurological manifestations of
Ehlers-Danlos syndrome(s): a review. Iran J Neurol 13:190208
90. Savasta S, Merli P, Ruggieri M, Bianchi L, Sparta MV (2011)
Ehlers-Danlos syndrome and neurological features: a review.
Childs Nerv Syst 27:365371.
91. Martin MD, Bruner HJ, Maiman DJ (2010) Anatomic and biome-
chanical considerations of the craniovertebral junction.
Neurosurgery 66:26.
92. Tubbs RS, HallockJD, Radcliff V, Naftel RP, Mortazavi M,Shoja
MM, Loukas M, Cohen-Gadol AA (2011) Ligaments of the
craniocervical junction. J Neurosurg Spine 14:697709. https://
93. Koby M (2016) The discordant report - pathological radiological
findings: A peripatetic review of salient features of neuropatholo-
gy in the setting of an erstwhile standard 'normal' radiological
assessment. In: Batzdorf U (ed) Co-Morbidities that Complicate
the Treatment and Outcomes of Chiari Malformation. Chiari
Syringomyelia Foundation Inc., Lulu, p 50
94. Steinmetz MP, Mroz TE, Benzel EC (2010) Craniovertebral junc-
tion: biomechanical considerations. Neurosurgery 66:712.
95. Dvorak J, Hayek J, Zehnder R (1987) CT-functional diagnostics of
the rotatory instability of the upper cervical spine. Part 2. An
evaluation on healthy adults and patients with suspected instabil-
ity. Spine 12:726731
96. Tubbs RS, Stetler W, Shoja MM, Loukas M, Hansasuta A, Liechty
P, Acakpo-Satchivi L, Wellons JC, Blount JP, Salter EG, Oakes
WJ (2007) The lateral atlantooccipital ligament. Surg Radiol Anat
97. Geddes JF, Hackshaw AK, Vowles GH, Nickols CD, Whitwell
HL (2001) Neuropathology of inflicted head injury in children.
I. Patterns of brain damage. Brain 124:12901298
98. Hardman JM (1979) The pathology of traumatic brain injuries.
Adv Neurol 22:1550
99. Lindenberg R, Freytag E (1970) Brainstem lesions characteristic
of traumatic hyperextension of the head. Arch Pathol 90:509515
100. Riggs JE, Schochet SS Jr (1995) Spastic quadriparesis, dysarthria,
and dysphagia following cervical hyperextension: a traumatic
pontomedullary syndrome. Mil Med 160:9495
101. Nash L, Nicholson H, Lee AS, Johnson GM, Zhang M (2005)
Configuration of the connective tissue in the posterior atlanto-
occipital interspace: a sheet plastination and confocal microscopy
study. Spine 30:13591366
102. Milhorat TH, Chou MW, Trinidad EM, Kula RW, Mandell M,
Wolpert C, Speer MC (1999) Chiari I malformation redefined:
clinical and radiographic findings for 364 symptomatic patients.
Neurosurgery 44:10051017
103. Pang D, Thompson DN (2011) Embryology and bony
malformations of the craniovertebral junction. Childs Nerv Syst
104. Thakar S, SivarajuL, Jacob KS, Arun AA, Aryan S, Mohan D, Sai
Kiran NA, Hegde AS (2018) A points-based algorithm for prog-
nosticating clinical outcome of Chiari malformation type I with
syringomyelia: results from a predictive model analysis of 82 sur-
gically managed adult patients. J Neurosurg Spine 28:2332.
105. Celletti C, Galli M, Cimolin V, Castori M, Albertini G, Camerota
F (2012) Relationship between fatigue and gait abnormality in
joint hypermobility syndrome/Ehlers-Danlos syndrome hypermo-
bility type. Res Dev Disabil 33:19141918.
106. Dyste GN, Menezes AH, VanGilder JC (1989) Symptomatic
Chiari malformations. An analysis of presentation, management,
and long-term outcome. J Neurosurg 71:159168.
107. Goel A, Shah A (2009) Reversal of longstanding musculoskeletal
changes in basilar invagination after surgical decompression and
stabilization. J Neurosurg Spine 10:220227.
108. da Silva JA, Brito JC, da Nobrega PV (1992) Autonomic nervous
system disorders in 230 cases of basilar impression and Arnold-
Chiari deformity. Neurochirurgia 35:183188
109. Henderson FC, Geddes JF, Vaccaro AR, Woodard E, Berry KJ,
Benzel EC (2005) Stretch-associated injury in cervical spondylotic
myelopathy: new concept and review. Neurosurgery 56:1101
1113 discussion 1101-1113
110. Fielding JW (1957) Cineroentgenography of the normal cervical
spine. J Bone Joint Surg Am 39:12801288
111. Werne S (1957) Studies in spontaneous atlas dislocation. Acta
Orthop Scand Suppl 23:1150
112. White AA, Panjabi MM Clinical biomechanics of the spine 2nd
edition Y11990
113. Wiesel SW, Rothman RH (1979) Occipitoatlantal hypermobility.
Spine 4:187191
114. Wolfla CE (2006) Anatomical, biomechanical, and practical con-
siderations in posterior occipitocervical instrumentation. The spine
journal : official journal of the North American Spine Society 6:
115. Dickman CA, Douglas RA, Sonntag VH (1990) Occipitocervical
fusion: posterior stabilization of the craniovertebral junction and
upper cervical spine. BNI Quarterly 6:214
116. Batzdorf U, Henderson FC, Rigamonti D (2016) Co-Morbidities
that Complicate the Treatment and Outcomes of Chiari
Malformation. Proceedings of the CSF Colloquium 2014. Chiari
Syringomyelia Foundation, Inc., Lulu
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Neurosurg Rev (2019) 42:915936 935
117. Menezes A (1995) Primary Craniovertebral anomalies and the
hindbrain herniation syndrome (Chiari I): Data Base analysis.
