Orbit, 2014; 33(1): 45–51 ! Informa Healthcare USA, Inc. ISSN: 0167-6830 print / 1744-5108 online DOI: 10.3109/01676830.2013.851253
ORIGINAL ARTICLE
Ocular Manifestations and the Clinical Course of Carotid Cavernous Sinus Fistulas in Asian Patients Anna C. S. Tan1,2, Saadia Farooqui1, Xiang Li3,5, Yar Li Tan1, James Cullen1, Winston Lim4, Seah Lay Leng1,2,3, Audrey Looi1,2, and Sharon Tow1,2,3 Singapore National Eye Centre, Singapore, 2Singapore Eye Research Institute, Singapore, 3National University of Singapore, Singapore, 4Interventional Radiology Department, Singapore General Hospital, Singapore, and 5 Department of Statistics and Applied Probability, National University of Singapore, Singapore
ABSTRACT Purpose: To study the clinical course with regard to both the angiographic and visual outcomes of carotid cavernous fistulas (CCFs). Background: Carotid cavernous sinus fistulas (CCFs) are conditions which often present with ocular signs and symptoms. The clinical presentation of CCFs is varied according to the anatomy, haemodynamics and size of the CCF. CCFs causing significant symptoms or vision loss should be treated with embolization. Methods: This is a retrospective review of the medical records of all CCF cases seen in the Singapore National Eye Centre from September 2002 to December 2011. Results: 45 patients who had confirmed CCF on conventional cerebral angiography were included. Anterior draining CCFs presented with orbital congestion while posterior draining CCFs presented with pain, diplopia and cranial nerve palsies. Mild residual symptoms were still present in 85% of treated direct CCFs despite complete angiographic closure however 52% of treated dural CCFs had complete resolution of symptoms despite only half of those achieving angiographic closure. Treated and untreated dural CCFs had similar outcomes (87% versus 76% recovered or improved (p40.05)). Poor outcomes can result from residual diplopia or vision loss from complications of the CCF itself (e.g. compressive optic neuropathy, glaucoma, retinopathy) or complications from CCF embolization treatment (e.g. central retinal artery occlusion). Conclusion: Presenting symptoms and signs are related to the angiographic drainage of CCFs. Angiographic outcomes after embolization treatment may not always correlate with clinical outcomes. Keywords: Carotid-cavernous sinus fistulas, neuro-ophthalmology, orbit
INTRODUCTION
have an acute presentation with orbital congestion and ophthalmic symptoms. Dural arteriovenous fistulas on the other hand, result from connections between the cavernous sinus and branches of the meningeal arteries arising from the internal and/or external carotid artery. Those that drain posteriorly into the petrosal sinuses can be asymptomatic or present with painful, isolated cranial nerve palsies sometimes in the absence of orbital congestion.3,4 Posterior draining dural CCFs with cerebral vascular drainage can sometimes cause mortality through brainstem congestion and rarely intra-cranial haemorrhage.5 Posterior dural CCFs may
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1
A carotid cavernous fistula sinus (CCF) is an abnormal communication between the cavernous sinus and carotid arterial system. Classifications of CCF types can be divided by (1) anatomy; direct versus dural fistulas1 or posterior versus anterior draining fistulas2 (2) haemodynamic properties; high flow versus low flow (3) cause; spontaneous versus traumatic. Direct CCFs arise from a direct connection between the cavernous sinus and the cavernous portion of the internal carotid artery. Direct CCFs are usually associated with trauma and due to their high flow
Received 28 January 2013; Revised 7 September 2013; Accepted 30 September 2013; Published online 6 November 2013 Correspondence: Anna Tan, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751. E-mail: [email protected], [email protected]
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46 Tan et al. be difficult to diagnose and if left to progress may lead to a change in the drainage pattern. If the drainage becomes anterior, patients will then develop orbital congestion associated with ocular complications. Proptosis, lid swelling, conjunctival injection and chemosis and corkscrew vessels are all clinical signs associated with anterior draining dural CCFs. Ophthalmoplegia may be due to both orbital congestion and cranial nerve palsies. Pain and discomfort are common symptoms. Raised intra-ocular pressures (IOP) can occur from a raised episcleral venous pressure or an angle closure mechanism when venous congestion in the iris and choroid causes the lens iris diaphragm to move forward.6–8 When a patient presents with clinical signs and symptoms suggestive of CCF, investigations