^CLINICAL INVESTIGATION —————————————————————————— ^
Transvascular Autonomic Modulation: A Modified Balloon Angioplasty Technique for the Treatment of Autonomic
Dysfunction in Multiple Sclerosis Patients
Michael Arata, MD, and Zohara Sternberg, PhD
Synergy Health Concepts, Newport Beach, California, USA.
: To describe the use of transvascular autonomic modulation (TVAM) to improve cardiovascular autonomic nervous system (ANS) dysfunction in multiple sclerosis (MS) patients, comparing the safety and efficacy of this modified technique with traditional balloon angioplasty.
Methods: Twenty-one MS patients (11 men; mean age 48.7613.0 years) who presented with symptoms of cardiovascular ANS dysfunction underwent TVAM. These patients were compared with age/sex-matched MS patients (10 men; 49.3611.1 years) in the same stages of the disease who presented with chronic cerebrospinal venous insufficiency (CCSVI) and who underwent venous balloon angioplasty. TVAM involved the coupling of balloon angioplasty of the internal jugular veins with the application of external manual ompression and dilation of the azygos and renal veins; unlike traditional angioplasty for
CCSVI, which treats only abnormal veins (50% stenosis or static valve), all targeted vessels were treated with TVAM regardless of the presence of an abnormality. The effect of TVAM on ANS function was indicated by determining heart rate variability based on the electrocardiographic R-R interval lengths using vector analysis to derive the mean circular
resultant (MCR) and the expiration/inspiration (E/I) ratio, the Valsalva ratio, and the 30:15 postural ratio at 24 hours after intervention.
Results: Left renal vein compression was common among the TVAM patients and resulted in 50% luminal compromise in 10 of 21 patients. Azygos vein abnormalities (a static valve) were identified in 5 patients. Overall, 18 patients met the diagnostic criteria for CCSVI with at least one lesion .50%, but only 10 lesions were considered treatable by traditional
balloon angioplasty. After intervention, the R-R interval values, including the 30:15 postural ratio (p¼0.01), the MCR (p¼0.1), and E/I ratio (p¼0.1), were higher for the TVAM patients compared to the control group. The safety profile of the TVAM procedure was similar to that of traditional balloon angioplasty.
Conclusion: The combination of balloon angioplasty of anatomically normal veins coupled with external compression during dilation of these veins can improve indicators of ANS dysfunction. The safety and efficacy of TVAM in MS patients observed in this pilot study is encouraging, paving the way for the treatment of dysautonomia in pathological states other than MS. Further studies should investigate TVAM in a larger MS cohort.
J Endovasc Ther. 2014;21:417–428
Corresponding author: Michael Arata, MD, Synergy Health Concepts, 4501 Birch Street, Newport Beach, CA 92660
USA. E-mail: email@example.com
Chronic cerebrospinal venous insufficiency (CCSVI) in patients with multiple sclerosis (MS) has been described as hemodynamic disturbances of the central nervous system (CNS) drainage pathway owing to obstructing lesions of the extracranial veins, particularly the internal jugular veins (IJVs) and the azygos vein, leading to venous hypertension
and subsequent disruption of the blood-brain barrier integrity, initiating inflammatory processes. 1,2 In the face of IJV occlusion and suboptimal blood drainage, this function is then carried out by the collateral network. 3 In addition, the obstructing lesions are thought to lead to cerebral venous outflow resistance4 and to reduced cerebral blood flow and
perfusion.5 These altered hydrodynamics can in turn impair blood flow from the brain to the heart6 and reduce CSF net flow.7 The levels of these anomalies have been shown to correlate with the severity of the obstructive lesions.5,7
Zamboni et al.1,8 initially described the features of CCSVI based on Doppler findings. However, due to differences in the set of accepted criteria and the method of measurement, subsequent studies have been inconclusive in establishing a relationship between extracranial venous obstruction or reflux and MS manifestations.9,10 A study by Zaharchuk et al.11 demonstrated extra-jugular collateral drainage as a hemodynamic feature present in the majority of MS patients they studied.