Pediatr Neursurg 23:260269.
118. Jacome DE (1999) Headache in Ehlers-Danlos syndrome.
Cephalalgia 19:791796.
119. Satti SR, Leishangthem L, Chaudry MI (2015) Meta-analysis of
CSF diversion procedures and Dural venous sinus stenting in the
setting of medically refractory idiopathic intracranial hyperten-
sion. AJNR Am J Neuroradiol 36:18991904.
120. Goel A (2012) Instability and basilar invagination. Journal of
craniovertebral junction & spine 3:12.
121. Izeki M, Neo M, Takemoto M, Fujibayashi S, Ito H, Nagai K,
Matsuda S (2014) The O-C2 angle established at occipito-
cervical fusion dictates the patient's destiny in terms of postoper-
ative dyspnea and/or dysphagia. Eur Spine J 23:328336. https://
122. Breig A (1970) Overstretching of and circumscribed pathological
tension in the spinal corda basic cause of symptoms in cord
disorders. J Biomech Eng 3:79
123. Bendik EM, Tinkle BT, Al-shuik E, Levin L, Martin A, Thaler R,
Atzinger CL, Rueger J, Martin VT (2011) Joint hypermobility
syndrome: a common clinical disorder associated with migraine
in women. Cephalalgia 31:603613.
124. Bulbena A, Baeza-Velasco C, Bulbena-Cabré A, Pailhez G,
Critchley H, Chopra P, Mallorquí-Bagué N, Frank C, Porges S
(2017) Psychiatric and psychological aspects in the Ehlers
Danlos syndromes. Am J Med Genet 175:237245
125. Bulbena A, Pailhez G, Bulbena-Cabré A, Mallorquí-Bagué N,
Baeza-Velasco C (2015) Joint hypermobility, anxiety and psycho-
somatics: two and a half decades of progress toward a new phe-
notype. Clinical Challenges in the Biopsychosocial Interface
(Karger Publishers) 34:143157
126. Castori M, Morlino S, Ghibellini G, Celletti C, Camerota F,
Grammatico P (2015) Connective tissue, Ehlers-Danlos syn-
drome(s), and head and cervical pain. American journal of medi-
cal genetics part C, seminars in medical. genetics 169c:8496.
127. Farb RI, Vanek I, Scott JN, Mikulis DJ, Willinsky RA, Tomlinson
G, terBrugge KG (2003) Idiopathic intracranial hypertension: the
prevalence and morphology of sinovenous stenosis. Neurology
128. Hamonet C, Ducret L, Marié-Tanay C, Brock I (2016) Dystonia in
the joint hypermobility syndrome (aka Ehlers-Danlos syndrome,
hypermobility type). SOJ Neurol 3:13
129. Tinkle BT (2014) Joint hypermobility and headache. Headache
130. Sasso RC, Jeanneret B, Fischer K, Magerl F (1994)
Occipitocervical fusion with posterior plate and screw instrumen-
tation. A long-term follow-up study. Spine 19:23642368
131. Morishita YFJ, Naito M, Hymanson HJ, Taghavi C, Wang JC
(2009) The kinematic relationships of the upper cervical spine.
Spine 34:26422645
132. Klimo P Jr, Kan P, Rao G, Apfelbaum R, Brockmeyer D (2008)
Os odontoideum: presentation, diagnosis, and treatment in a series
of 78 patients. Journal of neurosurgery Spine 9:332342. https://
133. Menezes A (2014) Clival and Craniovertebral junction
Chordomas. World Neurosurg 81:690692.
134. Tubbs RS, McGirt MJ, Oakes WJ (2003) Surgical experience in
130 pediatric patients with Chiari I malformations. J Neurosurg
135. Breig A (1989) Skull traction and cervical cord injury: a new
approach to improved rehabilitation. Springer-Verlag, New York
136. Shi R, Whitebone J (2006) Conduction deficits and membrane
disruption of spinal cord axons as a function of magnitude and
rate of strain. J Neurophysiol 95:33843390
137. Gennarelli TA (1997) The pathobiology of traumatic brain injury.
Neuroscientist 3:7381.
138. Jafari SS, Maxwell WL, Neilson M, Graham DI (1997) Axonal
cytoskeletal changes after non-disruptive axonal injury. J
Neurocytol 26:207221
139. Maxwell WL, Domleo A, McColl G, Jafari SS, Graham DI (2003)
Post-acute alterations in the axonal cytoskeleton after traumatic
axonal injury. J Neurotrauma 20:151168.
140. Maxwell WL, Islam MN, Graham DI, Gennarelli TA (1994) A
qualitative and quantitative analysis of the response of the retinal
ganglion cell soma after stretch injury to the adult Guinea-pig
optic nerve. J Neurocytol 23:379392
141. Maxwell WL, Kosanlavit R, McCreath BJ, Reid O, Graham DI
(1999) Freeze-fracture and cytochemical evidence for structural
and functional alteration in the axolemma and myelin sheath of
adult Guinea pig optic nerve fibers after stretch injury. J
Neurotrauma 16:273284.
