Rationale and preliminary results ...... Doc to text

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Rationale and preliminary results ...... Doc to text

Postby CureOrBust » Tue Aug 25, 2009 6:03 am

The preliminary results paper by Zamboni is a scanned document, and therefore cannot be searched through or easily quoted, so I recently ran the pages into an on-line OCR site, and got the following. I thought others might find it of some use.

NB: I have not proof read the pages, they are literally full of mistakes.

Page 3 wrote:
Rationale and preliminary results of endovascular treatment of multiple sclerosis, the liberation procedure
P Zamboni, R Galeotti, E Menegatti, AM Malagoni, F Mascoli, S Dall'Ara,
I Bartolomei, F Salvl


Multiple sclerosis is an inflammatory, demyelinating disease of the central nervous system of unknown pathogenesis; it is considered to be autoimmune in nature.^1-2 It is the most common disease causing disability in young people. The clinical course is usually classified as relopsing remitting [characterized by acute exacerbations of the disease followed by complete or partial recovery], secondary progressive [characterized by progressive deterioration of neurologic function after several years of relapsing remitting course), and primary progressive (characterized by a progressive clinical course starting from the beginning).^3

Magnetic resonance venography^4-7 and postmortem studies^8 demonstrated a topographic correspondence between multiple sclerosis plaques and the cerebral venous system. Histologic examination of the involved veins reveals unequivocally the presence of characteristic signs of impaired venous drainage, such as periverrous iron deposits and fibrin cuffs, particular to chronic venous insufficiency.^9

All of these elements convinced the current authors to investigate Doppler cerebral venous hemodynamics.^10 Cerebrospinal venous return in multiple sclerosis patients was found to be anomalous with respect to controls (including healthy subjects matched for age and gender, patients affected by other neurologic diseases, and healthy subjects older than the median age of onset of multiple sclerosis).^11-13 Venous hemodynamics was investigated by combining cxtracranial echo-colour—Doppler of the internal jugular veins — vertebral veins. Trans-cranial colour—Doppler sonography was used for studying the deep cerebral veins, focus- ing on the detection of live anomalous parameters, which are absent in normal subjects (Table 1)^10

Sensitivity, specificity, positive predictive value and negative predictive value were tested for significance by the two—sided Fisher exact test, by comparing the gold standard diagnostic assessment, represented by clinical and magnetic resonance imaging revised McDonald criteria for diagnosis of multiple sclerosis, with the proposed echo-colour—Doppler-trans-cranial colour-Doppler sonography protocol.

Page 4 wrote:Table 1. Echo—colour-Doppler-trans-cranial colour-Doppler sonographv parameters of abnormal cerebral venous outflow in multiple sclerosis

Echo-colour-Doppler- Multiple Control Sensitivity Specificity p
{gg trans-cranial colour- sclerosis (%] populations (%l Positive predictive value-
et Doppler sonographv Negative predictive value
• parameters [95% Cl]
1. Spontaneous reflux 70% 0% 100% [95-100] < 0.0001
constantly present in the 84% [79-89]
internal jugular veins and 70% (60-78]
or vertebral veins in both 100% [98-TDD]
sitting and supine posture

2. Flefl us propagated 50% 0% 100% [93-100] < 0.0001
upward to the deep 77% [71432}
cerebral veins 50% (41-60]
100% [93-100}
3-. High resolution Bmode 28% 0.5% 97% {83-99) < 0.0001
evidence of proximal 69% (63-75)
. internal jugular vein 2% (10-37)
stenosies 99% [97-100]

4. Flow not Doppler 32% 0.E% 97% [85-99} < 0.0001
detectable in the 70% [64-75)
internal jugular veins 32% (23-42)
and / or vertebral veins 99% {97-100]
despite numerous deep inspirations.
5. UV cross-sectional 58% 12% 74% 053-83] < 0..0001
area in sitting posture 76% [70-82]
than in supine posture 56% {46-65)

Conclusive Analysis 100% 0% 100% < 0.0001
Two or more Echo- 100%
*5 _ colour-Dopp|er—trans- 100%
cranial colour—0oppler 100%
Sonographv positive parameters

Venography and 'intent to treat' procedures

Diagnosis of suspicious abnormal extracranial cerebral venous outflow must fulfil at least two of the five criteria listed in Table 1 and is taken as an indication approved by the Ethical Committee of the current authors’ hospital to continue the study using selective venography in all suspected subjects

Selective venography demonstrates that anomalies in Doppler venous hemodynarnics are due to multiple significant extracranial venous stenosis, localized at the cervical, thoracic, and less commonly abdominal level of the principal cerebrospinal venous segments. In a further control population with negative ultrasound results, which includes subjects not affected by neurologic diseases who underwent venography for other reasons, stenotic patterns were never demonstrated in the internal jugular veins, azygous, and lumbar territory.^12 In particular. the azygous vein in the multiple sclerosis group was affected in 96% of cases. Most eases involved mernbranous obstructions

Page 5 wrote:of the junction with the superior vena cava, or, less frequently, twisting, Septums and atresias as can be seen in the x—rays in Figure 1.