Magnetic resonance venography (MRV) identified more collaterals as compared to contrast venography (CV). The two methods also differed in that the presence of collaterals by CV correlated with the severity of IJV obstruction, 11 whereas MRV depiction of collaterals was not dependent on parent vessel obstruction, suggesting that collateral flow seen in these patients arises from factor(s) other than IJV obstruction. Increased collaterals or relative increase in extra-jugular flow is a hemodynamic feature described in MS and is not commonly seen in normal subjects.
More recently, Allegra and Antegnani12 introduced the ‘‘morphological hemodynamic map,’’ which is based on the accumulated data on morphological venous anomalies and hemodynamic data derived from echo color Doppler. The map uses various symbols and terminologies to provide a more graded view of the hemodynamic anomalies of the venous
system, distinguishing venous narrowing due to compression and flattening from stenosis, which are subcategorized as morphological vs. hemodynamic stenosis (http://www.mem-net.it
). Furthermore, these investigators showed that the severity of venous anomalies is posture dependent and varies between the supine and erect positions.
Cardiovascular autonomic nervous system (ANS) dysfunction is an additional pathophysiology observed often in MS patients. ANS is composed of sympathetic and parasympathetic branches, with a respective role in the regulation of heart rate and blood pressure. 13,14 Dysfunction of both the sympathetic and parasympathetic ANS have been reported in MS patients, as indicated by reduced blood pressure at rest, in response to standing, and during sustained hand grip (sympathetic), as well as altered heart rate variability (HRV) and reduced R-R interval variance (parasympathetic).15–18 Abnormal HRV in MS patients correlates with both disease progression17 and with the degree of physical disability,19 whereas the abnormalities in sympathetic activity correlate with MS disease activity.19 In fact, ANS function tests show better sensitivity to disease
progression than the expanded disability status scores.20 Therefore, improving cardiovascular ANS functional activities has the potential for reducing MS disease activity and the rate of disease progression.
Cardiovascular ANS dysfunction has been shown to influence other clinical parameters in MS patients, including fatigue, which has been correlated with HRV.21 In addition, reduced parasympathetic function is known to contribute to sleep disturbances, often reported by MS patients.22 Furthermore, depression, which is a common MS clinical presentation,23 is associated with reduced HRV,24 fatigue, and MS disease severity.25 Accumulated data suggest that improving ANS function will likely lead to reductions in depression, fatigue, and sleep disturbances and a better quality of life for MS patients.
Based on CCSVI theory, endovascular repair, primarily balloon angioplasty of the venous lesions, has been studied as a
potential therapeutic modality for MS, with a documented safety profile.26–28 In a recent study we showed that balloon angioplasty and its modifications correct blood pressure deviation in CCSVI-positive MS patients.29 Since cardiovascular ANS function regulates blood pressure,13 alterations in this variable after angioplasty suggest that this intervention may beneficially influence the function of this system. In addition, venous balloon angioplasty is associated with a reduction in
the annual relapse rate, with a trend toward fewer T2 lesions,30 as well as improvements in physical and cognitive function.30,31 These results were confirmed in a 2-year follow-up study showing the beneficial effects of balloon angioplasty on reducing the rates of disease progression and MS clinical relapse.32 These improvements are consistent with the role of the cardiovascular ANS regulating immune system and processes involved in inflammation and neurodegeneration.33–35 Venous balloon angioplasty has also been shown to improve the quality of life in MS patients as indicated by reducing perception of fatigue and improving thermoregulation,36 parameters known to be controlled by ANS.37 These studies collectively suggest that the treatment effects of balloon angioplasty may be autonomic in nature rather than one of relief of venous flow obstruction.38 This conclusion is consistent with the observations in our own clinical practice where ~91% of patients who present with 50% IJV occlusion also exhibit three or more symptoms of
dysautonomia.29 The coexistence of CCSVI and ANS dysfunction suggests an association between the two phenomena.