142. Povlishock JT (1992) Traumatically induced axonal injury: path-
ogenesis and pathobiological implications. Brain Pathol (Zurich,
Switzerland) 2:112
143. Chung RS, Staal JA, McCormack GH, Dickson TC, Cozens MA,
Chuckowree JA, Quilty MC, Vickers JC (2005) Mild axonal
stretch injury in vitro induces a progressive series of neurofilament
alterations ultimately leading to delayed axotomy. J Neurotrauma
144. Saatman KE, Abai B, Grosvenor A, Vorwerk CK, Smith DH,
Meaney DF (2003) Traumatic axonal injury results in biphasic
calpain activation and retrograde transport impairment in mice. J
Cereb Blood Flow Metab 23:3442.
145. Bunge RP, Puckett WR, Becerra JL, Marcillo A, Quencer RM
(1993) Observations on the pathology of human spinal cord injury.
A review and classification of 22 new cases with details from a
case of chronic cord compression with extensive focal demyelin-
ation. Adv Neurol 59:7589
146. Geddes JF, Whitwell HL, Graham DI (2000) Traumatic axonal
injury: practical issues for diagnosis in medicolegal cases.
Neuropathol Appl Neurobiol 26:105116
147. Wolf JA, Stys PK, Lusardi T, Meaney D, Smith DH (2001)
Traumatic axonal injury induces calcium influx modulated by
tetrodotoxin-sensitive sodium channels. J Neurosci 21:19231930
148. Arundine M, Aarts M, Lau A, Tymianski M (2004) Vulnerability
of central neurons to secondary insults after in vitro mechanical
stretch. J Neurosci 24:81068123.
149. Li GL, Brodin G, Farooque M, Funa K, Holtz A, Wang WL,
Olsson Y (1996) Apoptosis and expression of Bcl-2 after com-
pression trauma to rat spinal cord. J Neuropathol Exp Neurol 55:
150. Liu XZ, Xu XM, Hu R, Du C, Zhang SX, McDonald JW, Dong
HX, Wu YJ, Fan GS, Jacquin MF, Hsu CY, Choi DW (1997)
Neuronal and glial apoptosis after traumatic spinal cord injury. J
Neurosci 17:53955406
151. Galbraith JA, Thibault LE, Matteson DR (1993) Mechanical and
electrical responses of the squid giant axon to simple elongation. J
Biomech Eng 115:1322
152. Povlishock JT, Jenkins LW (1995) Are the pathobiological chang-
es evoked by traumatic brain injury immediate and irreversible?
Brain Pathol (Zurich, Switzerland) 5:415426
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
936 Neurosurg Rev (2019) 42:915936
153. Shi R, Pryor JD (2002) Pathological changes of isolated spinal
cord axons in response to mechanical stretch. Neuroscience 110:
154. Torg JS, Thibault L, Sennett B, Pavlov H (1995) The Nicolas
Andry award. The pathomechanics and pathophysiology of cervi-
cal spinal cord injury. Clin Orthop Relat Res:259269
155. Botelho RVNE, Patriota GC, Daniel JW, Dumont PA, Rotta JM
(2007) Basilar invagination: craniocervical instability treated with
cervical traction and occipitocervical fixation. J Neurosurg Spine
156. Grahame R, Bird HA, Child A (2000) The revised (Brighton
1998) criteria for the diagnosis of benign joint hypermobility syn-
drome (BJHS). J Rheumatol 27:17771779
157. Sacheti A, Szemere J, Bernstein B, Tafas T, Schechter N,
Tsipouras P (1997) Chronic pain is a manifestation of the
Ehlers-Danlos syndrome. J Pain Symptom Manag 14:8893
158. Tinkle BT, Bird HA, Grahame R, Lavallee M, Levy HP, Sillence
D (2009) The lack of clinical distinction between the hypermobil-
ity type of Ehlers-Danlos syndrome and the joint hypermobility
syndrome (a.k.a. hypermobility syndrome). Am J Med Genet A
159. Wartolowska K, Judge A, Hopewell S, Collins GS, Dean BJ,
Rombach I, Brindley D, Savulescu J, Beard DJ, Carr AJ (2014)
Use of placebo controls in the evaluation of surgery: systematic
review. BMJ (Clinical research ed) 348:g3253.
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... Beighton score is used to assess joint hypermobility [2]. The need for reduction and stabilization in EDS cases is well recognized [3]. Although EDS was described in 1905, extensive work about symptoms was conducted since 2010. ...
... Treatment of cranio-cervical instability in this patient population has always intrigued clinicians across the globe due to the scarcity of literature. In 2019, Henderson et al. published the rst 5-year outcome of cranio-cervical reduction and fusion [3]. Various non-operative methods like the soft collar/rigid collar and door-hung neck traction have been used by patients for cranio-cervical instability related to EDS. ...
... Several studies have shown histopathological ndings of nerve injury due to abnormal stretching of neural elements [16,17,18,19]. In the EDS population, motor delay, developmental coordination disorder, headaches due to spinal compression, clumsiness, and the relatively high rate of dyslexia and dyspraxia have been recognized as a result of the effects of ligamentous laxity upon the central nervous system [3]. The interdigitation of the posterior atlantooccipital membrane with the pain-sensitive dura mater has also been proposed as a cause of headaches [20]. ...
