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DOI:10.2214/AJR.07.2851
AJR 2008; 190:966-971
© American Roentgen Ray Society

Original Research

Fluoroscopic Intralesional Injection with Pingyangmycin Lipiodol Emulsion for the Treatment of Orbital Venous Malformations

Yong Chen1, Yanhao Li1, Qiaohua Zhu1, Qingle Zeng1, Jianbo Zhao1, Xiaofeng He1 and Quelin Mei1

1 All authors: Department of Interventional Radiology, Nanfang Hospital, 1838 N Guangzhou Ave., Guangzhou, Guandong 510515, China.

Received July 10, 2007; accepted after revision October 27, 2007.

 
Address correspondence to C. Yong (zhqh2001gg{at}yahoo.com.cn).


Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
OBJECTIVE. The objective of our study was to evaluate the efficacy and safety of percutaneous intralesional injection under fluoroscopy with pingyangmycin Lipiodol emulsion (PLE) for the treatment of orbital venous malformations.

MATERIALS AND METHODS. This study is a retrospective analysis of 19 consecutive patients with distensible orbital venous malformations. Of the 19 patients, two had diffuse lesions. These patients presented with proptosis (n = 19), pain and orbital swelling (n = 11), reduction in visual acuity (n = 4), diplopia (n = 2), disk swelling (n = 5), and motility disturbance (n = 3).

RESULTS. All 19 patients underwent technically successful percutaneous intralesional PLE injection under fluoroscopy. Complete resolution of proptosis, swelling, and pain was achieved in 17 patients 3–9 months after the procedure. In the other two patients with diffuse lesions, light proptosis was still present after the first procedure. A second procedure was performed in these two patients, and the symptom disappeared 3 months later. All four patients with reduced visual acuity recovered their vision, and diplopia in two patients disappeared. Examinations of the fundus revealed normal findings in the five patients with preprocedural disk swelling. None of the patients presented with a motility disturbance after the procedure. Local swelling in the eyelid and epiphora were present for 1 month in one patient and disappeared after treatment. No other complications, including acute orbital compartment syndrome, were observed during follow-up periods. The mean follow-up was 23 months.

CONCLUSION. PLE sclerotherapy under fluoroscopic guidance is safe and effective for the treatment of orbital venous malformations and can be used as one of the treatment alternatives.

Keywords: fluoroscopic injection • orbital venous malformations • pingyangmycin Lipiodol emulsion • sclerotherapy


Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In 1999, a consensus statement about the terminology of orbital vascular malformations was published by the members of the Orbital Society [1]. Orbital vascular malformations are divided into three types: no flow, venous, and arterial. The cases in the present study are orbital venous malformations.

Currently, orbital venous malformations are treated in a multidisciplinary setting. As a key element of this collaborative approach, imaging-guided sclerotherapy through percutaneous injection of ethanol or other sclerosing agents was adopted to treat craniofacial and superficial orbital venous malformations [2–5]. However, aggressive sclerosants are not suitable for the treatment of lesions with deep orbital components [6]. Agents that can be used to treat this type of orbital venous malformations should thus bear safe, tolerable, and effective properties.

Pingyangmycin (PYM), the single component of bleomycin A5, is an anticancer agent that is refined from Streptomyces pingyangensis and shows a strong damage function to vascular endothelial cells. PYM alone or mixed with iodinated oil (pingyangmycin Lipiodol emulsion [PLE]) can be used to treat vascular anomalies as a sclerosing agent [7].

For another study [8] that we undertook, we obtained a series of data about the safety and efficacy of direct puncture injection with PLE in treating superficial venous malformations. Given the characteristics of PLE, beginning in April 2000, we used the method [8] to treat orbital venous malformations. In the present study, we describe our experience and evaluate the efficacy and safety of intralesional injection with PLE for the treatment of orbital venous malformations.


Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients and Evaluation
This is a retrospective study of 19 consecutive patients (10 males and nine females; age range, 8–34 years; mean age, 15 years) with distensible orbital venous malformations. These patients underwent percutaneous sclerotherapy with the use of a direct intralesional injection of PLE under fluoro scopy between April 2000 and April 2006. The interventional protocol was approved by the Nanfang Ethics Committee. In all cases, written informed consent was obtained from the patients before the procedures.

