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Upper Cervical Vertebral Subluxation in Multiple Sclerosis Subjects with Chronic Cerebrospinal Venous Insufficiency: A Pilot Study

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Objective: The purpose of this study is to evaluate the relationship between Atlas vertebra misalignments identified via radiographs and patients with multiple sclerosis (MS) and chronic cerebrospinal venous insufficiency (CCSVI). Clinical Features: Four patients with MS and CCVSI, three women and one man were evaluated according to revised McDonald criteria. These four patients were compared to a control group of four patients of similar age but with no neuro-degenerative diseases. Intervention and Outcomes: This is the first report on Atlas (C1) misalignment in MS patients with CCVSI. Four patients were evaluated using the Zamboni's criteria using the following: Echo Color Doppler (ECD) MyLab Vinco System Esaote, Upper cervical x-ray examination, Myofunctional Map, and Tytron thermal scanning instrumentation. In this study we found different alterations of C1 alignment in the MS patients versus the control group. Analysis of the x-ray examination permits us to identify a severe rotation and anterior intrusion of C1 in the MS patients with CCVSI. Conclusion: We found not only endovenous congenital malformations, but also external venous compression that blocks drainage flow. This confirms the validity of our Mechanical Posture Vascular Compressive Block. We hypothesize that extracranial venous compression is linked to severe misalignment of C1. We can also catalogue misalignments into two types of degrees: moderate and severe. This staging permits us to begin to distinguish paraphysiological misalignments from true pathological misalignments.
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Upper Cervical Vertebral Subluxation in Multiple Sclerosis Subjects
with Chronic Cerebrospinal Venous Insufficiency: A Pilot Study
Sandro Mandolesi, MD,1Giuseppe Marceca, MD,2Stephen Conicello, DC,3Eriece Harris, DC4
ABSTRACT
Objective: The purpose of this study is to evaluate the relationship between Atlas vertebra misalignments identified via
radiographs and patients with multiple sclerosis (MS) and chronic cerebrospinal venous insufficiency (CCSVI).
Clinical Features: Four patients with MS and CCVSI, three women and one man were evaluated according to revised
McDonald criteria. These four patients were compared to a control group of four patients of similar age but with no
neuro-degenerative diseases.
Intervention and Outcomes: This is the first report on Atlas (C1) misalignment in MS patients with CCVSI. Four
patients were evaluated using the Zamboni’s criteria using the following: Echo Color Doppler (ECD) MyLab Vinco
System Esaote, Upper cervical x-ray examination, Myofunctional Map, and Tytron thermal scanning instrumentation. In
this study we found different alterations of C1 alignment in the MS patients versus the control group. Analysis of the x -
ray examination permits us to identify a severe rotation and ant erior intrusion of C1 in the MS patients with CCVSI.
Conclusion: We found not only endovenous congenital malformations, but also external venous compression that blocks
drainage flow. This confirms the validity of our Mechanical Posture Vascular Compressive Block. We hypothesize that
extracranial venous compression is linked to severe misalignment of C1. We can also catalogue misalignments into two
types of degrees: moderate and severe. This staging permits us to begin to distinguish paraphysiologic al misalignments
from true pathological misalignments.