Full-text available
Introduction: Cranio-cervical instability (CCI) is a condition commonly found in patients with connective tissue disorders such as Ehlers-Danlos Syndrome (EDS), leading to various symptoms. Assessing patients for surgical fusion as a treatment for CCI is challenging due to the complex nature of EDS-related symptoms. This study aimed to evaluate the role of pre-fusion Halo traction in alleviating symptoms and determining suitable candidates for fusion surgeries. Methods: A case series of 15 EDS patients with neurological symptoms underwent halo traction between 2019 and 2022. Patients completed a CCI Questionnaire before and after the traction, reporting symptoms related to headache, vision, hearing, equilibrium, and performance. Symptom groups were assigned scores based on patient responses, with one point for each affirmative answer. The scores were statistically analyzed using a paired t-test. Patients experiencing over 50% improvement in the majority of symptoms were considered for fusion surgery, and 7 out of 12 patients subsequently underwent the procedure. Results: The average age of the patients was 38 years, with a female-to-male ratio of 14:1, consistent with existing literature. Significant improvements were observed in various symptom categories after halo traction, including headache (63% improvement, p < 0.001), brainstem functions (72% improvement, p < 0.001), cerebellar functions (59% improvement,p < 0.001), hearing (65% improvement, p < 0.001), motor functions (62% improvement, p < 0.001), vision (53% improvement, p < 0.001), cardiovascular functions (58% improvement, p< 0.05), sensory and pain (56% improvement, p < 0.001), high cortical functions (54% improvement, p < 0.01), GI functions (41% improvement, p < 0.05), bladder functions (55% improvement, p< 0.001), and Modified Karnofsky score (26% improvement, p < 0.05). Conclusion: halo traction proved to be a simple and effective method for both evaluating patients for surgery and providing symptomatic relief in EDS-related CCI cases. It also allows surgeons to monitor patients with stable cranio-cervical junctions before committing to surgery. However, the study's limitations include the small sample size and the absence of a validated questionnaire with a scoring system.
... These diseases include systemic lupus, rheumatoid arthritis, and genetic disorders such as Ehlers-Danlos syndrome-hypermobility type/joint hypermobility syndrome (EDS-HT/JHS), Marfan syndrome, Loeys-Dietz syndrome, Stickler syndrome, Cleidocranial dysostosis, Morquio syndrome, osteogenesis imperfecta, and Down's syndrome. This broad group of genetic diseases characterized by generalized joint hypermobility can bring on laxity of the spinal ligaments that provoke severe symptoms due to CCI [1,6]. ...
... Cervical medullary syndrome (CMS) may be involved in the development of more severe proprioceptive disturbances. Furthermore, CMS is considered an important medical factor that contributes to widespread severe pain in patients with CCI and EDS-HT/ JHS [6]. CMS may explain some of the neurological and ancillary symptoms in patients with CCI and EDS-HT/JHS, particularly when a Chiari malformation is present. ...
... CMS may be explained by the traumatic deformation of axons that induces abnormal sodium influx through mechanically sensitive Na+ channels, which subsequently triggers an increase in intraaxonal calcium via opening of the voltage-gated calcium channel, upregulation of the glutaminergic pathway, chronic neuroinflammation, and apoptosis [4]. The most frequent clinical manifestations observed in patients with CMS are mentioned in Table 2. [6,13]. There may also be signs of dysautonomia such as POTS, sensory loss, functional gastrointestinal disturbances, delayed gastric emptying, chronic(slow transit) constipation, rectal evacuatory dysfunction and bladder dysfunction [5,15,16]. ...
Full-text available
Patients suffering from connective tissue disorders like Ehlers–Danlos syndrome hypermobility type/joint hypermobility syndrome (EDS-HT/JHS) may be affected by craniocervical instability (CCI). These patients experience myalgic encephalomyelitis, chronic fatigue, depression, extreme occipital-cervical pain, and severe widespread pain that is difficult to relieve with opioids. This complex and painful condition can be explained by the development of chronic neuroinflammation, opioid-induced hyperalgesia, and central sensitization. Given the challenges in treating such severe physical pain, we evaluated all the analgesic methods previously used in the perioperative setting, and updated information was presented. It covers important physiopathological aspects for the perioperative care of patients with EDS-HT/JHS and CCI undergoing occipital-cervical/thoracic fixation/fusion. Moreover, a change of paradigm from the current opioid-based management of anesthesia/analgesia in these patients to the perioperative opioid minimization strategies used by the authors was analyzed and proposed as follow-up considerations from our previous case series. These strategies are based on total-intravenous opioid-free anesthesia, multimodal analgesia, and a postoperative combination of anti-hyperalgesic coadjuvants (lidocaine, ketamine, and dexmedetomidine) with an opioid-sparing effect.
... These include the Grabb-Oakes measurement (or pB-C2, which is the perpendicular measurement from the dura at the level of C1 to a line drawn from basion to the posterior inferior C2 vertebra), the Harris (Basion to posterior axial line), and the angular displacement between C1 and C2. 1 Current reported series suggest the commonest used diagnostic criteria (and the measurements quoted as abnormal) are the CXA (<135 ), pB-C2 (>9mm), Harris (>12 mm), BDI (>12 mm), and C1/C2 angular displacement (>41 ). 1,4 Three pathophysiological mechanisms for the symptoms due to craniocervical instability in hEDS have been proposed. In the series described above, 71% of the HDCT group were said to have pannus of 3mm or more and basilar invagination, supporting a direct compressive mechanism on the brainstem. ...