Distensibility was considered present when there was clinical or radiologic evidence of transient expansion with increased venous pres sure asso ciated with dependent positioning, the Valsalva maneuver, and coughing or by visualization of distention with increased venous pressure [1]. Orbital venous malformations were classified as superficial if they involved the periorbital skin, conjunctiva, or eyelid without expansion posterior to the equator of the globe. Deep orbital lesions were those located posterior to the equator of the globe without extraorbital involvement. Lesions with both superficial and deep orbital components were described as combined lesions [9]. All 19 patients had com bined orbital venous malformations.

Initial evaluation of all patients was composed of physical examination, recordings of case history, CT findings (LightSpeed 16, GE Healthcare), or MRI findings at 1.5 T (Magneton Vision Plus, Siemens Medical Solutions). When CT or MRI was performed, patients were in the prone position or the homonymy jugular vein was under com pression and these cases presented with forward displacement of one globe from 2 mm to approxi mately 8 mm more than the other globe (mean, 4.2 mm) (Fig. 1A). Eleven patients experienced pain and orbital swelling. Four noticed a reduction in visual acuity and two had diplopia. Examinations of the fundus revealed normal findings in 14 patients and disk swelling in five patients. A motility disturbance, restricted toward the lesion, was present in three patients. Of all the patients, four had recurrent cases previously treated with percutaneous local injection of PYM or urea alone in other hospitals.


Figure 1
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  		Fig. 1A —34-year-old woman with orbital venous malformation in right inferior orbit (patient 2 in Table 1). Photograph taken before procedure shows proptosis, swelling of lower lid, restricted motility, and dysraphism.

 
The locations of the orbital venous malformations were variable: four were in the upper inner quadrant; two, the lower inner quadrant; six, the upper outer quadrant; three, the lower outer quadrant; and two, superior part. Of the 19 patients, two had a diffuse lesion with involvement of the same-side temple (Table 1).


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  		TABLE 1: Clinical and Radiologic Features of Orbital Venous Malformations, Treatment, and Outcome

 

Procedure
The PLE in this study was prepared before the procedure as follows: 8 mg of PYM was dissolved in 3 mL of iopamidol (Iopamiron, Bracco) and was then mixed with emulsified iodized oil with a ratio of 1:1 [10]. The dosage of PYM varied from 0.05 to 0.2 mg/kg of body weight according our experience.

Half an hour before the procedure, 10 mg of diazepam (5 mg in patients < 10 years old) was administered IV for sedation. Orbital venography was performed before the procedure in all patients. The location for percutaneous direct puncture was the site of the lesion most protruding when patients were in a dependent position or the homonymy jugular vein was being compressed. The needle route was determined on the basis of CT or MRI findings. Percutaneous direct puncture was performed after sterilization of the ocular region and administration of local anesthetic (2% lidocaine). A 1.5-inch (3.8-cm) 25-gauge needle was used for the puncture. When reflux of venous blood was confirmed, contrast medium (iopamidol 300) was injected manually to obtain an orbital venogram to confirm the diagnosis, determine the draining venous system, and determine the extent and volume of the lesion.


Figure 2
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  		Fig. 1B —34-year-old woman with orbital venous malformation in right inferior orbit (patient 2 in Table 1). Photograph taken 5 days after procedure shows orbital swelling at its peak.

 


Figure 3
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  		Fig. 1C —34-year-old woman with orbital venous malformation in right inferior orbit (patient 2 in Table 1). Photograph taken 3 months after procedure shows proptosis and orbital swelling have decreased dramatically.

 
After the diagnosis of orbital venous malformations was confirmed and the point of the needle found intralesionally, a test injection of con trast agent was washed out before sclerosing agent was injected. Under simultaneous fluoro scopy, PLE was injected slowly to ensure that the sclerosing agent was confined solely to the lesions and the injection was stopped when the lesion was suffi ciently filled or when the PLE began to enter the draining veins. The amount of sclerosing agent injected was estimated by the initial amount of PLE minus that of the remaining amount. Patients were observed during the procedure and for at least 24 hours after the procedure for detection of early com plications. Systemic corticosteroids (dexam etha sone, 5–10 mg/d for 3–5 days) were administered to manage postprocedural orbital swelling, peri orbital swelling, or both. Nonsteroidal anti inflammatory agents were used for pain relief when necessary.