Keywords: Multiple sclerosis, chronic cerebrospinal venous insufficiency, upper cervical, subluxation
Introduction
Multiple sclerosis (MS) is considered a chronic disease of the
brain and spinal cord characterized by inflammatory-
demyelinating and neurodegenerative features that coexist
from early stages.1It is estimated that it currently affects
400,000 individuals in the United States, with 12,000 being
new cases annually, with more people being diagnosed now
than in the past.2MS affects twice as many women as it does
men, mimicking the unexplained bias found in other
ORIGINAL RESEARCH
1. Professor Cardiovascular and Respiratory Science
Department, Sapienza University of Rome, Rome, Italy
2. Professor School of Medicine, Sapienza University of
Rome, Rome, Italy
3. Private Practice of Chiropractic, Rome, Italy
4. Private Practice of Chiropractic, Naples, FL
J. Upper Cervical Chiropractic Research September 23, 2013 65
Multiple Sclerosis
autoimmune disorders.3This autoimmune disorder usually
begins in subjects around the ages of 20-40.2The majority of
MS patients (80%) present with the relapsing/remitting form
of the disease.3This form is characterized by relapsing of
symptoms followed by full recovery, relapse with persistent
deficit, and finally secondary progression.3In about a quarter
of the patients, MS never affects activities of daily living;
conversely 15% become severely disabled in a short period of
time.3Recognized and described over 150 years ago by a
French neurologist Charcot, the exact cause of the disease
remains unknown.4
In general, we consider MS to be caused by an autoimmune
mechanism with multiple etiological factors such as genetic,
infectious, and environmental.4Recently, chronic
cerebrospinal venous insufficiency (CCSVI) has been
described as a condition that may possibly contribute to the
symptoms often experienced by patients with MS.4CCSVI
has been described as a vascular condition characterized by
anomalies of the main extra-cranial cerebrospinal venous
routes that interfere with normal venous flow.1These
anomalies have been reported to affect the internal, vertebral
and azygous veins.1
The origin of CCSVI related venous anomalies has not been
determined.5It has been suggested that the origin of these
abnormalities could be physiological, age-dependent,
congenital, and a possible consequence of an inflammatory
process or environmental factors.5It has been hypothesized
that cerebrospinal venous anomalies may cause alterations to
blood flow that result in iron deposition, decreased brain
parenchyma metabolism, degeneration of neurons and
characteristic brain injury patterns found in MS.1This
hypothesis is referred to as “The Big Idea”.6
The Big Idea hypothesis was created by Paolo Zamboni. In
2006 Zamboni researched and published a paper in the Journal
of the Royal Society of Medicine entitled The Big Idea:
Iron-dependent inflammation in venous disease and proposed
parallels in multiple sclerosis”.6His paper outlines the
mechanism of pathology in CCSVI and MS. This paper also
suggests that there is a connection due to similarities in tissue
response. To summarize the findings of the paper, the
correlation begins with increased iron stores in areas of the
body - mainly the legs, due to extravasation of red blood cells
(RBC) in conditions of significant venous stasis in CCSVI.
The RBC’s are degraded by interstitial macrophages and the
released iron is converted into ferritin. Eventually the ferritin
is transformed into haemosiderin and then deposited into
venous tissue. This increase of iron storage in the body as
well as interstitial proteins attracts potent chemicals that
represent the initial chronic inflammatory signal response for
white blood cell recruitment and migration in the matrix.6The
predominate cells migrating into the extra cellular matrix are
macrophages and T-lymphocytes.
Similarly, the inflammation in MS is characterized by
expression of adhesion molecules followed by the migration
of macrophages and T-lymphocytes across the blood brain
barrier. In both scenarios there is an over expression of matrix
metallo-proteases (MMPs) that are not substantially balanced
by their physiological tissue inhibitors (TIMPs). If MMP is
unrestricted it leads to matrix break down and ulcer onset.10
Ajay has proposed the use of susceptibility weighted
neuroimaging techniques to confirm the hypothesis of iron
playing a role in the formation of MS.14 This imaging is able
to detect the iron deposits in the brain tissue.14
The proposed correlation in the two diseases comes from the
similar altered venous haemodynamics. The altered venous
haemodynamics are considered the trigger mechanism that
caused the inflammatory process in CVD. This has to be
studied further in relation to MS.18
Methods
Eight patients were selected to participate. Four of the
patients were diagnosed with MS according to the revised
McDonald criteria and CCSVI. The median age for the
patients is 33 with a maximum age of 36 and minimum of 30.
The gender of the patients consisted of three women and one
man. Disease duration for the patient group did not exceed 15
years. The other four patients were the control sample group
composed of subjects of the same age, without any neuo-
degenerative diseases.
Each patient was examined using the following: ECD,
Doppler Ultrasonography dynamic test, total body
myofunctional map, upper cervical radiography, and Tytron
C-5000 thermal scanning.
