Downloaded from http://bjo.bmj.com/ on February 18, 2016 - Published by group.bmj.com Clinical science treatment of orbital lymphatic malformations: a large single-centre experience Alex M Barnacle,1 Maria Theodorou,2 Sarah J Maling,2 Yassir Abou-Rayyah2

– 1Department of Radiology, ABSTRACT sclerosing agents and techniques.8 14 Results are Great Ormond Street Hospital Background Percutaneous sclerotherapy is an promising in terms of reduction in lesion size and for Children, London, UK 2 alternative to surgery for the treatment of orbital improvement in proptosis. Detailed VA outcomes Department of 14 Ophthalmology, Great Ormond lymphatic malformations (LMs). We present a large series have only been documented in one series. We Street Hospital for Children, of patients undergoing sclerotherapy for macrocystic LMs report the largest single-centre experience of sclero- London, UK with detailed visual acuity (VA) outcome data. therapy in patients with orbital LMs including Methods Data were collected prospectively in all detailed VA outcome data. Correspondence to Dr Alex M Barnacle, patients with macrocystic orbital LMs undergoing Department of Radiology, sclerotherapy. Sclerotherapy was performed under MATERIALS AND METHODS Great Ormond Street Hospital general anaesthesia, instilling sodium tetradecyl sulfate A retrospective analysis was undertaken of all for Children, London under imaging control. Procedures were repeated at WC1N 3JH, UK; patients at our institution undergoing sclerotherapy [email protected] 2-week to 6-week intervals, depending on clinical for macrocystic orbital LMs. IRB/Ethics Committee response. Patients underwent ophthalmological ruled that approval was not required for this study. Received 19 January 2015 assessment, ultrasound and/or MRI before and after All patients had a history of proptosis. A unilateral Revised 29 May 2015 treatment. Primary outcome measure: change in maximal orbital LM was confirmed with ultrasound (US) Accepted 30 May 2015 radiological diameter of the LM. Secondary outcome Published Online First and MRI. Only those patients with macrocystic 17 June 2015 measure: change in VA after treatment. LMs were included in this study. Patients with Results 29 patients underwent 71 procedures (1–8 microcystic orbital LMs were excluded from the procedures per patient) over 6.7 years. Mean study as alternative primary sclerosing regimes were age=7.31 years. 11 patients (37.9%) had undergone considered for these lesions. previous treatment, including excision biopsy, drainage The primary outcome of this study was defined and decompression. All patients presented with proptosis as radiological change in maximal diameter of the and/or pseudoptosis. 23 patients (79.3%) had decreased LM, assessed with US±MRI before and after treat- VA at presentation. Average follow-up was 21.8 months ment. A preoperative MRI was performed in all (range 3–75 months). All patients achieved a reduction cases; post-treatment MRIs were performed only in maximal lesion diameter of ≥50%, with complete when clinically indicated. All US were performed radiological resolution in 51.7% (n=15). VA improved in by a single radiologist (AMB). The imaging proto- 18/23 patients (78.2%). Average logMAR before col involved US performed before treatment, treatment=0.43 (SD ±0.47); average after between treatments, 6 weeks after final treatment treatment=0.25 (SD ±0.32); p<0.01. There was one and then at six monthly intervals for 2 years. complication (1.4%): one patient required a lateral Radiological response to treatment was defined as a canthotomy for an intralesional haematoma 2 h after change in maximal lesion diameter: resolved=no sclerotherapy. evidence of residual malformation in the orbit; Conclusions Sclerotherapy is a safe and highly good response=>75% reduction in maximal lesion effective treatment for orbital LMs with excellent VA diameter; partial response=50–75% reduction in outcomes. It should be considered as the first-line maximal lesion diameter; poor response=<50% treatment for this condition. reduction in maximal lesion diameter; and no response=no improvement in maximal lesion diameter. INTRODUCTION The secondary outcome was defined as change in Lymphatic malformations (LMs) or VA following treatment. All patients underwent of the orbit are benign vascular malformations, preoperative ophthalmological assessment and were often diagnosed in childhood. Complications reassessed 1 day after treatment and again at include intralesional haemorrhage, cellulitis, ambly- 6 weeks. Visual assessment was conducted by the opia and impaired visual acuity (VA). Historically, orthoptic team; all patients had age-appropriate the management of orbital LMs has involved visual testing (Cardiff cards, Kay pictures or complex, aggressive surgical intervention with vari- crowded logMAR). A paired Student’s t test was able results and high recurrence rates.12 used to compare VA before and after sclerotherapy Percutaneous intralesional sclerotherapy is now treatment in patients in whom VAwas measurable. well established as a first-line treatment for LMs elsewhere in the body using a variety of sclerosing Sclerotherapy technique agents including sodium tetradecyl sulfate (STS), All sclerotherapy procedures were carried out ethanol, OK-432 (Picibanil), bleomycin and doxy- under general anaesthesia by an interventional radi- To cite: Barnacle AM, – Theodorou M, Maling SJ, cycline.3 7 Small series of up to 13 patients have ologist (AMB) in a biplane suite. All et al. Br J Ophthalmol reported the use of percutaneous sclerotherapy in patients received a single dose of intravenous dexa- – 2016;100:204 208. the management of orbital LMs with a variety of methasone (0.25 mg/kg) on induction. Antibiotics