Definitions and Follow-Up
The effectiveness of sclerotherapy was assessed on the basis of the clinical findings and the radiologic findings of follow-up CT or MRI. In patients who did not present with proptosis or orbital regional swelling and who gained complete pain relief even under compression on the jugular vein, the procedure was considered to be effective. In patients who had partial symptomatic relief but still experienced minor symptoms when the homonymy jugular vein was compressed, the procedure was considered to be beneficial. In patients in whom there was no symptom improvement or the symptoms had even become aggravated, the procedure was defined as ineffective.

Radiologic follow-up was performed 6 or more months after the procedure. The duration of the follow-up period ranged from 6 to 42 months (mean, 23 months).


Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Direct orbital venography was performed successfully in all patients. Dilated, saccular, or tangled plexus venous lesions draining through the pterygoid plexus or cavernous sinus to the jugular vein were seen on venography (Fig. 2A and Table 1).


Figure 4
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  		Fig. 2A —26-year-old woman with left orbital venous malformation (patient 15 in Table 1). Percutaneous puncture of lesion under fluoroscopic guidance. Venous malformation (arrowheads) is filled with nonionic contrast material (black arrows) in medial left orbit and drainage is shown. White arrow = puncture needle.

 
Efficacy Outcomes
All 19 patients underwent technically successful percutaneous intralesional PLE injection under fluoroscopy. The technique success rate of sclerotherapy was 100%. The volume of PLE injected ranged from 1.5 to 3.0 mL (total dose of PYM, 2.0–4.0 mg; 0.033–0.174 mg/kg of body weight), with an average volume of 2.2 mL. PLE was well distributed in the lesions (Fig. 2B).


Figure 5
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  		Fig. 2B —26-year-old woman with left orbital venous malformation (patient 15 in Table 1). Five minutes after procedure, pingyangmycin Lipiodol emulsion (black arrows) has distributed well in lesions. White arrow = puncture needle.

 
Complete resolution of proptosis, swelling, and pain was achieved 3–9 months after the procedure in 17 of the 19 patients (Figs. 1B, 3A, and 3B). All four patients with reduced visual acuity had recovered their vision, and diplopia in the two affected patients disappeared. Examinations of the fundus revealed normal findings in the five patients with preprocedural disk swelling. None of the patients presented with a motility disturbance after the procedure. The procedure was considered beneficial in two patients with diffuse lesions. A second procedure was performed in those two patients and their symptoms had disappeared 3 months later.


Figure 6
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  		Fig. 3A —17-year-old boy with orbital venous malformation who had proptosis (approximately 7 mm) (patient 5 in Table 1). CT scan obtained before sclerotherapy shows mass in right orbit.

 

Figure 7
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  		Fig. 3B —17-year-old boy with orbital venous malformation who had proptosis (approximately 7 mm) (patient 5 in Table 1). Nine months after sclerotherapy, CT scan shows proptosis has disappeared and there are few pingyangmycin Lipiodol emulsion deposits in lesion.

 
Safety Outcomes
Orbital or periorbital swelling (or both) and light pain occurred in all patients after sclerotherapy and regressed spontaneously in 3–7 days after the procedure without specific management. One patient with orbital venous malformations that involved the left endocanthion experienced 1-month local swelling in the eyelid and epiphora, which disappeared after the administration of antiinflammatory agents and physical therapy. Other complications, such as acute orbital compartment syndrome, intraorbital hemorrhage, cutaneous necrosis, symptomatic embolism of sclerosing agent into circulation, and periorbital scar, were not observed during the follow-up periods.


Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
To date, the treatment modality for orbital venous malformations has not been standardized definitely, but if intervention is indicated, less invasive methods, such as CO2 laser ablation and percutaneous ethanol sclerotherapy and endovascular treatment by platinum Guglielmi detachable coil embolization, have been advocated as being among the first-line treatments [5]. Carbon dioxide laser ablation can be used for the treatment of selected superficial and combined orbital venous malformations, but it is undoubtedly limited by anatomic sites and the extent of surgical exposure, especially for diffuse lesions or when deep components are involved.

Although percutaneous ethanol sclerotherapy can be used for the treatment of superficial orbital venous malformations, the use of ethanol will cause great pain and swelling because it is an aggressive sclerosant. Sometimes the pain is intolerable. Ethanol is applied limitedly to sclerotherapy for combined and deep orbital venous malformations because of the swelling induced by the intense inflammatory and instant clotting reaction and because of concern about the risk of optic nerve injury secondary to leakage of ethanol within the orbit.