Results
Echo Color Doppler
According to Menegatti ECD demonstrated to be an ideal non
invasive tool for screening patients.7There was a question of
the reproducibility of the instrumentation based on the training
of the individual performing the exam.7The conclusion of the
36 subject study showed ECD is a powerful non-invasive and
reproducible tool for screening CCSVI and MS but the
individual needs special training.7ECD was used to measure
outflow in veins and inflow in arteries. In the MS sample the
venous outflow assessment showed: jugular vein stenosis in
50%, not visible vertebral veins in 25%, reflux in 50%,
blockage in 50%, and compression block in 25% of the
sample. The control sample assessment revealed ectasia of the
jugular vein only in 50% of the sample. The ECD arterial
inflow assessment of MS sample showed thoracic outlet
syndrome on the left side in 100%, kinking in vertebral
arteries in 75% of the sample. The control sample showed
kinking of the carotid arteries only in 25% of sample.
Myo-functional Map
Myo-functional assessment is an objective hand examination
of the skeletal muscle system that allows us to find, in an
objective way, the muscular contractures perceived
(spontaneous painful) from those not perceived
(spontaneously not painful). We then draw specific symbols
on an accurate Myo-functional Map. In the MS sample we
found muscular contractures of the total body examination:
Median 47±21, 9, Points min: 22 and Points max: 28. In the
control sample we found muscular contracture of the total
body examination: Median 15, Points min: 2, Points max: 28
Multiple Sclerosis
66 J. Upper Cervical Chiropractic Res. September 23, 2013
Cervical Radiographic Examination
Each patient received a series of cervical radiographs. The
following projections were taken and measured for each
sample group: APOM (anterior posterior open mouth), lateral
cervical and base posterior.
APOM
This projection is used to measure left or right laterality of C1.
To measure this a horizontal line was drawn through the upper
½ to 1/3 portion of the foramen magnum. The foramen
magnum is then bisected with a vertical line. A line is then
drawn from the vertical line to the edge of the lateral mass on
the right and left side. Measure both sides and the longer side
is the side of laterality of C1.
Base Posterior
This projection is used to measure the rotational component of
C1. To measure the anterior or posterior rotation first a dot
must be placed in the center of each transverse process. Then
a line is drawn connecting the two dots. The is called the atlas
line. A dot is then placed in the middle of the nasal septum.
Draw a line through the dot in the middle of the nasal septum
through the middle of the basilar process. This line should
intersect the atlas line. The angle is measured on the side of
laterality to check for posterior or anterior rotation.
Lateral Cervical
This projection is used to measure anterior intrusion of C1.
This is measured by drawing a line from the posterior foramen
magnum to the posterior neural canal of axis. This will be
labeled as line A. Another line is then drawn from the
posterior portion of the neural canal of the posterior arch of
atlas to the posterior of foramen magnum. This line will be
labeled line B. Another line is then drawn from the posterior
of the neural canal of the posterior arch of the atlas to the
posterior neural canal of axis. This line will be labeled line C.
Measure the distance from the point where B and C meet at
posterior neural canal at the posterior arch of atlas to line A at
a perpendicular angle.
The normal values for these radiographs are as follows: tilt of
18-22 degrees, no laterality, no rotation, and no intrusion into
the spinal laminar line (neural canal). The moderate categorey
values are as follows: inferior tilt of 16-18 degrees, superior
tilt of 22-24 degress, laterality of < 1.5mm, rotation of < 1
degree, and anterior intrusion of < 1.8mm. The severe
categorey values are as follows: inferior tilt of <16 degrees,
superior tilt of > 24, laterality > 1.5mm, rotation of > 1 degree,
and anterior intrusion of > 1.8 mm.
The radiographic results of the study are displayed in Figure 1.
J. Upper Cervical Chiropractic Research September 23, 2013 67
Multiple Sclerosis
The MS sample group results show that 25% of participants
presented with severe inferior tilt, severe left laterality,
moderate right laterality, severe right lateraltiy, moderate
anterior right rotation, severe anterior right rotation, severe
posterior right rotation, and severe posterior left rotation.
Normal superior tilt was found in 75% of the MS sample
group and no left rotation was found in any paticipants. The
major finding is that 100% of sample group presented with
severe anterior instrusion into the neural canal with the
maximum being 4.07mm.
The control sample group results show 25% of the participants
presented with normal tilt values and no anterior intrusion.