In 12 Cases the Azygous system presented stenosies at several points up to even atresia or agenesis of the lumbar plexuses (l8(’lb). As for the jugular veins, they were found to be stenosed unilaterally or bnlaterally in 59 out of 65 cases (91%). The stenosies were frequently annulus (Fig. 2) and septum, followed by atresias, and rarely by ageneses twisting was observed, sometimes coexistent valvular anomalies and bone compression were also observed. Interestingly, the distribution of the extracranial venous stenosies significantly influences the clinical course as well as the onset of symptoms.

Selective phlebography enabled the current authors to perform a first treatment of the identified venous obstructive lesion at the time of the diagnostic evaluation by the means of balloon angioplasty, the so called liberation procedure. Twisting of the azygous vein in nonresponders has been subsequently treated by stent insertion.

Intent to treat procedures at the time of diagnostic phlebography was performed in 77 consecutive cases. The ethical committee approved this study in February 2007.

Figure 1. (Top left) Preoperative venography of the azygous vein affected by combination of membraneous obstruction of the outlet into the superior vena cava and proximal atresia, with reflux extended downward to the emiazygous vein. (Top right) Postoperative result with reflux disappearance. (Bottom left) Preoperative venography of azygous vein affected by twisting. [Bottom right) Postoperative result after angioplasty.

Page 6 wrote:Figure 2. (a) Closed stenosis of the internal jugular vein. [bl The same ease after balloon angloplasty.

Results of venous endovascular procedures in multiple sclerosis

All procedures were performed in day hospital and under local anesthesia. The procedure was well tolerated. Post—procedura1 observation was carried out at 4 hours and the patients were discharged with a compressive dressing on the left femoral vein, I the preferred site of vascular access. The dressing could be removed the day after the procedure. A prophylactic dose of low-molecular-weight heparin is strongly recommended for the subsequent 3 weeks."* No operative and postoperative complications were registered, including vessel rupture, thrombosis, or side effects caused by the contrast media. Minor hemorrhages with hematomas in the site of vascular access were occasionally seen.

Patients who underwent a cerebrospinal venous e-ndovascular procedure were followed up by means of a validated clinical test for investigating the motility of upper and lower extremities as well as the cognitive function (the so-called multiple sclerosis limctional composite MSFC), the expanded disability status scale, EDSS, and a recognized QoL questionnaire MSQoL-54, in addition to clinical and magnetic resonance imaging measure. The venous potency and its relationship with the clinical course was also evaluated.

Clinical results
Acute attack in relapsing remltting patients
About 85% of multiple sclerosis cases begin with relapsing rernitting disease; this evolves through recurrent exacerbations with subsequent full or partial recovery

Page 7 wrote:before entering the progressive phase, in which any recovery of function is rare. Relapse events average about 1.1 per year early in the disease course.^21

Relapse in the relapsing remitting clinical course is unpredictable and clinically manifests with the impairment of one or more neurologic functions. Acute attacks are usually managed with high—dose corticosteroids for 5 days. Relapse is associated with Magagnetic resonance imaging evidence of inflammation.

In Emergency, 18 consecutive patients were treated without use of corticosteroids, using the endovascular techniques described earlier. A total recovery time ranging from 4 hours to 4 days from endovascular treatment was observed. This was the best evidence that venous obstructions play a causative role in the complex pathogenesis of multiple sclerosis. This group of patients was followed up together with the other patients of the relapsin remittin roup treated electively. Outcome measures will be described next.

