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

Abstract

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.

Full text

ORIGINAL ARTICLE
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
1,2
&C. A. Francomano
1
&M. Koby
1
&K. Tuchman
2
&J. Adcock
3
&S. Patel
4
Received: 10 October 2018 /Revised: 28 November 2018 / Accepted: 10 December 2018 / Publ ished online: 9 January 2 019
Abstract
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.
Keywords Ehlers-Danlos syndrome .Craniocervical instability .Clivo-axial angle .Cervical medullary syndrome
Neurosurgical Review (2019) 42:915–936
https://doi.org/10.1007/s10143-018-01070-4
Introduction
Many studies have drawn attention to the presence of
craniocervical instability or basilar invagination in patients
with Chiari one and Chiari zero malformation [1–23]. 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 [10,17,24–36] and hereditary hypermobile and
*Fraser C. Henderson, Sr
Henderson@FraserHendersonMD.com
1
Doctor’s Community Hospital, Lanham, MD, USA
2
The Metropolitan Neurosurgery Group, LLC, Silver Spring, MD,
USA
3
Harvey Institute of Human Genetics, Greater Baltimore Medical
Center, Baltimore, MD, USA
4
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) [8,18,21,26,31,37–50].
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 [18,41,51–66].
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,
69–75].
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 authors’hypothesis 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 (2011–2012), 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
present.
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 (0–10/10).
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
2years.
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) 42:915–936
Fig. 1 The Karnofsky Performance Status Scale
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Neurosurg Rev (2019) 42:915–936 917
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,
c).
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,
77].
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 [76–78]. 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,
massage)
*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
[80–82]. 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) 42:915–936
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
odontoid
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
inferred
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
study.
Results
Nineteen subjects were female and one male, with an average
age of 24 years (range of 12–53 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) 42:915–936 919
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
a
% With worsening of
frequency post-surgery
a
pvalue
b
% With onset
post-surgery
c
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
a
For those participants who had presence of symptom/problem prior to surgery
b
Comparing frequencies of symptom/problem pre vs. post-surgery, a significant pvalue indicates less frequent symptom/problem post-surgery
c
For those participants who did not have the presence of symptom/problem prior to surgery
920 Neurosurg Rev (2019) 42:915–936
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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
6/20.
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) 42:915–936 921
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
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 [76–78]. 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 McRae’s 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) 42:915–936
0%
10%
20%
30%
40%
50%
60%
70%
Strongly
Agree
Agree Somewhat
Agree
Somewhat
Disagree
Disagree Strongly
Disagree
% of Subjects
If I had a family member or close friend in a
similar situaon, I would feel comfortable
recommending the craniovertebral fusion
surgery
Fig. 10 Opinion regarding recommending surgery
0%
10%
20%
30%
40%
50%
60%
70%
Strongly
Agree
Agree Somewhat
Agree
Somewhat
Disagree
Disagree Strongly
Disagree
% of Subjects
In looking back I would sll choose to have the
craniovertebral fusion surgery
Fig. 9 Opinion regarding choice of surgery
0%
5%
10%
15%
20%
25%
30%
35%
40%
Strongly
Agree
Agree Somewhat
Agree
Somewhat
Disagree
Disagree Strongly
Disagree
% of Subjects
Having this surgery improved my symptoms and
decreased my limitaons.
Fig. 12 Opinion regarding symptoms and limitations
0%
10%
20%
30%
40%
50%
60%
Strongly
Agree
Agree Somewhat
Agree
Somewhat
Disagree
Disagree Strongly
Disagree
% 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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Discussion
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 (0–10 scale) among
participants pre- vs. post-surgery
(n=20)
Area of pain Pre-
surgery
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
surgery
a
Normal after
surgery
Improvement after
surgery
b
No change in abnormal
finding
b
Worsening after
surgery
c
Strength
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%)
Reflexes
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%)
Other
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
movements
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%)
a
Some participants did not have completed documentation for certain pre-op findings
b
Participants who had abnormal finding prior to surgery
c
Participants who had normal finding prior to surgery and developed abnormal findings s/p surgery
Neurosurg Rev (2019) 42:915–936 923
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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 [84,86–88]. 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-
surgery
Patient CXA pre-
op
a
CXA post-
op
Grabb-Oakes pre-
op
b
Grabb-Oakes
post-op
HHM pre-
op
c
HHM post-
op
c