Other sclerosant drugs, such as sodium tetradecyl sulfate, are, like ethanol, too aggressive to be used for sclerotherapy because of the development of orbital compartment syndrome and subsequent loss of vision [11]. Some adhesives, such as N-butyl-2-cyanoacrylate, also an aggressive sclerosant, although widely used in neuroradiology, cannot be applied for the treatment of orbital venous malformations because of the reasons mentioned and because of the occupied effect caused by the occurrence of chronic granulomatous foreign-body reaction and fibrosis during the late stages of treatment [12]. To our knowledge, this article is the first clinical case series describing percutaneous sclerotherapy using PLE for the treatment of orbital venous malformations with deep components.

PYM damage to the endothelial cells, termed "devascular effect," has been proven to be mild and depends on dosage and time [13, 14]. In an experiment performed by Kong and colleagues [14] in which they studied the effect of PYM on the proliferation and cell cycle of the cultured ECV304 cell, the inhibition rates on the cells elevated along with the increasing PYM concentration. In an experiment performed by Zeng and colleagues [13] using rabbits, edema and partial intimal detachment were observed within 1 week after infusion of PLE (4 mg/mL) to the posterior auricular artery. Thrombosis in the posterior auricular artery was found in 8–14 days. Iodinated oil was successfully used as a suspension medium for PYM.

As a drug-carrying agent with a high viscosity, we speculate iodized oil (Lipiodol, Guerbet) accumulates in malformed veins and makes PYM release slowly. In study the study by Zhao et al. [15] in which a PYM–water solution injection was used for the treatment of superficial orbital venous malformations involved with eyelid and conjunctiva, two to five sessions of the procedure were needed. The probable reason for the increased number of sessions needed is that water solution of PYM could be easily drained together with blood. In contrast, only two patients with diffuse lesions needed a second procedure in our study.

From CT scans obtained 9 months after the procedure, PLE deposition within the lesion can be seen (Fig. 3B). In the present study, satisfactory efficacy was obtained with 17 effective cases and two beneficial cases after one session of PLE injection.

The location for percutaneous puncture and the needle route should be determined on the basis of clinical and imaging findings to avoid causing damage to adjacent orbital structures. In our procedure, percutaneous puncture was performed when patients were in a dependent position or the homonymy jugular vein was being compressed. Real-time monitoring of percutaneous PLE injection under fluoroscopic guidance is possible because PLE is radiopaque. The diffusion and distribution of PLE within orbital venous malformations can be observed. The volume of PLE can be controlled as well. This capability allows operators to administer adequate PLE into the lesion and decreases the risk of leakage of PLE. Thus, therapeutic efficacy was increased and the rates of side effects, such as subsequent optic nerve injury and fast egression of a large amount of sclerosant into the pulmonary circulation, were reduced.

In our study, only one patient with orbital venous malformations involving the left endocanthion experienced 1-month local swelling in the eyelid and epiphora. We believe these complications are associated with swelling and obstruction of the nasolacrimal duct caused by leakage of PLE into normal tissue. Other serious complications, such as intraorbital hemorrhage, cutaneous necrosis, symptomatic embolism of the sclerosing agent into the circulation, and periorbital scar were not observed during the follow-up periods.

Acute orbital compartment syndrome is a rare but treatable complication of increased pressure within the confined orbital space. In the present study, cases of acute orbital compartment syndrome were not found periprocedurally. This can be explained by the mild quality of PYM. In clinical studies, pulmonary fibrosis occurs in up to 15% of patients when the cumulative dose of PYM administered IV exceeds 300 mg, whereas pulmonary fibrosis occurs in 30% of patients when the cumulative dose of bleomycin (another drug that simulates the actions of PYM) exceeds 450 mg [16, 17]. We adopted a much lower dosage (1–2 mg) and no pulmonary fibrosis occurred in any of the 19 patients; this finding was also proven in our other study [8].

Considering that this is our initial experience using percutaneous PLE sclerotherapy for the treatment of orbital venous malformations, we excluded patients who had deep lesions in the past several years. On retrospective analysis, we believe that this method can be used to treat deep orbital venous malformations if the lesion can be punctured successfully.

