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Appendix e-1:

LENGTH OF EXAM: 45 minutes

EQUIPMENT: Esaote-Biosound MyLabGOLD25 equipped with 2.5 and 7.5-10 MHz transducers. Motorized chair capable of tilting from 90° to 0°.

We used a phantom (GAMMEX Model 1430GS Mini Doppler Flow System, Middleton, WI, USA) for calibration, which was conducted every 6 months. The quality control procedure with the phantom examines the Doppler for signal sensitivity, color flow sensitivity, flow sensitivity at depth, color flow B-mode image congruency, directional discrimination, accuracy of flow velocity readout and sample gate positioning accuracy.

CONTRAINDICATIONS AND LIMITATIONS

Contraindications for echo-color Doppler assessment in the Combined Trans-cranial and Extra-cranial Venous Doppler(CTEVD) study were few; however, some limitations existed and may included the following:

  • Subjects with short, thick, muscular necks
  • Subjects who have had recent surgery (penetration and visualization may be limited secondary to the presence of edema, hematoma, surgical staples, dressings)
  • History of chronic obstructive pulmonary disease (COPD) and arthritic necks (may not be able to lie flat)
  • Subjects who are unable to cooperate with the evaluation due to changes in mental status (advanced dementia, advanced Alzheimer’s, mental retardation, etc.) and involuntary movement
  • Subjects who have a thick skull bone, limiting the acoustic window

ULTRASOUND GEL

A water-soluble, hypoallergenic, medium density ultrasound gel was used for sound transmission. Gel was maintained at a warm temperature in a Thermasonic Gel Warmer.

SPECIFIC DOPPLER PARAMETERS:

Scanning protocol listed here is by VH criteria. Scanning protocol was completed by position and side for time efficiency and subject comfort.

A minimum of two (2) minutes wait time was requiredfor change insubject position from upright to supine, to allow for circulatory adjustment.

Venous hemodynamic (VH) Criterion 1: Reflux in internal jugular veins (IJV’s) and/or vertebral veins (VV’s)

Definition: Reflux (backwards flow) present in the IJV and/or VV for greater than 0.88 seconds with the head at 90 and 0.

Probe: Esaote Linear Array (LA332)

Positioning: VH criterion 1 was assessed in both upright (90°) and supine (0°) positions.

Technique used for upright position (90º) and supine position (0°):

  • Subject placed in upright position with head in neutral position looking straight ahead
  • Probe placed on left IJV in transverse plane with minimum pressure. Probe held at approximately 90° angle
  • With color Doppler, scanned from superior point (uppermost visible portion) of left IJV to subclavian vein in transverse plane. Pulse Repetition Frequency (PRF) adjusted to prevent aliasing, saturation and obliteration of color.
  • Repeated on right IJV
  • Probe placed on left VV in longitudinal plane. The section of interrogation was between C3-4, C4-5 or C5-6 (inter-vertebral) and extra-vertebral vein to subclavian vein.
  • Repeated on right VV

Above techniques repeated in supine position (0°)

Documentation:

With the above-described IJV technique, transverse left IJV/left carotid artery at mid and lower level of thyroid, right IJV/right carotid artery at mid and lower level of thyroid and additional images to demonstrate reflux, if applicable, were documented. When reflux was present, documentation with a video clip or spectral analysis was performed to demonstrate the length of reflux time.

With the above-described VV technique, the left and right inter-vertebral veins and extra-vertebral veins were documented. When reflux was present, use of spectral analysis in triplex mode across both VV and the vertebral artery (VA) was utilized to document direction of flow.

Fulfillment of VH criterion 1:

IJV is located slightly anterior then lateral and adjacent to the carotid artery. Blood flow in the IJV travels downward away from the brain while the carotid flows upward towards the brain. In color Doppler this is depicted by opposing colors of red and blue. If reflux is present, the color will appear the same. That is, the IJV and carotid will both show as blue or both show as red, indicating flow in the same direction.

VV is located adjacent to the VA or can spiral around the VA. Blood flow in the VV travels downward while the VA flows towards the brain. When reflux is present, the color will appear the same. Due to curvature of the spine and tortuosity of the VV, color flow may require verification with spectral analysis. Reflux time measurement on the spectral waveform will document reflux time greater than 0.88 seconds.

Pathology Definition:

Reflux is flow directed toward the brain for a duration of >0.88 sec, in the IJVs and/or VV`s. To be denoted as positive, reflux must be noted in both supine andupright positions in the same vein/same side.

VH Criterion 2: Reflux propagated upward in the deep cerebral veins (DCV’s) and/or from the white matter (WM) to the subcortical gray matter (SCGM)

Definition: Reflux (backwards flow) present in the DCV’s and/or from the WM to the SCGM for greater than 0.50 seconds. Internal cerebral veins, vein of Rosenthal and the Galen vein are the DCVs considered for color Doppler assessment

Probe: Esaote Phased Array (PA240)

Positioning: VH Criterion 2 is assessed in both the upright (90) and supine (0) positions.