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
a
Clivo-axial angle abnormal (≤135); abnormal preop 20/20; post-op 0/20
b
Grabb-Oakes abnormal > 9, n=9/18
c
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
post-surgery*
% With worsening
of frequency
post-surgery
a
pvalue
b
%Withonset
post-surgery
c
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)
a
For those participants who had presence of symptom/problem prior to surgery
b
Comparing frequencies of symptom/problem pre vs. post-surgery, a significant pvalue indicates less frequent symptom/problem post-surgery
c
For those participants who did not have the presence of symptom/problem prior to surgery
924 Neurosurg Rev (2019) 42:915–936
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Table 6 Two- and five-year patient Karnofsky scores and current functioning levels
Patient
#
Age at
surgery
Gender Karnofsky
pre-op
Karnofsky
2 years post-
op
Karnofsky
5 years post-
op
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 4–5 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
2013–2015, 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
mom’s 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 ADL’s 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 A’s, taking dance classes. Has 3–4 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
home
Neurosurg Rev (2019) 42:915–936 925
Current work/school sta-
tus
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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 occiput–C1 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,
17,18,21,25–28,30–35,37,42,44–46,48,49]. 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 [30,71,98–100].
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
[18,51,53–60,62,66]. Interdigitation of the posterior-
atlanto-occipital membrane with the pain-sensitive spinal
dural layer has also been implicated in the genesis of headache
[101].
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)
Patient
#
Age at
surgery
Gender Karnofsky
pre-op
Karnofsky
2 years post-
op
Karnofsky
5 years post-
op
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 ~ 90–120 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
otherwise
Superior mesenteric artery syndrome “nutcracker syndrome”, L renal vein compression, pneumonia,
vascular digestive issues, had SMA transposition (1–2 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
self-care
20 17 F 60 80 60 New born, unable to
work
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) 42:915–936
Current work/school sta-
tus
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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) [1,3–5,77,79].
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
Chiari”with ventral brainstem compression or craniocervical
instability present with other genetic conditions—such as
HOX D3 homeotic transformation, Klippel Feil malforma-
tion, hereditary connective tissue disorders [102–104]—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,
70,71,105–107]. 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,
70–75,79,109]. 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,
10,76,77,79,110–114].
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 activities—impact sports and
prolonged sitting or driving, the importance of frequent rest
periods, physical therapy—for 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
undertaken.
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,
115].
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 [2,3,11,18,19,21–23,116,117].
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,
119].
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) 42:915–936 927
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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
gazing”from 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,
123–129].
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) 42:915–936
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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 C1–C2, 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, C2–3, 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 control—should 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
stabilization?
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 0–3, avg. 0.5 60%(12/20) range 0–9, avg. 1.7 <0.04
Chiari decompression 25% (5/20)
a
0<0.05
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)
a
NS
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)
a
NS
Lumbar puncture 0 10% (2/20) NS
a
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) 42:915–936 929
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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°
[15].
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.
Pathophysiology
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 [137–142].
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 [148–150].
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 [149,151–154].
Controversy
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 [56,62,18,41,51,53–55,57–61,
66]. Because this information is new, there is a dearth of ev-
idence upon which to base the management of these genetic
disorders.
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
[156–158]. 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) 42:915–936
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Neurosurg Rev (2019) 42:915–936 931
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].
Conclusion
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://
creativecommons.org/licenses/by/4.0/), 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.
Publisher’sNote Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.
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