204 Barnacle AM, et al. Br J Ophthalmol 2016;100:204–208. doi:10.1136/bjophthalmol-2015-306657 Downloaded from http://bjo.bmj.com/ on February 18, 2016 - Published by group.bmj.com Clinical science were only given if active infection was suspected (n=2). The with <75% reduction in lesion size on US and in conjunction affected orbit was scanned using a high-resolution linear 5– with VA findings. STS was used as the sclerosant in all cases, at a 13 MHz US probe. The malformation was accessed percutan- strength of 1.5–3%. The average volume of sclerosant used was eously with a 22 gauge two-part needle through an upper lid 1.12 mL (range 0.22–3.8 mL). medial or lateral approach, depending on the position of the The average length of clinical follow-up was 21.8 months malformation. Needle placement was controlled with real-time (range 3–75 months, median 22 months). The procedural com- US throughout the procedure. Where possible, cyst contents plication rate was 1.4% (1/71 procedures). The first patient in were aspirated. Contrast medium (Omnipaque 240, GE the series (age 1.6 years) experienced an acute retrobulbar Healthcare, Oslo) was then instilled in small volumes (<1 mL) haemorrhage 2 h after the second sclerotherapy treatment for into the cyst during digital subtraction angiography (DSA) using an extensive LM. 3.8 mL of STS 3% was instilled during the biplane imaging. This allowed the operator to exclude commu- procedure, and a standard procedural technique was used. The nication between the cyst and the cavernous sinus, ophthalmic haemorrhage was managed with acetazolamide and an uncom- artery or other structures. Sclerosant was only injected if no plicated lateral canthotomy. She underwent two subsequent communication was seen. STS sclerosant was then instilled in uncomplicated sclerotherapy procedures, with complete reso- small aliquots into the largest cyst(s) under US control. The lution of the malformation (follow-up 75 months) and some sclerosant was left to dwell in the cyst and not aspirated. improvement in VA (no interest in Cardiff cards pre-treatment; Postoperative orbital bandaging was not used. Patients returned logMAR 0.87 post-treatment). to an inpatient ward with oral morphine prescribed on an ‘as The primary outcome measure was radiological change in size required’ basis and were closely monitored for acute proptosis of the lesion US±MRI after treatment. Radiological improve- caused by an intralesional bleed or severe swelling. All patients ment was assessed in all patients on US±MRI. All patients underwent ophthalmology assessment the following day prior achieved a reduction in lesion size of ≥50%. Fifteen patients to discharge. Routine follow-up took place at 6 weeks unless the (51.7%) demonstrated complete radiological resolution of their need for a repeat sclerotherapy procedure was predicted due to malformation, and 11 patients (37.9%) showed a good response. a large volume of cysts, in which case sclerotherapy was In many patients in whom the malformation was no longer repeated at 2–6 weeks. detected, there was residual heterogeneity of the fat in the poster- ior orbit, taken to reflect the presence of previous inflammation/ disease in the orbit. Examples of radiological appearances before RESULTS and after treatment are shown in figures 2–4. Twenty-nine patients were referred for treatment between The secondary outcome measure was change in VA after treat- October 2007 and September 2014. All had macrocystic orbital ment. Twenty-three patients (79.3%) had decreased VA in the fi LMs, with associated microcystic disease of the face in ve. affected eye at presentation. Of those 23 patients, VA improved None of the patients had microcystic disease affecting the orbit in 18 patients (78.2%), remained stable in 3 (13%), remained fi itself, and none of the lesions had a signi cant venous compo- unrecordable in 1 and worsened in 1 (logMAR 0.52 pre- nent. Mean age at the time of treatment was 7.31 years (range treatment, 0.70 post-treatment). Statistical analysis of change in – 0.3 21.6 years, median 5.8 years). The commonest mode of VA could not include two patients that had no interest in fi presentation was pain and/or proptosis ( gure 1). Twenty-three Cardiff cards at presentation or the patient who was NPL at patients (79.3%) had decreased VA in the affected eye at presen- presentation and in whom understandably this did not improve. tation, ranging from several logMAR letters of visual loss to no Excluding these three patients, average VA before treatment was perception of light (NPL). Eleven patients (37.9%) had under- 0.43 (SD±0.47) and after treatment was 0.25 (SD±0.32). A gone ophthalmological treatment prior to referral, including paired Student’s t test was used to compare VA before and after excision biopsy, drainage and orbital decompression. sclerotherapy treatment, p<0.01. Proptosis subjectively – Twenty-nine patients underwent 71 procedures (1 8 proce- improved in all patients, but an accurate measure of proptosis dures per patient). Repeat treatment was considered in patients was not possible in every patient prior to treatment due to the age range of the patients in this group.