Technique:

Subject placed in upright position (90º). Subject’s head is in neutral position, looking straight ahead.

  • Probe placed on left cheek, at the level of the condylar process of the mandible, anterior to the tragus, with approximately 40 posterior angle and 20 upward angle. Angles may require adjustment per subject dynamics.
  • With color Doppler, scanned DCV’s for directional information. Increase in breaths in/out through the nasal cavity may increase visibility of DCV’s.
  • Flow duration may be documented either by video clip or spectral analysis time measurement

Above technique repeated in supine position 0.

Documentation:

Color flow direction documented with the above DCV technique. Note made on image of respiration phase (inspiration or expiration) at the time the image is captured.

Fulfillment of VH criterion 2:

Reflux must be noted in one of the DCVs in either position.

Pathology Definition:

Reflux is noted as reverse flow for a duration of >0.5 seconds, in one of the DCVs, internal cerebral vein, basal vein of Rosenthal or the great vein of Galen in either the supine or upright position.

VHCriterion 3: High resolution B-mode evidence of proximal IJV stenosis and/or other B-mode anomalies

Definition of parameters for VH criterion 3:

  • Stenosis – Cross-sectional area (CSA) measurement of ≤3 mm2 .
  • Block – no color flow noted in vein, despite deep breaths
  • Paradox – vein wall not reacting to respiratory phase; non-compliant
  • Flap – thin linear echogenic structure extending from endothelial lining of vein wall
  • Septum – thin linear echogenic structure extending from endothelial lining of vein wall with attachment to vein wall at both ends. Septum may extend across vein to attach on opposing sides or attach on same side.
  • Web – multiple septae and/or flaps located in a cluster
  • Annulus – thickened vein wall, restricting vein from fully expanding with respiratory or positional changes

Probe: Esaote Linear Array (LA332)

Positioning: VH Criterion 3 is assessed in both the upright (90 ) and supine (0) positions.

Technique upright position (90º):

  • Subject positioned in the upright position (90º) with head in neutral position looking straight ahead
  • Probe placed on skin over left IJV in transverse plane with minimum pressure
  • In gray scale with ultrasound unit controls adjusted to obtain optimal image throughout, scanned from uppermost visible portion of left IJV to subclavian vein in transverse plane.
  • With probe positioned longitudinally, scanned from superior point of left IJV to subclavian vein.
  • In color Doppler, scanned from superior point of left IJV to subclavian vein in transverse plane to gauge the narrowest flow diameter of the IJV. At the narrowest flow diameter measured CSA. Adjustment of PRF was continuously required to ensure no over-saturation or under-saturation of flow state.
  • Utilized minimal probe pressure on skin
  • Repeated above technique on right IJV

Above techniques repeated in supine position (0º) for right and left IJV.

Documentation:

All visible portions of IJV were assessed with documentation at a minimum of two levels; upper thyroid level and mid-to-lower thyroid level in transverse plane in both color and gray scale. Documented visible length of the IJV in longitudinal plane. Additional images obtainedto demonstrate stenosis, block, flap, septum, web, paradox and/or annulus, if applicable. Documentation with video clip obtained when anomaly present. CSA measurement of each IJV imaged.

Fulfillment of VH criterion 3:

Criteria 3 fulfilled when any one of the B-mode anomalies is documented and/or stenosis present. B-mode anomalies refer to flap, septum, web, paradox and/or annulus.

Pathology Definition:

B-mode anomaly (i.e., flap, web, septum, annulus, paradox, block) noted in the lumen of the IJV and/or stenosis referenced as CSA ≤0.3 cm² denotes a positive finding.

VHCriterion 4: Flow not Doppler detectable in the IJVs and/or VVs despite numerous deep breaths

Definition: Flow not Doppler-detected as defined when both color Doppler and spectral analysis do not detect flow in the IJV and/or VV despite deep breaths, but neverusing the valsalva maneuver, utilizing optimal Doppler settings and angles.

Probe: Esaote Linear Array (LA332)

Positioning: VH Criterion 4 is assessed in both the upright (90) and supine (0) positions.

Technique used for IJVs in upright position (90º):

  • Subject positioned in the upright position (90º) with head in neutral position looking straight ahead.
  • Probe placed on skin over left IJV with minimum pressure
  • In color Doppler, scan from superior point of left IJV to subclavian vein in transverse plane to assess color flow in the IJV. Adjustment of PRF and wall filter required to assess low flow states In color Doppler, turn probe longitudinally, steer color box to enhance Doppler angles. Adjust PRF as needed for optimal imaging. If minimal or no flow noted, have subject take deep in/out breaths, but not valsalva.
  • Always using minimal probe pressure on skin
  • Repeat above technique for right IJV.