Fifty percent of the sample group presented with moderate left
laterality, moderate right laterality, moderate impairment on
left and right in anterior rotation. The control group also
presented with moderate superior tilt and moderate
impairment in anterior intrusion in 75% of participants. The
major finding in this group is 100% of sample group presented
with anterior rotation.
Tytron Thermal Scanning
Thermocouple devices have been used in chiropractic as early
as 1924 to measure side-to-side skin temperature
differentials.8According to Owens the Tytron shows very
high intraexaminar and interexaminer reliability with
intraclass correlation coefficient values between .91 and .98.8
When scanned using the tytron the MS sample group had
greater temperature alterations than the control group.
Discussion
CCVSI as a potential etiopathic entity in MS has recently been
suggested and gained significant attention.9It is widely
accepted that MS is an autoimmune disease but now we are
faced with a new model of it being possibly vascular or
degenerative. There is also a possiblility of there being a
mechanical component involving the C1 vertebra. To begin to
adress these concerns we must first look at the current
literature.
Williams created a study to evalute the hypothesis of Zamboni
in the Big Idea. In order to evaluate this hypothesis she
developed an animal model. The conclusion of her study
showed that MS caused the vascular abnormalities, not the
other way around.10
There is also controversy about the frequency and the role of
CCVSI in patients with MS.12-13 Laupacis performed a
systematic review and meta-analysis of all the peer review
studies that compared the frequency of CCVSI among patients
with MS.11 The meta-analysis published in 2011 included 8
studies and the article concluded that there was a strong and
statistically significant association between CCVSI and MS.11
The article did have a limitation of a small sample size but
found a strong association between CCVSI and MS.11 The
study concluded that more high quality studies using identical
ultrasound protocols are needed.11
Awad published a critical review on the subject. He states the
controversy of the subject is due to the inability of any other
researchers to reproduce the results published by Zamboni.9
Awad goes on to list six different recent studies that have been
done to recreate Zamboni’s results but have been
unsuccessful.9Awad goes on to discuss the plausibility of
CCVSI being biologically linked to MS and states the gold
standard to confirm would be a tissue diagnosis.9
One common theme that seems to reoccur is the use of ECD in
evaluating CCVSI. The instrumentation has been deemded
reliable but only if the ultrasonographer is trained properly.
More and better quality reasearch needs to be done on the
subject in order to determine causality.
The presence of substitute circles in Zamboni type
hemodynamic classification, when joined to external
compression of the jugular veins, suggests to us that a venous
vertebral and/or jugular postural venous compression block
may be caused by misalignment of C1.19
This intermittent compression block of vertebral and jugular
veins may be one of the multi-factorial causes of the worst
clinical conditions in MS patients with CCSVI, the
Mechanical Postural Vascular Block (MPVB) (Mandolesi-
Marceca, 2010 hypothesis).20 These patients frequently had
head and neck trauma.
There is a proposed relationship between MS and upper
cervical subluxation. Elster conducted a study on upper
cervical subluxation and it’s connection to MS and Parkinsons
disease.15
The retrospective study consisted of 81 patients. Of the 81
patients 44 had MS and all were diagnosed with upper cervical
subluxations. These patients were diagnosed using paraspinal
digital infrared imaging and laser-aligned radiography.
After the instrumentation and radiograph anaylsis were done,
the patients were adjusted using Knee Chest technique. The
result of this study showed 91% of the participants responded
to care with improved or reversed symptoms, and no further
progression of symptoms. The results suggested a link
between trauma, upper cervical injury, and disease onset for
both MS and Parkinsons.15 In addition to this study Stude
presented a case study showing conservative spinal
manipulations had positive effects in an MS patient. The
patient presented in the case did not have any upper cervival
subluxations but did have significant reduction in symptoms
posttreament.16
There seems to be some similarities in this study and the study
done by Elster. Two of the same examinations were used,
Tytron and upper cervical radiographs. They both also show a
relationship between C1 subluxation and the presence of MS.
The differences are Elster’s paper was focused on trauma as a
possible cause of MS while this paper is focused the
relationship between misalignment and CCVSI in patients
with MS.
Conclusion
As far as we know, this is the first report on C1 misalignment
in MS patients with CCSVI. In this study we found a
significant parameter of C1 misalignment (anterior intrusion)
in patients with MS with CCVSI versus control subjects.