This study had certain limitations. First, the follow-up periods were relatively short compared with those in the studies of Arat et al. [5] and Lacey et al. [9]. Additional studies are needed to evaluate the long-term efficacy of percutaneous PLE sclerotherapy. Second, the number of study patients was limited; however, considering the subtype of orbital vascular malformation—that is, combined orbital venous malformations, the number of patients in this study is greater than in previously reported case series [5, 9].

In summary, percutaneous PLE sclerotherapy for the treatment of orbital venous malformations is safe and effective and can be used as one of the treatment alternatives.


References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Harris GJ. Orbital vascular malformation: a consensus statement on terminology and its clinical implication—Orbital Society. Am J Ophthalmol 1999; 127:453 -455[CrossRef][Medline]
  2. Berenguer B, Burrows PE, Zurakowski D, Mulliken JB. Sclerotherapy of craniofacial venous malformations: complications and results. Plast Reconstr Surg 1999;104 : 1-11; discussion 12-15[Medline]
  3. Choi YH, Han MH, O-Ki K, Cha SH, Chang KH. Craniofacial cavernous venous malformations: percutaneous sclerotherapy with use of ethanolamine oleate. J Vasc Interv Radiol 2002;13 : 475-482[Medline]
  4. Gelbert F, Enjolras O, Deffrenne D, Aymard A, Mounayer C, Merland JJ. Percutaneous sclerotherapy for venous malformation of the lips: a retrospective study of 23 patients. Neuroradiology2000; 42:692 -696[CrossRef][Medline]
  5. Arat YO, Mawad ME, Boniuk M. Orbital venous malformations: current multidisciplinary treatment approach. Arch Ophthalmol2004; 122:1151 -1158[Abstract/Free Full Text]
  6. Burrows PE, Mason KP. Percutaneous treatment of low flow vascular malformations. J Vasc Interv Radiol 2004;15 : 431-445[Medline]
  7. Zhang J, Chen C, Zhang Z. Intralesional injection of pingyangmycin for hemangiomas and vascular malformations in oral and maxillofacial region: a systematic review of the Chinese literature. China J Oral Maxillofacial Surg (Chin) 2003;1 : 102-105
  8. Zeng Q, Li Y, Chen Y, et al. Pingyangmycin lipiodol emulsion intracavitary injection in the treatment of superficial venous malformations. J Interv Radiol (Chin) 2001;10 : 274-276
  9. Lacey B, Rootman J, Marotta TR. Distensible venous malformations of the orbit: clinical and hemodynamic features and a new technique of management. Ophthalmology 1999;106 : 1197-1209[CrossRef][Medline]
  10. Zeng QL, Li YH, Chen Y, et al. Clinical application of pingyangmycin lipiodol emulsion embolization to treat cavernous hemangioma of liver. Chin J Radiol (Chin) 2000;34 : 456-458
  11. Siniluoto TM, Svendsen PA, Wikholm GM, Fogdestram I, Edström S. Percutaneous sclerotherapy of venous malformations of the head and neck using sodium tetradecyl sulphate (Sotradecol). Scand J Plast Reconstr Surg Hand Surg 1997;31 : 145-150[Medline]
  12. Canter HI, Vargel I, Mavlll ME, Gököz A, Erk Y. Tissue response to N-butyl-2-cyanoacrylate after percutaneous injection into cutaneous vascular lesions. Ann Plast Surg2002; 46:520 -526
  13. Zeng QL, Li YH, Chen Y, et al. The experimental study of intra-arterial infusion of pingyangmycinlipiodol emulsion in rabbits. J Clin Radiol (Chin) 2000;19 : 376-379
  14. Kong WD, Li YH, Zeng QL, Chen Y, He XF. Effect of pingyangmycin on the growth and cell cycle of human vascular endothelial cells [in Chinese]. Di Yi Jun Yi Da Xue Xue Bao 2003;23 : 830-832, 836[Medline]
  15. Zhao QX, Chen Y, Liu HR, et al. Local injection of pingyangmycin to treat ocular hemangioma. Recent Advances in Ophthalmology (Chin) 1998; 18:151 -152
  16. Hongbing W, Guochun L. Complications of yingyangmycin: a review. Chin J Clin Pharm (Chin) 2001;10 : 53-55
  17. Blum RH, Carter SK, Agre K. A clinical review of bleomycin: a new antineoplastic agent. Cancer 1973;31 : 903-914[CrossRef][Medline]

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