Most intriguing, ~50% of MS patients do not have IJV stenosis but rather compression or flattening of the IJVs,12 conditions that could not be corrected by balloon angioplasty, further strengthening the notion that relief of venous flow obstruction is not the cause of the observed clinical benefits post venous angioplasty. The venous balloon angioplasty autonomic effects are consistent with the reported clinical benefits of vagal nerve stimulation in MS patients and its potential
as a novel therapeutic modality.39 Although objective tests for ANS dysfunction are broadly available, these tests are
neither typically part of routine clinical practice nor have they been utilized in any of the published studies evaluating CCSVI. Based on the involvement of cardiovascular ANS dysfunction in the pathophysiology of MS and angioplasty-induced improvement in the parameters controlled by this system, we propose extending the angioplasty procedure beyond dilation of obstructing lesions. Drawing on the physiological basis of renal denervation as a theoretical model, with its potential for transvascular augmentation of periadventitial autonomic fibers as an alternate route for modulating ANS function,40,41
we have modified Zamboni’s technique to expand the ability of angioplasty to better stimulate ANS function. In a technique we call transvascular autonomic modulation (TVAM), we include the delivery of mechanical energy to the periadventitial fibers associated with the IJVs, azygos vein, and renal veins during balloon dilation. In this pilot study, we detail the technique of TVAM and compare the safety of this approach with traditional balloon angioplasty in MS patients. Changes in HRV are used as indicators for the efficacy of the two techniques in modulating and improving cardiovascular
Study Design and Patient Samples
A matched-pairs pilot study was performed to compare TVAM to traditional balloon angioplasty of the bilateral internal jugular, azygos, and left renal veins using the Zamboni technique in MS patients. Traditional angioplasty involves dilation of only abnormal veins, which were defined by Zamboni et al.42 as a compromise in luminal diameter by either a 50% stenosis or by a static valve.
TVAM deviates from traditional angioplasty in that all targeted vessels were treated regardless of the presence or absence of an abnormality. The effect on ANS function was indicated by determining the changes in the electrocardiographic R-R interval during deep breathing, Valsalva maneuver, and postural change at 24 hours post intervention.
Twenty-one consecutive patients (11 men; mean age 48.7613.0 years) with MS [10 relapsing remitting (RR), 5 secondary progressive (SP), and 6 primary progressive (PP)] presenting with symptoms of cardiovascular ANS dysfunction were offered TVAM. These patients were compared with 21 age and gender-matched patients (10 men; 49.3611.1 years) with MS (10 RR, 5 SP, and 6 PP) who had the traditional BA procedure for CCSVI.
Patients with hypercoagulable state and pregnant patients were excluded from the study.
All patients gave written informed consent before the procedure. Demographics of the two groups are depicted in Table 1. All patients underwent magnetic resonance venography (MRV) with a Siemens 3T TRIO scanner (Siemens Medical Solutions, Malvern, PA, USA) to define anatomy and confirm vessel patency using a 2D time-of-flight protocol and gadolinium-enhanced 3D MRV of the neck.
Balloon Angioplasty and TVAM
All invasive procedures were performed with light sedation at an outpatient vascular center. Diagnostic venography was performed per the method of Zamboni et al.,42 which included interrogation of the bilateral IJVs, azygos, and left renal veins. Abnormalities of the IJVs at the level of the valve were characterized as extrinsic compression or flattening (Fig. 1), which were considered unlikely to respond to dilation. Collateral drainage was also noted when present.
Intravascular ultrasound (IVUS) evaluation (Visions PV 018; Volcano Corporation, San Diego, CA, USA) of each vessel was undertaken following venography to measure the target vessel areas for optimal balloon sizing and for enhanced morphological assessment at the valvular level. Kevlar balloons (Bard Peripheral Vascular, Tempe, AZ, USA) were sized to overdilate each target vessel by 10% to 25% of the IVUS measured area.
In TVAM, jugular vein dilation was carried out at the level of the valve using IVUS as the localizing instrument. In the jugulars, the treatment site was slightly more cephalad when using IVUS (Fig. 2) compared to venographic depiction of the valve. TVAM involved the coupling of balloon dilation of the IJVs with the application of external manual compression
and dilation of the azygos and renal veins. Maximum balloon pressure was held for 3 minutes, similar to traditional angioplasty.
Vessels were treated sequentially starting with the left jugular followed by the right jugular, azygous, and finally the left renal vein. Compression was applied during the initial 30 seconds of jugular balloon inflation
Imaging Findings in the TVAM Group Left renal vein compression, which was common among the TVAM patients (8/21),
contributed to 50% luminal compromise in 10 of 21 patients (Table 2). Azygos vein abnormalities were also identified in 5
patients who exhibited a static valve. Overall, 18 patients (Table 3) met the diagnostic criteria for CCSVI with at least one lesion .50%. Among the 21 patients, 10 had treatable lesions, whereas 11 demonstrated compressive lesions unsuitable for treatment with angioplasty. All patients demonstrated abnormal collateral drainage.