Technique used for VV in upright position (90º):

  • Subject positioned in upright position (90º) with head in neutral position looking straight ahead.
  • Probe placed on neck over left VV.
  • In color Doppler, scan from C3-4 to C5-6 level of left VV in longitudinal plane, document color flow in the VV. Steer color box to enhance Doppler angles. PRF and wall filter adjusted to assess slow flow states, as required.
  • If color flow not visible in VV, assessed with spectral analysis for verification.
  • Repeated above technique for right VV

Above techniques repeated in supine position (0º) for IJVs and VVs

Documentation:

Documented color flow in transverse and longitudinally of IJVs in both positions. Documented color flow in longitudinal plane of VV with spectral analysis, if required.

Fulfillment of VH criterion 4:

No flow detected in IJV and/or VV.

Pathology Definition:

Flow not Doppler-detectable in the IJVs and/or VVs despite multiple deep breaths. To be denoted as positive, lack of Doppler venous flow must be noted.

VHCriterion 5: Negative ΔCSA in the IJV

Definition: CSA is calculated by obtaining, in transverse plane, the width and anterior-posterior (AP) measurement of the vessel flow. The delta () CSA is calculated by subtracting the upright CSA from the supine CSA.

Probe: Esaote Linear Array (LA332)

Positioning: VHCriterion 5 is assessed in both the upright (90 ) and supine (0) positions.

Technique:

  • Positioned subject in upright position (90º) with head in neutral position looking straight ahead.
  • In color Doppler, scanned from superior point of left IJV to subclavian vein in transverse plane to gauge the narrowest flow diameter of the IJV. At the narrowest flow diameter, measured CSA. Mark placed on skin at the point of measurement. Adjustment of PRF was continuously required to ensure no over-saturation or under-saturation of flow state.
  • Minimal probe pressure used on neck
  • Repeat technique on right IJV
  • Positioned subject in supine position (0º) with head in neutral position looking straight ahead
  • In color Doppler, scanned in transverse plane over the marked site from the upright position. At this level, measured the CSA. Adjustment of PRF was continuously required to ensure no over-saturation or under-saturation of flow state with minimal probe pressure on skin
  • Repeated technique on right IJV

Documentation:

CSA measurement of both IJVs imaged, in both the upright and supine positions.

Fulfillment of VH criterion 5:

A negative ΔCSA value.

Pathology Definition:

The IJV is the predominant outflow pathway in the supine position, with VVs the predominant outflow pathway in the upright position. There is compliant reduction of the CSA between the IJV and VVs. IJVs are measured for CSA. A negative ΔCSA represents the loss of the normal postural control, denoting a positive finding.

CCSVISTATUS ASSESSMENT:

Each subject was assigned a total criteria VH score which was calculated by counting the number of criteria that subject fulfilled.

CCSVI positive:

A subject was considered CCSVI-positive if ≥2 VH criteria are fulfilled.

CCSVI negative:

A subject was considered CCSVI-negative if <2 VH criteria are fulfilled.

CCSVI borderline:

Subjects who were not assessed for some VH criterion, due to technical difficulty, were assumed not to have fulfilled that criterion. Subjects who fulfilled exactly one of the other 4 criteria and were not assessed on one VH criterion are classified CCSVI borderline.

CEREBRAL VENOUS DOPPLER WORKSHEET

Subject ID:
Date of Exam: / Time of Exam:
Vascular Tech:
Right / Left
IJV 90° / Width
Anterior-posterior (AP)
CSA mm²
Reflux
No flow detected (assumes block)
Stenosis
B mode anomaly / Annulus
Flap / Septum / Web
Paradox
Velocity
VV 90° / Reflux
No flow detected (assumes block)
Paradox
Phasic waveform
Velocity
IJV 0° / Width
Anterior-posterior (AP)
CSA mm²
Reflux
No flow detected (assumes block)
Stenosis
B mode anomaly / Annulus
Flap / Septum / Web
Paradox
Velocity
VV 0° / Reflux
No flow detected (assumes block)
Paradox
Phasic waveform
Velocity
IJV DELTA CSA mm²
III V / Diameter 90°
Diameter 0°
III V DELTA CSA diameter
+' Finding / NonDiagnostic
DCVs / Reflux 90º
Reflux 0º
SCGM / Reflux 90º
Reflux 0º
Not Assessed / Assessed / Positive
VH Criterion 1
VH Criterion 2
VH Criterion 3
VH Criterion 4
VH Criterion 5
Normal Study / Abnormal Study / Borderline Study / # of VH Criteria / Vascular Technologist