Multiple Sclerosis
68 J. Upper Cervical Chiropractic Res. September 23, 2013
We postulate that the severe rotation and anterior intrusion
should be an important radiological marker for MS patients
with CCSVI. Further study with a larger sample size of these
CCSVI patients is recommended.
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J. Upper Cervical Chiropractic Research September 23, 2013 69
Multiple Sclerosis
Figure 1. Results from Radiographic Study
Multiple Sclerosis
70 J. Upper Cervical Chiropractic Res. September 23, 2013
... A correlation has been found between chronic cerebrospinal venous insufficiency and multiple sclerosis and is thought to be a possible cause of the neurodegenerative disease. 4,8 The study revealed positive outcomes for patients with both MS and CCVI. The authors hypothesized that a severe C1 misalignment is linked to extracranial venous compression which is thought to participate in the pathophysiology of MS. 4,8 In 2014, Gibson and Gallagher reported on the improvement in quality of life of a 36-year-old female diagnosed with MS, who was received chiropractic care. ...
... 4,8 The study revealed positive outcomes for patients with both MS and CCVI. The authors hypothesized that a severe C1 misalignment is linked to extracranial venous compression which is thought to participate in the pathophysiology of MS. 4,8 In 2014, Gibson and Gallagher reported on the improvement in quality of life of a 36-year-old female diagnosed with MS, who was received chiropractic care. The doctors analyzed the patient through Thompson and Mastering Chiropractic with Certainty (MC 2 ) protocols and adjusted the patient manually and with the Integrator TM adjusting instrument for 12 visits over one month. ...
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Objective: The purpose of this study is to report on the structural and symptomatic improvements made in a patient with a 22-year history of multiple sclerosis using Chiropractic BioPhysics® technique. Clinical Features: A 58-year-old female confined to a wheel chair presented for chiropractic care with a diagnosis of multiple sclerosis. An anteriorposterior lower cervical x-ray displayed 16.2mm left head translation (ideal is 0mm). Paraspinal thermography revealed a significant asymmetry in the cervical region with moderate asymmetry at C1 and C5 and severe asymmetry at C2-C4. Spirometry revealed a peak expiratory lung flow volume of 200 L/min and a forced expiratory lung volume of 1.48 L. Grip strength assessment revealed a maximum left-hand grip strength of 2.8 lbs and a maximum right-hand grip strength of 3.0 lbs. Intervention and Outcomes: The patient received Chiropractic BioPhysics® technique protocols. Follow-up examination revealed that the patient achieved a correction of left head translation of 17.0mm from 16.2mm to -0.8mm; an improvement in peak expiratory flow volume of 27 L/min from 200 L/min to 227 L/min; an improvement in forced expiratory lung volume of 0.18 L from 1.48 L to 1.66 L; an improvement in left-hand grip strength of 9.2 lbs from 2.8 lbs to 12 lbs and in right-hand grip strength of 5 lbs from 3.0 lbs to 8.0 lbs. Conclusions: Reduced vertebral subluxations, improved posture and a concomitant improvement in respiratory function, dysautonomia, and grip strength were achieved.
... 20 Recent research focuses on altered cerebrospinal fluid and blood flow dynamics at the atlas in conjunction with or possibly as a result of dentate cord distortion, which may help explain physiologic change observed in recent publications. [21][22][23] Continued research in these areas is necessary. ...
... 126,127 Recent investigations previously cited have reported alterations in CSF outflow following correction of the upper cervical misalignment. [21][22][23] From these case reports one conclusion of overreaching speculation, would suggest a possible relationship in head and neck trauma to the patient reported pathophysiologies and an upper cervical misalignment. These cases were not 'cherry-picked' to make this point. ...
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Presented here is a narrative review of upper cervical procedures intended to facilitate understanding and to increase knowledge of upper cervical chiropractic care. Safety, efficacy, common misconceptions, and research are discussed, allowing practitioners, chiropractic students, and the general public to make informed decisions regarding utilization and referrals for this distinctive type of chiropractic care. Upper cervical techniques share the same theoretical paradigm in that the primary subluxation exists in the upper cervical spine. These procedures use similar assessments to determine if spinal intervention is necessary and successful once delivered. The major difference involves their use of either an articular or orthogonal radiograph analysis model when determining the presence of a misalignment. Adverse events following an upper cervical adjustment consist of mild symptomatic reactions of short-duration (< 24-hours). Due to a lack of quality and indexed references, information contained herein is limited by the significance of literature cited, which included non-indexed and/or non-peer reviewed sources.