such as computed tomography scanning (CT) or magnetic resonance imaging (MRI) with angiography (MRA), Doppler and other ultrasound imaging may help confirm the diagnosis. However the gold standard diagnostic test is still cerebral catheter angiography. Angiography should be done to confirm the presence of the CCF and to plan subsequent treatment. Most direct CCFs have usually rapidly progressing orbital congestion and ocular symptoms requiring treatment. However 20–50% of dural CCFs close spontaneously despite presenting with significant orbital congestion. This closure of the CCF and resolution of the clinical symptoms can occur days or years after presentation.5,8 Treatment of a CCF is considered when the patient experiences significant ocular symptoms or complications. Vision loss in CCF is a serious complication and can result from orbital congestion causing compressive optic neuropathy and glaucoma. Progressive proptosis may lead to lagophthalmos and exposure keratopathy. In cases where there is either spontaneous or post-treatment thrombosis in the superior ophthalmic vein, a central retinal artery occlusion or ischaemic optic neuropathy can occur. Chronic ischaemia can lead to anterior segment ischaemia, neovascular glaucoma and proliferative retinopathy with vitreous haemorrhage. Other posterior segment complications include central retinal vein occlusion, retinal detachment, choroidal effusion and choroidal folds. In cases of CCFs related to trauma, traumatic optic neuropathy must also be considered if visual loss is present.8–10 Treatment of CCFs can be divided into conservative (e.g. observation or external manual ipsilateral carotid artery compression),11 radiological or surgical. Endovascular embolization and gamma knife surgery have achieved high rates (480%) of CCF closure.12–14 Local treatment of ocular complications is required if they are severe, but the treatment of the underlying CCF should be a priority. Lubricants or tarrsorraphy for exposure keratopathy can be considered. Topical glaucoma medications have a limited effect and
glaucoma surgery should only be considered if intra-ocular pressure is still elevated despite CCF closure. Pan retinal photocoagulation can be performed for proliferative retinopathy from ocular ischemia.8,15 A successful outcome of CCF treatment in most studies has been defined as anatomical closure of the fistula.14 More recent studies9,12,16 have also reported clinical resolution of symptoms which may not necessarily correlate to the anatomical closure of the CCF. In Asia, many case series14,17,18 have been small and details of ocular signs, symptoms and rates of visual complications have not been fully described.
METHODS Study Design This was a retrospective review of the medical records of all CCF cases seen in our centre from September 2002 to December 2011. All hospital, outpatient charts, angiographic and imaging studies were analysed. History of potential risk factors and the medication use was obtained from medical records. The angiographic outcome was determined at the end of the last treatment and the clinical outcome was assessed at the last follow-up visit.
Definitions and Classifications Poor visual acuity was defined as worse than 6/60. Proptosis was defined as more than 2 mm difference between the Hertel’s exophthalmometer measurement in unilateral cases, and a measurement of more than 20 mm in bilateral cases. Raised intraocular pressure was defined as more than 21 mmHg measured with Goldmann tonometry.
Outcomes Outcomes were divided into anatomical and clinical outcomes. Anatomical outcomes of the CCFs were determined on follow up imaging after treatment and were classified as completely closed, partially closed, open or recurrent. Clinical outcomes taken at the last follow-up visit were divided into (i) complete resolution, (ii) stable with residual mild symptoms still acceptable to the patient or (iii) poor outcomes where patients still had significant residual symptoms.
Statistical Analysis Statistical analysis was performed using R version 2.15.2 (R Development Core Team, Vienna, Austria, Orbit
Carotid-Cavernous Sinus Fistulas 2012). Characteristics of the study population were examined using proportions or means and standard deviation (SD). Wilcoxon’s Rank Sum test, McNemar’s test or Fisher’s exact test was performed to test the difference in distribution of potential risk factors between direct and dural CCFs and the difference in the incidence of various poor clinical outcomes. The Mann–Whitney U-test was used to test the association between two ordinal anatomical and clinical outcome variables. The association between clinical outcome and potential risk factors was assessed by using age-gender adjusted logistic regression.