DISCUSSION LMs are benign vascular malformations that are present at birth and grow commensurately with the child.315They are defined within the group of slow-flow malformations in the classification devised by Mulliken and Glowacki and recently updated by the International Society for the Study of Vascular Anomalies.16 They occur most commonly within the head and neck but are rare in the orbit.4 Histologically, LMs consist of cystic dilatation of lymphatic channels lined by vascular endothelium; they contain proteinaceous fluid.6 They are thought to be a result of erroneous embryogenesis.5 Typically there is no communication with the functioning systemic lymphatic system although lesions often fluctuate in size with systemic viral illness. LMs are classi- fied as macrocystic or microcystic lesions, with macrocysts usually defined as cysts >10 mm in diameter.357 Figure 1 A 13.6-year-old female with a macrocystic lymphatic Subclassification of LMs into microcystic or macrocystic lesions malformation of the left orbit showing (A) proptosis and lateral appears to be relevant clinically and prognostically when identi- deviation of the globe at presentation and (B) significant improvement fying lesions that may respond to specific forms of therapy such in the appearances of the left orbit after five sclerotherapy procedures. as sclerotherapy.7 Some LMs are asymptomatic and do not

Barnacle AM, et al. Br J Ophthalmol 2016;100:204–208. doi:10.1136/bjophthalmol-2015-306657 205 Downloaded from http://bjo.bmj.com/ on February 18, 2016 - Published by group.bmj.com Clinical science