... Various types of venous flow obstructions and vein malformations, both intrinsic (intraluminal) [12][13][14][15] and extrinsic [16][17][18], have been associated with MS (and other neurovascular disorders). This paper focuses on intraluminal flow obstructions and defects. ...
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This paper hypothesizes, based on fluid dynamics principles, that in multiple sclerosis (MS) non-laminar, vortex blood flow occurs in the superior vena cava (SVC) and brachiocephalic veins (BVs), particularly at junctions with their tributary veins. The physics-based analysis demonstrates that the morphology and physical attributes of the major thoracic veins, and their tributary confluent veins, together with the attributes of the flowing blood, predict transition from laminar to non-laminar flow, primarily vortex flow, at select vein curvatures and junctions. Non-laminar, vortex flow results in the development of immobile stenotic valves and intraluminal flow obstructions, particularly in the internal jugular veins (IJVs) and in the azygos vein (AV) at their confluences with the SVC or BVs. Clinical trials’ observations of vascular flow show that regions of low and reversing flow are associated with endothelial malformation. The physics-based analysis predicts the growth of intraluminal flaps and septa at segments of vein curvature and flow confluences. The analysis demonstrates positive correlations between predicted and clinically observed elongation of valve leaflets and between the predicted and observed prevalence of immobile valves at various venous flow confluences. The analysis predicts the formation of sclerotic plaques at venous junctions and curvatures, in locations that are analogous to plaques in atherosclerosis. The analysis predicts that increasing venous compliance increases the laminarity of venous flow and reduces the prevalence and severity of vein malformations and plaques, a potentially significant clinical result. An over-arching observation is that the correlations between predicted phenomena and clinically observed phenomena are sufficiently positive that the physics-based approach represents a new means for understanding the relationships between venous flow in MS and clinically observed venous malformations.
... While this paper focuses on stenosed, immobile valves in the IJV, other forms of obstruction such as muscular or cervical subluxation, as observed in MS [59][60][61][62][63][64][65], may cause similar standing pressure waves and associated stagnant and reversing flow patterns. Hence, the analysis is not dependent on stenosed valves, but is dependent on the obstruction being sufficiently large that any standing waves in deep cerebral veins have sufficiently large pulsatility indices, that reversing flow occurs in the DCVs. ...
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Stenotic immobile valves and other malformations obstruct normal cerebrospinal venous outflow, resulting in reflux flow which combines with the normal outflow to produce standing pressure waves in the internal jugular and other cerebrospinal veins. It is hypothesized that, if the cerebrospinal venous structure between the obstruction and the deep cerebral veins is sufficiently non-compliant, the standing wave will result in bidirectional flow in the fine cerebral veins. Bidirectional flow in the fine veins, over extended periods of time, will cause disorder in the veins’ endothelial morphology, and ultimately, result in the disruption of the blood-brain barrier as observed in multiple sclerosis. This physics-based analysis demonstrates a positive correlation between clinically observed MS attributes with the predicted flow patterns and venous malformations that are based on fluid dynamics principles that include venous compliance influences. The physics-based approach used in this analysis provides new insights into MS pathologies based on predicted pressure and flow patterns.
... We found an improvement in all the subluxations of C1-C2 after the Upper Cervical care with respect to the evaluation before the correction/treatment, with significant statistical differences. Our results show that a misalignment of C1-C2 can compromise the normal cerebral venous outflow in patients suffering from MS. [12][13] In fact, regarding the C1-C2 vertebra, we found a significant statistical difference in the X-ray characteristics pre and post Chiropractic Upper Cervical care (p<0.00001 for the left laterality; p<0.00001 for right laterality; p=0.0034 for the left front rotation; p<0.0174 for the right front rotation; p<0.00001 for the left posterior rotation; p<0.00001 for the right posterior rotation; p=0.0005 for the superior inclination; p=0.0032 for the lower tilt and p<0.00001 for the front sliding. The anomalies identified in the X-ray examination improved in all the patients after four months of Upper Cervical care (Table IV). ...