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RESULTS Forty-five patients who had confirmed CCFs on conventional cerebral angiography were included in this study (Table 1). There were 8 (18%) direct CCFs and 37 (82%) dural CCFs, 16 (36%) were anterior draining, 8(17%) were posterior draining, 20 (44%) were both anterior and posterior draining and for 1 patient the drainage pattern was not available. Angiographic drainage pattern of the CCF affects the initial clinical presentation (Figure 1).
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Radiological and Clinical Outcomes of Treated and Untreated CCFs In our study 7 patients (87%) with direct CCFs were treated and 1 patient (13%) was observed. 29 (78%) patients with dural CCFs were treated and 8 (22%) of patients were observed. Indications for treatment include reduced visual acuity, raised IOP, significant orbital congestion and diplopia. No further imaging was performed for the observed patients and hence no angiographic outcomes were available for these patients. Fewer patients had raised intra-ocular pressure (34% versus 9%), significant proptosis (42% versus 11%) and diplopia (56% versus 19%) after treatment when compared to initial clinical presentation (Table 2A). The number of patients with visual acuity loss was more after treatment than before (9% versus 6%).The reasons for poor visual acuity are summarised in Table 4. The angiographic and clinical outcomes of treated direct and dural CCFs (Table 2B and 2C) and the clinical outcomes between treated and untreated dural CCFs were compared (Table 2D). The numbers of direct CCFs were too small for any meaningful statistical analysis (Table 2B). There was no significant association with angiographic outcomes and the incidence of poor clinical outcomes (Table 2C).
TABLE 1. Baseline characteristics for direct and dural CCFs.
Average age Gender Male Female Race Chinese Malay Indian Others Laterality Right Left Both Mean follow-up time in months (range) Mean time to presentation in months (range) Mean time to treatment in months (range) Trauma Hypertension Hyperlipidemia Diabetes Intervention Treated Observed
Direct CCF (n = 8)
Dural CCFs (n = 37)
41(18–54)
58(31–82)
5(62%) 3(38%)
11(30%) 26(70%)
4(50%) 0 0 4(50%)
33(89%) 2(5%) 1(3%) 1(3%)
p 50.01 0.11
0.01
0.01 4(50%) 3(38%) 1(12%) 12.4(2–53)
3(8%) 20(54%) 17(46%) 37.0(1–166)
0.01
2.9(0–9)
2.5(0–12)
0.81
2.9(0–10)
4.6(1–16)
0.23
A significantly higher percentage of patients on anticoagulant or anti-thrombotic medications had a poor clinical outcome (50% versus 3% p50.05) (Table 3). Presenting visual acuity less than 6/60 was also associated with a poor clinical outcome (33% versus 3%, p50.05). There was no association between ischaemic risk factors such as hypertension, hyperlipidemia and diabetes or the type of CCF (direct versus dural) and a poor clinical outcome in both treated and
TABLE 2A. The comparison of clinical characteristics of treated CCFs before and after treatment (n = no. of available results). Clinical characteristics of CCFs
7(88%) 0 1(13%) 1(13%)
2(5%) 15(41%) 17(46%) 8(22%)
50.01 0.04 0.12 1.00
7(87%) 1(13%)
29(78%) 8(22%)
1.00
p Value based on Fisher’s exact test or Wilcoxon’s Rank Sum test. !
Risk Factors for Poor Clinical Outcomes in Direct and Dural CCFs
2014 Informa Healthcare USA, Inc.
Visual acuity of worse than 6/60 (n = 33) Before treatment After treatment p
Intra-ocular pressure Significant 421 proptosis* Diplopia (n = 32) (n = 28) (n = 32)
2(6%)
11(34%)
12(42%)
18(56%)
3(9%)
3(9%)
3(11%)
5(16%)
0.56
50.01
p Value based on McNemar’s test. #2 patients were seen only after treatment.
0.01
50.01
48 Tan et al. untreated groups. Five (17%) patients with treated dural CCFs had poor outcomes with significant residual symptoms despite treatment (Table 4).