... 3 A second proposition is that hypermobility at the craniocervical junction increases strain on the brain stem, associated tracts, and the axons. 4 Stretching of axons affects synaptic firing rates and amplitude, NMDA expression, mitochondrial function, and can eventually lead to apoptosis. Fixation is postulated as reducing the strain and microtrauma of hypermobility. 4 The final hypothesis relates to the myodural bridge that attaches the craniocervical dura to the adjacent musculature. ...
... Fixation is postulated as reducing the strain and microtrauma of hypermobility. 4 The final hypothesis relates to the myodural bridge that attaches the craniocervical dura to the adjacent musculature. This is said to support and limit movement of the spinal cord and adjacent brain stem, and when deficient, as in EDS patients, leads to excessive pathological spinal cord motion. ...
... The symptoms induced by CVJ instability may range from neck pain and restricted neck movements to sensory and motor abnormalities and gait instability [68]. The concept of CVJ instability is based on both bony abnormalities and on excessive laxity/loss of insertion of the atlanto-occipital and atlantoaxial ligaments. ...
... It is a measure of the encroachment of the odontoid process into the upper spinal canal (basilar invagination) and investigates ventral brainstem compression. A measurement ≥9 mm is considered pathological [68]. ...
... The translational BAI and translational BDI are the change in mm of the BAI and BDI between the flexion and extension positions of the head [68]. ...
Full-text available
The craniovertebral junction (CVJ) is a complex transition area between the skull and cervical spine. Pathologies such as chordoma, chondrosarcoma and aneurysmal bone cysts may be encountered in this anatomical area and may predispose individuals to joint instability. An adequate clinical and radiological assessment is mandatory to predict any postoperative instability and the need for fixation. There is no common consensus on the need for, timing and setting of craniovertebral fixation techniques after a craniovertebral oncological surgery. The aim of the present review is to summarize the anatomy, biomechanics and pathology of the craniovertebral junction and to describe the available surgical approaches to and considerations of joint instability after craniovertebral tumor resections. Although a one-size-fits-all approach cannot encompass the extremely challenging pathologies encountered in the CVJ area, including the possible mechanical instability that is a consequence of oncological resections, the optimal surgical strategy (anterior vs posterior vs posterolateral) tailored to the patient’s needs can be assessed preoperatively in many instances. Preserving the intrinsic and extrinsic ligaments, principally the transverse ligament, and the bony structures, namely the C1 anterior arch and occipital condyle, ensures spinal stability in most of the cases. Conversely, in situations that require the removal of those structures, or in cases where they are disrupted by the tumor, a thorough clinical and radiological assessment is needed to timely detect any instability and to plan a surgical stabilization procedure. We hope that this review will help shed light on the current evidence and pave the way for future studies on this topic.
... In some cases, patients have concomitant craniocervical instability and basilar invagination necessitating occipitocervical fusion in addition to decompression. [4][5][6] Multimodal intraoperative neuromonitoring (IONM) has been found to be beneficial in a wide range of pediatric neurosurgical interventions involving the posterior fossa, ABBREVIATIONS BAEP = brainstem auditory evoked potential; CA = clival angle; CLV = Chamberlain's line violation; CSF = cerebrospinal fluid; IONM = intraoperative neuromonitoring; MEP = motor evoked potential; pB-C2 = Grabb-Oakes measurement; sEMG = spontaneous electromyography; SSEP = somatosensory evoked potential. ...
... Several radiographic measurements are used to evaluated skull base deformity, including CA, pB-C2, and the relationship of the odontoid process to CLV. 4 All patients who had true-positive IONM signal changes had CA < 135°. It has been suggested that CA < 150° may be associated with ventral cord compression. ...
... [20][21][22][23][24][25] Flexion of the neck, such as in positioning for Chiari decompression, can further decrease the CA by 9°-11°. 4,26,27 This suggests that the inherent craniocervical kyphosis in these patients, exacerbated by the "military tuck" position, may compromise the adjacent neural structures. We hypothesize that such severe stretching of the cervicomedullary junction may predispose these patients to subtle intraoperative insults, resulting in IONM changes despite stable signals immediately after positioning. ...
Objective: Surgical treatment for symptomatic Chiari I malformation involves surgical decompression of the craniovertebral junction. Given the proximity of critical brainstem structures, intraoperative neuromonitoring (IONM) is employed for safe decompression in some institutions. However, IONM adds time and cost to the operation, and the benefit to the patient has not been defined. Given the diversity in surgical practices, there is no evidence-based standard of care regarding when to use IONM and which modalities are most helpful. The purpose of this study was to review a single-surgeon experience with IONM in order to determine the sensitivity, specificity, and predictive values of various IONM modalities routinely used in pediatric Chiari I decompression; to examine the associations between patient, clinical, and radiographic characteristics and IONM alerts; and to obtain data regarding the usefulness of these modalities during the surgical process to improve patient outcomes. Methods: A retrospective review was performed for 300 consecutive pediatric patients who underwent suboccipital craniectomy and C1 laminectomy for Chiari decompression performed by a single surgeon over a 15-year period. Clinical, radiographic, and IONM data were collected. Radiographic measurements of the skull base morphological abnormalities, including clival angle, Chamberlain's line, and Grabb-Oakes line, were compared between patients with and without true IONM signal changes. Results: A total of 291 cases were included, with an age range of 6 months to 19 years. Among 291 cases, somatosensory evoked potentials (SSEPs) were monitored in 291, motor evoked potentials (MEPs) in 209, cranial nerve spontaneous electromyography (sEMG) in 290, and brainstem auditory evoked potentials (BAEPs) in 110. Sensitivity, specificity, positive predictive value, and negative predictive value, respectively, were as follows: 1.00, 1.00, 1.00, and 1.00 for SSEPs; 1.00, 0.99, 0.67, and 1.00 for MEPs; 0.00, 0.88, 0.00, and 1.00 for sEMG; and not appliable, 1.00, not applicable, and 1.00 for BAEPs. Six patients had true IONM signal changes. These patients had radiographic evidence of more severe concomitant craniocervical instability and basilar invagination, with steeper clival angles (124° vs 146°, p = 0.02) and larger Grabb-Oakes lines (10.1 mm vs 6.7 mm, p = 0.02), when compared with the patients without any true IONM changes. Conclusions: Intraoperative neuromonitoring may be best utilized for patients who show radiographic features of abnormal skull base morphology, defined as a clival angle < 135° or Grabb-Oakes line > 9 mm. When IONM is employed, SSEP and MEP monitoring are the most useful modalities.