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Chronic cerebrospinal venous insufficiency (CCSVI) was recently proposed as a contributing factor in the pathology of multiple sclerosis. This concept has gained remarkable attention, partly because endovascular neurointervention has been suggested as a treatment strategy. This review summarizes available evidence and provides a critical analysis of the published data. Currently, there is inconclusive evidence to support CCSVI as an etiological factor in patients with multiple sclerosis. Endovascular procedures should not be undertaken outside of controlled clinical trials.
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Perivenular inflammation is a common early pathological feature in multiple sclerosis (MS). A recent hypothesis stated that CNS inflammation is induced by perivenular iron deposits that occur in response to altered blood flow in MS subjects. In order to evaluate this hypothesis, an animal model was developed, called cerebral experimental autoimmune encephalomyelitis (cEAE), which presents with CNS perivascular iron deposits. This model was used to investigate the relationship of iron deposition to inflammation. In order to generate cEAE, mice were given an encephalitogen injection followed by a stereotactic intracerebral injection of TNF-α and IFN-γ. Control animals received encephalitogen followed by an intracerebral injection of saline, or no encephalitogen plus an intracerebral injection of saline or cytokines. Laser Doppler was used to measure cerebral blood flow. MRI and iron histochemistry were used to localize iron deposits. Additional histological procedures were used to localize inflammatory cell infiltrates, microgliosis and astrogliosis. Doppler analysis revealed that cEAE mice had a reduction in cerebral blood flow compared to controls. MRI revealed T2 hypointense areas in cEAE animals that spatially correlated with iron deposition around vessels and at some sites of inflammation as detected by iron histochemistry. Vessels with associated iron deposits were distributed across both hemispheres. Mice with cEAE had more iron-labeled vessels compared to controls, but these vessels were not commonly associated with inflammatory cell infiltrates. Some iron-laden vessels had associated microgliosis that was above the background microglial response, and iron deposits were observed within reactive microglia. Vessels with associated astrogliosis were more commonly observed without colocalization of iron deposits. The findings indicate that iron deposition around vessels can occur independently of inflammation providing evidence against the hypothesis that iron deposits account for inflammatory cell infiltrates observed in MS.
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Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) most commonly characterized by focal areas of myelin destruction, inflammation and axonal transection. The multicentric inflammation and demyelination of the brain and spinal cord are associated with variable neurologic symptoms ranging from mild dysfunction to debilitating. Typically, these symptoms are marked by episodes of clinical worsening followed by improvement. The cause of this disease remains unclear currently, but the underlying etiology is generally considered to be immunologically based. Other factors, including genetic, environmental and infectious influences have been implicated, as well. Now recent studies have proposed that extracranial venous obstruction, termed chronic cerebrospinal venous insufficiency (CCSVI) may have a role in the pathogenesis of MS or many of its associated clinical manifestations. It is postulated that venous narrowing affecting one or more of the jugular veins and/or the azygous vein in the chest may be responsible for abnormal blood flow in the veins draining the brain and spinal cord. The abnormal flow may initiate and/or sustain a local inflammatory response at the blood-brain barrier that promote pathological changes within the CNS. This review presents the history of the relationship between the vascular system and MS and explores the background of basic and clinical investigations that led to the concept of CCSVI.
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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS caused by the interplay of genetic and environmental factors. In the last years, it has been suggested that an abnormal venous drainage due to stenosis or malformation of the internal jugular and/or azygous veins may play a major pathogenetic role in MS. This abnormality called chronic cerebro-spinal venous insufficiency (CCSVI) could result in increased permeability of blood brain barrier, local iron deposition and secondary multifocal inflammation. In the present paper, literature data in favour and against this hypothesis are reported. A great variability of CCSVI has been found in both MS patients (ranging from 0 to 100%) and in control subjects (from 0 to 23%). This large variability is explained by methodological aspects, problems in assessing CCSVI, and differences among clinical series. It is urgent to perform appropriate epidemiological studies to define the possible relationship between CCSVI and MS.