Figure 2 A 1.6-year-old female with a macrocystic lymphatic malformation (LM) of her right orbit. Images from a heavily T2-weighted axial MR sequence showing (A) a large LM expanding the right orbit and causing severe proptosis, and (B) radiological change after five sclerotherapy procedures. There is now minimal proptosis and the high T2 signal cystic malformation has shrunk to a small, intermediate T2 signal lesion lateral to the optic nerve complex.

require treatment but many are prone to intralesional haemor- (figures 2 and 4). Patients present with acute painful proptosis rhage and infection. In certain locations, malformations can due to intralesional haemorrhage or with slow, insidious swel- cause significant morbidity due to mass effect, such as in the ling. Once symptomatic, they cause significant ocular comorbid- airway, mesentery or orbit. ity, such as extraocular muscle dysfunction, infection, amblyopia LMs of the orbit appear to be more commonly macrocystic and decreased VA.21317When the LM lies anteriorly within than microcystic, although macrocystic orbital LMs may be asso- the orbit and is well circumscribed, complete surgical resection ciated with microcystic disease elsewhere in the face, as seen in may be possible. However, more commonly the LM forms a 19% of our cohort.217A proportion of macrocysts convert to a complex, infiltrative lesion in the posterior orbit, making surgi- more solid microcystic morphology after infection, haemorrhage cal excision difficult and often incomplete.12Reported compli- or sclerotherapy. Orbital macrocysts occur in both intraconal cation rates are high and recurrence is common.12 and extraconal locations, often surrounding the optic nerve Percutaneous sclerotherapy is widely reported in the manage- complex.13 Cysts vary in size and often contain altered blood, ment of LMs throughout the body and is increasingly accepted – as demonstrated by varying signal characteristics on MRI as the first-line, non-surgical treatment for these lesions.3 7

Figure 3 A 5.8-year-old female with a macrocystic lymphatic malformation of the right orbit. (A) Ultrasound image of the orbit at presentation showing large thin-walled macrocysts (*) along the lateral sidewall of the orbit; (B) after one sclerotherapy procedure, the posterior orbit appears clear on ultrasound.

206 Barnacle AM, et al. Br J Ophthalmol 2016;100:204–208. doi:10.1136/bjophthalmol-2015-306657 Downloaded from http://bjo.bmj.com/ on February 18, 2016 - Published by group.bmj.com Clinical science

Figure 4 A 2.9-year-old female with a macrocystic lymphatic malformation of the left orbit. (A) T1-weighted axial MRI image showing a complex cystic lesion filling the anterior and posterior orbit and displacing the globe. The largest cyst has fluid levels within it. (B) T2-weighted axial MRI image showing a marked decrease in the size of the malformation after one sclerotherapy procedure. There is now just a small rounded residual mass at the orbital apex and the proptosis has resolved.