DISCUSSION
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Older studies19,20 quote 70–90% of all CCFs are direct CCFs but in our study, there was a significantly lower percentage of direct CCFs (18%). This may be a result of lower rates of head trauma due to improved safety regulations (e.g. increased helmet usage, stricter traffic regulations). An increase in the diagnosis of spontaneous dural CCFs by high resolution routine imaging and angiography may be another reason for a larger percentage of dural CCFs. Angiographic outcomes did not correlate with clinical outcomes
(Table 2B and 2C) and there was no significant difference in the clinical outcomes of treated and untreated dural CCFs. CCF is an evolving disease and the initial angiographic outcomes may not reflect the eventual clinical outcome. Similarly the improvement of symptoms in non-treated dural CCFs may be due to spontaneous thrombosis. The risk factors on presentation which were statistically significantly associated with a poor clinical outcome were the use of anti-coagulation or antithrombotic medication and a presenting visual acuity of 56/60 (Table 3). Classification of CCFs by their angiographic drainage pattern had a good correlation with the initial clinical presentation.2,6,21 In our study more dural CCFs had complete clinical resolution of symptoms than direct CCFs (52% versus 0%), however more direct versus dural
TABLE 2B. The association between anatomical and clinical outcomes of treated direct CCFs (n = 7). Poor clinical outcomes of CCF after treatment Anatomical outcomes after final treatment
Visual acuity of worse than 6/60
Intra-ocular pressure 421
Significant proptosis*
Residual diplopia
1 0 0
0 0 0
0 0 0
1 0 2
Completely closed CCF (n = 3) Partially closed CCF (n = 1) Partially closed initially then completely closed after 1 year (n = 3) Sample size too small for meaningful statistical analysis.
TABLE 2C. The association between anatomical and clinical outcomes of treated dural CCFs (n = 29). Poor clinical outcomes of CCFs after the final treatment Anatomical outcomes after final treatment
Visual acuity of worse than 6/60
Closed CCF (n = 10) Partially closed CCF (n = 12) Partially closed initially then completely closed after 1 year (n = 4) Recurrent CCF(n = 1) Result unavailable (n = 2) p
Intra-ocular pressure 421
Significant proptosis*
Residual diplopia
Anyy
1 1 0
1 1 0
0 1 1
2 1 0
3 2 1
0 1 0.57
0 1 0.52
0 1 0.19
1 0 0.91
1 2 0.92
p Value based on Mann–Whitney U-Test. yAny defined as any one of the four poor clinical outcomes of CCFs.
TABLE 2D. The comparison of clinical outcomes between treated and untreated dural CCFs (n = 37). Poor clinical outcomes of CCFs after the final treatment
Treated dural CCF(n = 29) Untreated dural CCF(n = 8) p
Visual acuity of worse than 6/60
Intra-ocular pressure 421
Significant proptosis*
Residual diplopia
3(10%) 1(13%) 1
3(10%) 2(25%) 0.29
2(7%) 0(0%) 1
5(17%) 1(13%) 1
p Value based on Fisher’s exact test. *Based on a difference of 42 mm in unilateral cases and 420 mm in bilateral cases on Hertel’s exophthalmometry measurement. Orbit
Carotid-Cavernous Sinus Fistulas
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TABLE 3. Risk factors for poor clinical outcome in direct and dural CCFs. Clinical outcome Overall (n = 43)
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Age Gender Female Male Hypertension No Yes Diabetes No Yes Hyperlipidemia No Yes Anticoagulation/ Anti-platelet No Yes Trauma No Yes Proptosis No Yes Presenting IOP Presenting visual acuity Presenting visual acuity of less 56/60 No Yes CCF Direct Dural