... Basilar invagination and/or vertebral artery occlusion can result in ventral compression of neural tissues and obstruction of cerebrospinal flow and arterial supply [4,5]. Reported symptoms although controversial range from headache, vertigo, perceived instability and sensorimotor dysfunction to impaired vision, dyspnea and dysautonomia [5][6][7][8]. However, patients present heterogeneously and may be referred for diagnostic procedures not specific to CCI. ...
... These are well defined for traumatic conditions but less so for nontraumatic etiology. Patients with CCI report symptoms and demonstrate signs of ventral compression during head and neck movements [6,7,9,[20][21][22]. Although the common static imaging techniques, such as erect radiography and recumbent MRI, might suffice to detect overt subluxations or neuroanatomical abnormalities [23,24], signs of mild instability or positional symptoms may be difficult to discern from images taken in a neutral or unloaded head-on-neck position. ...
... We aimed to utilize 50 participants' udMRI for this exploratory study, similar sample size to other investigative MRI studies related to craniocervical measures [7,20]. To determine the inter-tester reliability of the four measures used in the protocol, two of the investigators (senior radiologist ML and senior neurosurgeon PJR) independently measured these on all three images (neutral and maximal flexion and extension). ...
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Purpose To establish reference ranges for four most commonly used diagnostic measures of craniocervical instability (CCI) in three cervical sagittal positions. This necessitated development of a reliable measurement protocol using upright, dynamic MRI (udMRI), to determine differences in the extent of motion between positions, and whether age and sex correlate with these measures. Materials and Methods Deidentified udMRIs of 50 adults, referred for reasons other than CCI, were captured at three positions (maximal flexion, maximal extension and neutral). Images were analyzed, providing measures of basion-axial interval, basion-axial angle, basion-dens interval (BDI) and the Grabb–Oakes line (GOL) for all three positions (12 measures per participant). All measures were independently recorded by a radiologist and neurosurgeon to determine their reliability. Descriptive statistics, correlations, paired and independent t-tests were used. Mean (± 2 SD) identified the reference range for all four measures at each craniocervical position. Results The revised measurement protocol produced inter-rater reliability indices of 0.69–0.97 (moderate–excellent). Fifty adults’ (50% male; mean age 41.2 years (± 9.7)) reference ranges for all twelve measures were reported. Except for the BDI and GOL when moving between neutral and full flexion, significant extents of movement were identified between the three craniocervical positions for all four measures ( p ≤ 0.005). Only a minor effect of age was found. Conclusions This is the first study to provide a rigorous standardized protocol for four diagnostic measures of CCI. Reference ranges are established at mid and ends of sagittal cervical range corresponding to where exacerbations of signs and symptoms are commonly reported.
... Symptoms of UCI include: headaches, neck or facial pain, dizziness, vertigo, nausea, paresthesias, dyspnea, dysphonia, vision changes (blurred or tunnel vision, visual aura), hearing changes, dysphagia, choking, sleep apnea, memory deficits, and pre-syncopal episodes. Signs associated with UCI include: long-tract findings such as hyper-reflexia, positive Babinski and Hoffman's signs, loss of abdominal reflex, dysdiadochokinesia, as well as bowel/bladder problems, gait/balance deficits, weakness of arms and legs, sleep apnea and syncopal episodes (1,5,8). Dysautonomia is more likely to be present and severe with UCI and cervical myelopathy (9,10). ...
... Mild UCI in S-GJH may be relatively common (52-66%); (10,11) while severe UCI is uncommon (5%) (11), it can be debilitating (8). UCI is likely underdiagnosed in S-GJH (5,11). ...
... Although High Irritability patients are most likely to demonstrate concerning RF, patients in any level of irritability may present with RF. Various criteria exist for surgical treatment, and have been reviewed; (5) one set of criteria are (1) moderate to severe headache or suboccipital pain; (2) bulbar symptoms indicating cervical medullary syndrome; (3) neurological findings indicating myelopathy, and (4) radiographic evidence of instability (8). The therapist may choose to refer the patient without any conservative care, or refer while providing cautious conservative care. ...