A variety of sclerosing agents are used including STS, ethanol, cavernous sinus thrombosis, stroke or visual loss with escape of OK-432 (Picibanil), bleomycin and doxycycline. Orbital sclero- STS. Hill et al14 describe a staged percutaneous ablation and therapy was first described in 1999, and a number of small drainage technique with excellent results. This may be of par- – series have since described this procedure.8 14 ticular value in patients with large collections of fluid or in STS is an anionic surfactant buffered in benzyl alcohol 2%, lesions that are refractory to standard treatment. which causes endothelial necrosis via direct cytotoxic action.18 All patients in this series underwent follow-up US imaging; The authors chose to use this agent because of familiarity with follow-up MRI was performed rarely and only where clinically the drug in treating LMs elsewhere in the body and its relatively indicated. This was influenced in part by the age of the patients in high potency compared with alternative agents, meaning that a this series, necessitating general anaesthesia for most MRI studies. smaller volume of agent is required to produce effective scler- The same operator performed all US studies. Accurate volumetric osis; this is an advantage in the orbit where large volumes of data were not available from cross-sectional imaging in every any agent cannot be instilled. This has to be weighed against the patient as a large proportion of scans were performed in referring disadvantages of STS: significant swelling in the first 1–5 post- institutions and source data that would allow accurate volume operative days and the potential for neurological injury.19 20 measurements was unavailable in some cases. Hence, the primary The degree of swelling appears to correlate with the dose and outcome measure of radiological change in size of the lesion was strength of STS used, and both factors were altered several defined as change in maximal diameter of the lesion: times in the early part of this series as the operator (AMB) resolved=no evidence of residual malformation in the orbit; good gained experience. A volume of 3.8 mL of STS 3% was used in response=>75% reduction in maximal lesion diameter; partial the second procedure, and this was the only procedure resulting response=50–75% reduction in maximal lesion diameter; in an acute intralesional haemorrhage postoperatively. Since pro- poor response=<50% reduction in maximal lesion diameter; and cedure 19 ( January 2012), standard practice has been to use a no response=no improvement in maximal lesion diameter. The concentration of 2% STS and volumes of <2 mL. Volumes of as authors recognise this as a limitation of the study, as is the fact that little as 0.4 mL of STS 1.5% have been effective in this series. both preoperative and postoperative imaging was performed by Of note, STS is recognised to be more effective in macrocysts the operator with potential for bias. Allowing for this, the radio- than microcysts and bleomycin should be considered as a first- logical outcomes are striking, with 51.7% of patients having no line agent for solid microcystic disease. evidence of residual malformation on US±MRI after treatment. The procedural technique used in this series is similar to that Only one other paper has clearly documented VA data before described in other papers. Lesion puncture is technically chal- and after sclerotherapy.14 Hill et al14 report that all patients in lenging, even in experienced hands. All punctures were per- their series maintained or improved their preoperative VA with formed under US guidance, as this allows for precise needle an average of one Snellen line improvement, with a statistically placement and does not involve a radiation burden to the eye. significant improvement in the subset of patients with decreased Other papers have described fluoroscopically guided punctu- preoperative vision. VA outcomes in our series are comparable. res.910In this series, contrast medium was instilled into the Of the 23 patients with decreased VA, vision improved in 18 lesion during biplane DSA prior to instillation of sclerosant. (78.2%). Of the remaining patients, one was NPL at presenta- This was done to exclude any communication between the cyst tion and therefore VA could not be improved, three maintained and the cavernous sinus, ophthalmic artery or other structures. VA throughout treatment and one had a visual drop from 0.5 to Although there has been no evidence of contrast medium 0.7. At the time of writing this paper, he was undergoing occlu- outflow in this series, the authors still advocate this technique in sion therapy. At the start of this series, the authors did not con- view of the potential for devastating complications such as sider any significant improvement in VA to be likely in a cohort