Figure 2 ^ IVUS imaging first localizes the valve, typically above the clavicle. Then a metallic hemostat placed on the surface of the neck allows fluoroscopic localization of the IVUS probe at the site of balloon dilation. External manual compression is applied over the jugular segment being dilated.
Effect of Intervention on R-R Interval Baseline MCR did not differ between the TVAM and control groups (Table 4, Fig. 3A).
Post-intervention, the MCR was higher by an average of 30.4% in the TVAM group relative to baseline (3.260.4 vs. 2.560.5, p¼0.11) and 19.4% higher than post-intervention MCR values in the control group (3.260.4 vs.2.760.4, p¼0.18). In the control group, MCR increased 15.6% post intervention relative to baseline (p¼0.52). Furthermore, 100% of TVAM and 100% of controls had baseline and post-intervention MCR values below the age-matched normal ranges (31.9 to 117).45
The baseline E/I ratio (Table 4, Fig. 3B) did not differ between the TVAM and control groups. Post-intervention, the E/I ratio was higher by an average of 1.8% in the TVAM group relative to baseline (1.1160.01 vs. 1.0960.00, p¼0.39) and 3.7% higher than post-intervention E/I ratio in the control group (1.1160.0 vs. 1.0760.0, p¼0.10). In the control group, the post-intervention E/I ratio was 1.8% lower relative to baseline (p¼0.41).
Internal Jugular Vein Abnormalities in the TVAM and Control Groups
Right Left Bilateral Stenosis TVAM 1 1 0 Control 4 2 0
Valve TVAM 16 14 10 Control 12 13 7
No obstructionTVAM 4 6 1 Control 5 6 0
TABLE 4 onwards see paper
No periprocedural adverse events occurred in either group; specifically, no evidence of vascular injury was identified. Mild headache was a common side effect occurring in 52% of the TVAM group (Table 5). Mild neck pain, chest pain, access site pain, and mild dizziness were noted in the TVAM group. All side effects resolved within 72 hours, requiring no
We studied the clinical safety of TVAM and its efficacy in improving ANS dysfunction, comparing this modified technique with traditional balloon angioplasty. To our knowledge, no other study has reported therapeutic intervention in MS patients with ANS dysfunction. With the validity of CCSVI vascular selection criteria in dispute and the assumption that the
treatment response may be autonomic in nature, we selected patients based on autonomic abnormalities rather than vascular abnormalities. We report that TVAM does not result in an increased risk as evidenced by the absence of significant adverse events and the transiency of side effects, which were mild in nature. Compared to the traditional balloon angioplasty procedure, TVAM improved most significantly the R-R interval. Major improvement were observed in MCR and the 30:15 postural ratio, producing 30.4% and 69.2%, respectively, improvement above the values associated with tradition venous balloon angioplasty. MCR computed by vector analysis is resistant to ectopic beats and is not affected by intrinsic
heart rate as the E/I ratio is; thus, it is a preferred method for the assessment of ANS function. Although the sympathetic nervous system may affect these measures, R-R interval variations are known to be influenced mainly by parasympathetic activity.48 One plausible mechanism by which balloon angioplasty improves cardiovascular ANS function may entail alterations in the activities of high pressure arterial baroreceptors involved in the assessment of central venous pressure.49 The increase in central venous pressure is likely to be more significant after the TVAM procedure, which involves higher
mechanical pressure in multiple venous systems as compared to the traditional balloon angioplasty. However, peripheral venous distension has been shown to activate sympathetic function, independent of changes in volume.50 An additional mechanism may be direct balloon angioplasty stimulation of the vagus nerve. It is known that IJVs and azygos veins
run in parallel and adjacent to the vagus nerve, with intersection points between the veins and the nerve. In this scenario, venous balloon angioplasty could stimulate the vagus nerve via the intersection points. However, there exists great interindividual variability in the pattern and the number of the intersection points, which can in turn dictate the extent of
balloon angioplasty stimulation of the vagus nerve (personal communications).