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Experts in symptomatic generalized joint hypermobility (S-GJH) agree that upper cervical instability (UCI) needs to be better recognized in S-GJH, which commonly presents in the clinic as generalized hypermobility spectrum disorder and hypermobile Ehlers-Danlos syndrome. While mild UCI may be common, it can still be impactful; though considerably less common, severe UCI can potentially be debilitating. UCI includes both atlanto-occipital and atlantoaxial instability. In the absence of research or published literature describing validated tests or prediction rules, it is not clear what signs and symptoms are most important for diagnosis of UCI. Similarly, healthcare providers lack agreed-upon ways to screen and classify different types or severity of UCI and how to manage UCI in this population. Consequently, recognition and management of UCI in this population has likely been inconsistent and not based on the knowledge and skills of the most experienced clinicians. The current work represents efforts of an international team of physical/physiotherapy clinicians and a S-GJH expert rheumatologist to develop expert consensus recommendations for screening, assessing, and managing patients with UCI associated with S-GJH. Hopefully these recommendations can improve overall recognition and care for this population by combining expertise from physical/physiotherapy clinicians and researchers spanning three continents. These recommendations may also stimulate more research into recognition and conservative care for this complex condition.
... In 2005, Cook et al. reported the sixteen symptoms usually found in patients with cervical lumbar instability by using the Delphi study among specialists in musculoskeletal physical therapy [21]. These symptoms are also associated with other studies that reported the subjective examination of neck pain results in a diagnosis of cervical instability [14,[22][23][24][25][26][27]. Rueangsri et al. (2022) decided to select the lists of subjective examinations reported by Cook et al. (2005) to establish a screening tool for Thai patients with cervical spine instability. ...
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Neck pain, dizziness, difficulty supporting the head for an extended period, and impaired movement are all symptoms of cervical spine instability, which may produce cervical spondylolisthesis in patients who have more severe symptoms. To avoid problems and consequences, early detection of cervical spine instability is required. A previous study created a Thai-language version of a cervical spine instability screening tool, named the CSI-TH, and evaluated its content validity. However, other characteristics of the CSI-TH still needed to be evaluated. The objective of the current study was to assess the rater reliability and convergent validity of the CSI-TH. A total of 160 participants with nonspecific chronic neck pain were included in the study. The Neck Disability Index Thai version (NDI-TH), the Visual Analog Scale Thai version (VAS-TH), and the Modified STarT Back Screening Tool Thai version (mSBST-TH) were used to evaluate the convergent validity of the CSI-TH. To determine inter- and intra-rater reliabilities, novice and experienced physical therapists were involved. The results showed that rater reliabilities were excellent: the intra-rater reliability was 0.992 (95% CI = 0.989 ± 0.994), and the inter-rater reliability was 0.987 (95% CI = 0.983 ± 0.991). The convergent validities of the VAS-TH, NDI-TH, and mSBST-TH when compared with the CSI-TH were 0.5446, 0.5545, and 0.5136, respectively (p < 0.01). The CSI-TH was developed for use by physical therapists and is reliable. It can be used by physical therapists, whether they are experienced or novices, and has an acceptable correlation to other neck-related questionnaires. The CSI-TH is concise, suitable for clinical use, and lower-priced when compared to the gold standard in diagnosis for patients with cervical spine instability.
... 11 Additionally, there is a well-recognized but poorly understood association between female gender and CMI development. This association was further amplified in the subgroup who also harbored CTDs: 72.3% of the cohort without CTDs, versus 82.0% of the cohort with CTDs, were female (p < 0.001), an association further corroborated by Henderson et al and Milhorat et al. 11,14 Further research needs to be done looking at why the female gender is more prone to CMI and CTD. One hypothesis is the effect of estrogen on connective tissue, leading to increased susceptibility for both conditions in women. ...
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Background: Chiari malformation type I (CMI) is relatively common neurosurgical condition typically treated with posterior fossa decompression. However, the management of CMI in patients with heritable connective tissue disorders (CTDs), such as Ehlers-Danlos Syndrome, Marfan Syndrome, or Osteogenesis Imperfecta, involves a unique set of perioperative challenges. Objective: This study aims to define the demographic information, comorbidities, and perioperative course of patients with concomitant CMI and CTD. Methods: Patients with CMI admitted for surgical decompression from 2008 to 2015 were captured using the National Inpatient Sample (NIS). Information was collected based on ICD-9 codes. Descriptive and regression analyses were performed in SPSS (version 26). Results: 38,169 CMI patients, 353 of whom had CTD (0.92%), were identified. CMI patients with CTD were more likely to be female (p < 0.001) and present during teenage (p = 0.033) or young adult years (p < 0.001). They had more chronic issues (p < 0.001): systemic comorbidities include postural orthostatic tachycardia syndrome, cardiac dysrhythmias, and gastroparesis (all p < 0.001). CNS comorbidities include migraine, tethered spinal cord, and epilepsy (all p < 0.001). They have increased joint instability (both p < 0.001), as well as craniocervical instability (CCI). More posterior cervical fusion surgeries and application of cervical halo devices were seen during the same inpatient stay (both p < 0.001). Conclusions: Patients with concurrent CTD and CMI were more likely to present with complex Chiari and associated CCI. They were also younger, more often female, and had more systemic, CNS, and joint abnormalities. As such, preoperative recognition of an underlying CTD is imperative to achieve optimal outcomes in this patient population.