Barnacle AM, et al. Br J Ophthalmol 2016;100:204–208. doi:10.1136/bjophthalmol-2015-306657 207 Downloaded from http://bjo.bmj.com/ on February 18, 2016 - Published by group.bmj.com Clinical science of such complex patients and the results have been both surpris- 5 Shiels WE, Kang DR, Murakami JW, et al. Percutaneous treatment of lymphatic ing and encouraging. malformations. Otolarygol Head Neck Surg 2009;141:219–24. fi 6 Shergill A, John P, Amaral J. Doxycycline sclerotherapy in children with lymphatic This large cohort study con rms that US-guided puncture, malformations; outcomes, complications and clinical efficacy. Pediatr Radiol cystography and use of small aliquots of STS 2% is a reprodu- 2012;42:1080–8. cible and safe technique in experienced hands and that both 7 Cahill AM, Nijs E, Ballah D, et al. Percutaneous sclerotherapy in neonatal and radiological and VA outcomes are excellent. Close collaboration infant head and neck lymphatic malformations; a single centre experience. J Pediatr – between a specialist interventional radiologist and an experi- Surg 2011;46:2083 95. 8 Suzuki Y, Obana A, Gohto Y, et al. Management of orbital using enced ophthalmology team is mandatory. Where this is avail- intralesional injection of OK-432. Br J Ophthalmol 2000;84:614–17. able, sclerotherapy is strongly advocated as the first-line 9 Wojno TH. Sotradecol (sodium tetradecyl sulfate) injection of orbital lymphangioma. treatment of this complex disease. Ophthal Plast Reconstr Surg 1999;15:432–7. 10 Svendsen PA, Wikholm G, Rodriguez M, et al. Direct puncture and sclerotherapy Contributors AMB designed the study, undertook and monitored data collection, with sotradecol (®). Orbital lymphatic malformations. Interv Neuroradiol performed the statistical analysis and literature review, and drafted and revised the 2001;30:193–9. paper. She is guarantor. MT assisted with data collection and drafted and revised 11 Schwarcz RM, Ben Simon GJ, Cook T, et al. Sclerosing therapy as first line treatment the paper. SJM assisted with data collection, statistical analysis and drafted and for low flow vascular lesions of the orbit. Am J Ophthalmol 2006;141:333–9. revised the paper. YA-R assisted with data collection and drafted and revised the 12 Poonyathalang A, Preechawat P, Jiarakongmun P, et al. Sclerosing therapy for orbital paper. lymphangioma using sodium tetradecyl sulfate. Jpn J Ophthalmol 2008;52:298–304. 13 Greene AK, Burrows PE, Smith L, et al. Periorbital lymphatic malformation: clinical Competing interests None declared. course and management in 42 patients. Plast Reconstr Surg 2005;115:22–30. Patient consent Obtained. 14 Hill RH, Shiels WE, Foster JA, et al. Percutaneous drainage and ablation as first line Provenance and peer review Not commissioned; externally peer reviewed. therapy for macrocystic and microcystic orbital lymphatic malformations. Ophthal Plast Recontr Surg 2012;28:119–25. 15 Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg REFERENCES 1982;69:412–22. 1 Tunc M, Sadri E, Char DH. Orbital lymphangiomas: an analysis of 26 patients. Br J 16 Rootman J, Heran MKS, Graeb DA. Vascular malformations of the orbit: Ophthalmol 1999;83:76–80. classification and the role of imaging in diagnosis and treatment strategies. Ophthal 2 Harris GJ, Sakol PJ, Bonavolonta G, et al. An analysis of thirty cases of orbital Plast Reconstr Surg 2014;30:91–104. lymphangiomas: pathophysiologic considerations and management 17 Graeb DA, Rootman J, Robertson WD, et al. Orbital lymphangiomas: clinical, recommendations. Ophthalmology 1990;97:1583–92. radiologic and pathologic characteristics. Radiology 1990;175:417–21. 3 Poldervaart MT, Breugem CC, Speleman L, et al. Treatment of lymphatic 18 Rotter SM, Weiss RA. Human saphenous in vitro model for studying the action malformations with OK-432 (Picibanil): review of the literature. J Craniofac Surg of sclerosing solutions. J Dermatol Surg Oncol 1993;19:59–62. 2009;20:1159–62. 19 Rosenblatt M. Endovascular management of venous malformations. Phlebology 4 Mathur NN, Rana I, Bothra R, et al. Bleomycin sclerotherapy in congenital 2007;22:264–75. lymphatic and vascular malformations of the head and neck. Int J Pediatr 20 Stuart S, Barnacle AM, Smith G, et al. Neuropathy after sodium tetradecyl sulfate Otorhinolaryngol 2005;69:75–80. sclerotherapy of venous malformations in children. Radiology 2015;274:897–905.

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Sclerotherapy treatment of orbital lymphatic malformations: a large single-centre experience Alex M Barnacle, Maria Theodorou, Sarah J Maling and Yassir Abou-Rayyah

Br J Ophthalmol 2016 100: 204-208 originally published online June 17, 2015 doi: 10.1136/bjophthalmol-2015-306657

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