Nevertheless, other factors have been shown to contribute to the beneficial effects of venous angioplasty, among them an increase in cerebrospinal fluid (CSF) flow due to improvement in venous drainage.51 The four choroid plexuses are known as major organs in CSF production/secretion. In addition, CSF resorption into the bloodstream takes place through arachnoid granulations and lymphatics associated with extracranial segments of the cranial nerves. A dynamic secretion and
resorption of CSF is required to maintain intracranial pressure equilibria. A reduction in CSF production by the choroid plexus can contribute to reduced CSF flow. The choroid plexus receives both adrenergic and cholinergic innervation,52 suggesting neurogenic regulation of CSF production. Alteration in the activity of the adrenergic and cholinergic systems can affect choroid plexus blood flow, in turn influencing CSF production.53
Other factors contributing to CSF flow are the systolic phase arterial wave derived from cardiac cycles, the cyclic changes derived from the respiratory rhythm, and the vasomotor waves, or Traube-Herring Mayer (THM) waves that are cyclic changes in arterial blood pressure brought about by oscillations in arterial baroreceptors.54 The frequency and
peak occurrence of these waves depend on the function of both the sympathetic and parasympathetic ANS.54
MS patients show baroreflex dysfunction, indicated by reduced systolic blood pressure oscillations and reduced R-R interval oscillations in response to baroreceptor stimulation. 15 These anomalies can reduce the THM waves and CSF flow. In agreement with these results, comparison of blood pressure between MS patients and age- and gendermatched
non-MS patients shows significantly lower resting arterial systolic blood pressure in the former group.16 Reduced arterial blood pressure can lead to reduced peak systolic arterial waves and a decrease in CSF flow. Furthermore, it is thought that cerebral hypoperfusion stems from venous outflow obstructions5 and that venous balloon angioplasty corrects this hypoperfusion, increasing both the arterial and venous blood flow.55 In a recent review,38 we have described mechanisms
by which ANS dysfunction can bring about reduced arterial blood pressure and venous tone, leading to reduced cerebral
blood flow and perfusion. Our conclusion on the role of ANS function in regulating cerebral blood flow is in agreement
with that of D’Haeseleer et al.,56 who argued that the reduced cerebral blood flow is the result of reduced arterial blood flow rather than venous outflow obstructions. Similar conclusion was drawn by Monti et al.,57 who observed differences in cerebral venous outflow between MS patients and healthy controls using color Doppler sonography. Our results and those of others support the position that extra-jugular flow is pathophysiological in MS patients and is independent of
Although the results of this study are encouraging and may have far reaching implications for the future care of patients
suffering from ANS dysfunction, we do not have long-term data on TVAM patients and so do not know whether TVAM-induced significant changes in R-R intervals translate to an improved quality of life above what would be expected after traditional angioplasty. The lack of follow-up is owing to the long distances that these patients often travel to the clinic in search of treatment.
Furthermore, we have performed a combination of IJV, azygos, and left renal dilation.
The contribution of each of the three vascular interventions to the improvement of ANS dysfunction is unknown. Lastly, due to the small sample size, we could not stratify patients based on gender and disease stage.
The improved R-R intervals post TVAM achieved in the current study, combined with the results of our recent study showing
arterial blood pressure increase post venous angioplasty in MS patients with below-normal baseline pressure readings,29 strengthen the notion that angioplasty exerts beneficial effects by improving ANS function. The safety of this modified procedure, coupled with the efficacy observed in this pilot study, suggests its utility in improving symptoms of ANS
dysfunction. This modified technique could be further applied in other autoimmune and neurological diseases where dysautonomia plays a role in disease pathophysiology.
Nevertheless, one should note that the long-term effects of cerebral venous distension are currently unknown. One cannot
exclude the possibility that the increase in vagal activity post angioplasty may further disturb the autonomic balance in selected MS patients who initially present with reduced sympathetic ANS function. Additional study and replication of these results are required.
Acknowledgments: The authors thank Prof. Bernhard Schaller for the intellectual input and Frances DeBarge-Igoe
for technical assistance in conducting autonomic function tests.
REFERENCES See paper removed from post
Sections & Spacing editted many times in an attempt to make the paper easier to read. See Sharon's link for whole paper.
Mark Walker - Oxfordshire, England. Retired Industrial Pharmacist. 24 years of study about MS.