Preliminary results in relapsing remitting patients
A total of 51 patients were treated with the nelapsing remitting clinical course, 18 in Emergency for acute attack as described earlier, and 33 electivcly. Moreover 13 and 11 patients were treated, respectively, with secondary progressive and primary progressive clinical courses. This chapter herein refers exclusively to results obtained on the relapsing remitting patients. The outcome measures are those usually utilized in clinical trials evaluating multiple sclerosis treatment:

* Rate of relapse in the year subsequent to the endovascular procedure as compared to the rate registered in the same population in the preceding yer (Fig. 3]. The probability of acute attack decreased more than -4—fold after the endovascular ` 5.* treatment, OR = 4.4 [95% CI 1.5-1.3, p = 0.0072);

* MSFC Z-score, expressing the score of lower limb motility, plus upper limb motility, plus cognitive performance.^15-16 It was significantly improved 1 and 6 months postoperatively as can be easily seen in Figure 4;

Figure 3. Signlncant reduction ofthe relapse rate in the tirst year after venous balloon angioplasty.

Page 8 wrote:* QoL, by using a validated 54~item questionnaire focused on multiple sclerosis^18
The score was significantly increased by about 30%, as shown in Figure 5, in the composite parts concerning physical and mental status. QoL improvement is confirmed by the dramatic improvement registered in chronic Fatigue. The latter aspect was also measured separately, registering tl reduction of 50% on the validated fatigue scale^17 (p < 0.01). It is stressed that chronic fatigue is one of the more disabling symptoms in multiple sclerosis, and is actually orphan of any effective treatment;

* A follow-up MRI has not been carried out.

<Multiple Sclerosis Functional Composite>

Figure 4. Z—score mean ±SD of the multiple sclerosis functional composite at baseline and after the endovascular procedure (p < 0.05).

<Physical Health composite> <Mental Health composite>

Figure 5. QoL improvement after the endovascular procedure (mean ±SD, p < 0.05],

Endovascular results
Post-procedural cerebral venous outflow surveillance was performed at 1, 3, and 6 months, and subsequently on a 6-monthly basis, by means of the detection of the same echo-colour-Doppler-trans·-cranial colour—Dopp1er parameters shown in Table 1. Vascular ultrasonography was additionally performed in case of clinical relapse and/or clinical worsening. Detection of altered hemodynamics would represent an indication for venogtaphy. The endovascular results presented here are divided according to venous segment.

Page 9 wrote:Procedures on azygous vein
Membranous obstruction of the outlet of the azygous vein into the superior vena cava can be successfully managed by simple balloon dilation. This procedure was performed in 38 out of 77 cases, and no recurrence was recorded at l year. Twisting of the azygous vein was observed in seven out of 77 cases that were also treated by balloon angioplasty. The latter recurred in two cases (29%), which were subsequently treated by stent insertion with a 6-month patency (Fig. 6).

The same anti—platelet protocol is used in balloon angioplasty and stenting at the level of the coronary artery, in addition to administration of low-molecular weight heparin^23.

<Figure 6>

Figure 6. (a) Twisting of the azygous vein not responding to simple balloon angioplasty, causing reflux downward and inward to the spinal cord. (b) Successful stent insertion at the azygous arch with elimination of twisted stenosis and reflux.

Procedures on internal jugular veins
In contrast, overall intemal jugular vein stenosies were present in 94 of 144 patients and intemal jugular vein patency was achieved at l year in 66 of 94 patients (70%).

All patients with restenosis corresponded to those who manifested relapses in the year subsequent to the endovascular treatment (Fig. 3). Syrnptomatic and asymptomatic restenosies were again treated with balloon dilatation. However, no attempt at a stenting procedure was made in the absence of a dedicated device capable of preventing migration. This device would fit the particular morphology of the intemal jugular vein, similar to a upside down milk bottle, and, finally avoid protrusion into the brachiocephalic trunk.

Page 10 wrote:Summary

  • Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system of unknown pathogenesis. It is considered to be autoimmune in nature and is the most common disease causing disability in young people.
  • In multiple sclerosis the plaques are venocentric. with some histologic aspects particular to chronic venous disease. The Doppler hemodynamics of cerebrospinal venous return in multiple sclerosis patients is consistently altered.
  • Investigation of multiple sclerosis patients with Doppler anomalies of cerebral venous return by means of venography demonstrates multiple stenosies. Affecting the principal extracranial venous segments at the thoracic, cervical and sometimes abdominal level.
  • The majority of venous stenosies are treatable at the time of venography with conventional. minimally invasive. and safe endovascular techniques. the so called liberation procedure.
  • Endovascular treatment, with the limitation of a short follow up. Improves significantly the validated outcome measure in multiple sclerosis. including the multiple sclerosis functional compositum score and QoL assessment. In addition. it reduces by more than four times the relapse rate in the year subsequent to the procedure, as compared to the preceding year.
  • Treatment ofthe azygous vein and of the jugular vein showed a 1-year patency of 95% and 70%, respectively.
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