Individuals with Chiari malformation can present with symptoms of fatigue, lightheadedness, and syncope-the cardinal features of orthostatic intolerance. Similar orthostatic symptoms can complicate the clinical course following Chiari decompression. The presence of orthostatic intolerance in patients with Chiari malformation is not surprising given the location of the major circulatory control centers and their pathways in the brainstem. This article reviews the normal physiologic response to upright posture and the common forms of orthostatic intolerance encountered in clinical practice. The authors describe the relationship between orthostatic intolerance and Chiari malformation and provide suggestions regarding the evaluation and management of these disorders.
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OBJECTIVE Although various predictors of postoperative outcome have been previously identified in patients with Chiari malformation Type I (CMI) with syringomyelia, there is no known algorithm for predicting a multifactorial outcome measure in this widely studied disorder. Using one of the largest preoperative variable arrays used so far in CMI research, the authors attempted to generate a formula for predicting postoperative outcome. METHODS Data from the clinical records of 82 symptomatic adult patients with CMI and altered hindbrain CSF flow who were managed with foramen magnum decompression, C-1 laminectomy, and duraplasty over an 8-year period were collected and analyzed. Various preoperative clinical and radiological variables in the 57 patients who formed the study cohort were assessed in a bivariate analysis to determine their ability to predict clinical outcome (as measured on the Chicago Chiari Outcome Scale [CCOS]) and the resolution of syrinx at the last follow-up. The variables that were significant in the bivariate analysis were further analyzed in a multiple linear regression analysis. Different regression models were tested, and the model with the best prediction of CCOS was identified and internally validated in a subcohort of 25 patients. RESULTS There was no correlation between CCOS score and syrinx resolution (p = 0.24) at a mean ± SD follow-up of 40.29 ± 10.36 months. Multiple linear regression analysis revealed that the presence of gait instability, obex position, and the M-line–fourth ventricle vertex (FVV) distance correlated with CCOS score, while the presence of motor deficits was associated with poor syrinx resolution (p ≤ 0.05). The algorithm generated from the regression model demonstrated good diagnostic accuracy (area under curve 0.81), with a score of more than 128 points demonstrating 100% specificity for clinical improvement (CCOS score of 11 or greater). The model had excellent reliability (κ = 0.85) and was validated with fair accuracy in the validation cohort (area under the curve 0.75). CONCLUSIONS The presence of gait imbalance and motor deficits independently predict worse clinical and radiological outcomes, respectively, after decompressive surgery for CMI with altered hindbrain CSF flow. Caudal displacement of the obex and a shorter M-line–FVV distance correlated with good CCOS scores, indicating that patients with a greater degree of hindbrain pathology respond better to surgery. The proposed points-based algorithm has good predictive value for postoperative multifactorial outcome in these patients.
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There is growing recognition of the kyphotic clivo-axial angle (CXA) as an index of risk of brainstem deformity and craniocervical instability. This review of literature and prospective pilot study is the first to address the potential correlation between correction of the pathological CXA and postoperative clinical outcome. The CXA is a useful sentinel to alert the radiologist and surgeon to the possibility of brainstem deformity or instability. Ten adult subjects with ventral brainstem compression, radiographically manifest as a kyphotic CXA, underwent correction of deformity (normalization of the CXA) prior to fusion and occipito-cervical stabilization. The subjects were assessed preoperatively and at one, three, six, and twelve months after surgery, using established clinical metrics: the visual analog pain scale (VAS), American Spinal InjuryAssociation Impairment Scale (ASIA), Oswestry Neck Disability Index, SF 36, and Karnofsky Index. Parametric and non-parametric statistical tests were performed to correlate clinical outcome with CXA. No major complications were observed. Two patients showed pedicle screws adjacent to but not deforming the vertebral artery on post-operative CT scan. All clinical metrics showed statistically significant improvement. Mean CXA was normalized from 135.8° to 163.7°. Correction of abnormal CXA correlated with statistically significant clinical improvement in this cohort of patients. The study supports the thesis that the CXA maybe an important metric for predicting the risk of brainstem and upper spinal cord deformation. Further study is feasible and warranted.
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The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin extensibility, and tissue fragility. This communication briefly reports upon the neurological manifestations that arise including the weakness of the ligaments of the craniocervical junction and spine, early disc degeneration, and the weakness of the epineurium and perineurium surrounding peripheral nerves. Entrapment, deformation, and biophysical deformative stresses exerted upon the nervous system may alter gene expression, neuronal function and phenotypic expression. This report also discusses increased prevalence of migraine, idiopathic intracranial hypertension, Tarlov cysts, tethered cord syndrome, and dystonia, where associations with EDS have been anecdotally reported, but where epidemiological evidence is not yet available. Chiari Malformation Type I (CMI) has been reported to be a comorbid condition to EDS, and may be complicated by craniocervical instability or basilar invagination. Motor delay, headache, and quadriparesis have been attributed to ligamentous laxity and instability at the atlanto-occipital and atlantoaxial joints, which may complicate all forms of EDS. Discopathy and early degenerative spondylotic disease manifest by spinal segmental instability and kyphosis, rendering EDS patients prone to mechanical pain, and myelopathy. Musculoskeletal pain starts early, is chronic and debilitating, and the neuromuscular disease of EDS manifests symptomatically with weakness, myalgia, easy fatigability, limited walking, reduction of vibration sense, and mild impairment of mobility and daily activities. Consensus criteria and clinical practice guidelines, based upon stronger epidemiological and pathophysiological evidence, are needed to refine diagnosis and treatment of the various neurological and spinal manifestations of EDS. © 2017 Wiley Periodicals, Inc.