55.62 (13.47), n = 43 n = 43 28 (65.1%) 15 (34.9%) n = 43 29 (67.4%) 14 (32.6%) n = 43 34 (79.1%) 9 (20.9%) n = 43 26 (60.5%) 17 (39.5%) n = 43
Poor (n = 6) 56.81 (16.7), n=6 n=6 5 (83.3%) 1 (16.7%) n=6 4 (66.7%) 2 (33.3%) n=6 5 (83.3%) 1 (16.7%) n=6 5 (83.3%) 1 (16.7%) n=6
Good (n = 37) 55.43 (13.13), n = 37 n = 37 23 (62.2%) 14 (37.8%) n = 37 25 (67.6%) 12 (32.4%) n = 37 29 (78.4%) 8 (21.6%) n = 37 21 (56.8%) 16 (43.2%) n = 37
p Value 1 0.551
Reference 3.01 (0.41, 61.33)
0.34
Reference 1.25 (0.16, 11.93)
0.834
Reference 1.63 (0.21, 34.38)
0.68
Reference 4.39 (0.53, 96.73)
0.225
Reference 0.02 (0, 0.28)
0.008
1
0.376
0.006
36 (97.3%) 1 (2.7%) n = 37 31 (83.8%) 6 (16.2%) n = 36 22 (61.1%) 14 (38.9%) 20.19 (6.76), n = 36 0.26 (0.34), n = 36
0.889 0.089
n = 43
n=6
n = 37
0.047
36 (97.3%) 1 (2.7%) n = 37 6 (16.2%) 31 (83.8%)
0.933
1
3 (50%) 3 (50%) n=6 4 (66.7%) 2 (33.3%) n=5 4 (80%) 1 (20%) 19.8 (6.61), n = 5 0.89 (0.88), n = 5
4 (66.7%) 2 (33.3%) n=6 1 (16.7%) 5 (83.3%)
1 (0.93, 1.06)
p Value 2
0.403
39 (90.7%) 4 (9.3%) n = 43 35 (81.4%) 8 (18.6%) n = 41 26 (63.4%) 15 (36.6%) 20.15 (6.67), n = 41 0.34 (0.47), n = 41
40 (93%) 3 (7%) n = 43 7 (16.3%) 36 (83.7%)
OR (95% CI)*
0.308 Reference 0.2 (0.02, 2.07)
0.161
Reference 2.81 (0.31, 63.29) 1.07 (0.91, 1.29) 0.05 (0, 0.54)
0.405 0.423 0.061
Reference 0.04 (0, 0.58)
0.028
Reference 1.46 (0.06, 16.36)
0.769
0.636
1
p Value 1 based on Wilcoxon Rank Sum test or Fisher’s exact test. p Value 2 based on age-gender adjusted logistic regression. *OR represent the ratio in odds between patients with good clinical outcomes and patients with poor clinical outcomes (reference). Statistically significant p-values 50.05 in bold. TABLE 4. Complications and reasons for poor outcomes in direct and dural CCFs. Complications of CCF Direct CCF (treated) 1 Left compressive optic neuropathy Dural CCF (treated) 1 Residual bilateral CN VI palsies and orbital congestion 2 Central retinal vein occlusion with orbital congestion with raised IOP 3 Cranial nerve VI palsy Dural CCF (untreated) 4 Cranial nerve III palsy and glaucoma 5 Left central retinal vein occlusion with laser and left macular scarring
Angiographic closure
No. of treatments
Residual symptoms
Presenting VA
Final VA
Closed
1
Poor final visual acuity
N/A
NPL
Recurrent CCF
1
Diplopia, tinnitus and headache
R: 6/12 L: 6/6
R: 6/9 L: 6/6
Open CCF (partially closed after 3rd treatment) Partially closed
3
Poor final visual acuity
6/18
6/120
4
Diplopia
6/6
6/6
Poor final visual acuity Poor final visual acuity
CF
HM
CF*
6/30
Untreated
N/A
Untreated
N/A
R = right eye, L = left eye, CF = counting fingers closely, HM = hand movements, NPL = no perception of light. !
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50 Tan et al.
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FIGURE 1. Presenting signs and symptoms of CCFs according to their pattern of angiographic drainage (p40.05 unless stated).
CCFs achieved complete angiographic closure (86% versus 52%). Despite complete angiographic closure of a direct CCF, one patient had residual diplopia with compressive optic neuropathy and subsequent permanent poor visual acuity. This poor clinical outcome may be related to a more severe initial clinical presentation that may result in irreversible damage to orbital and ocular structures despite subsequent treatment and complete anatomical closure of the fistula. Overall, both our angiographic outcomes and clinical outcomes were comparable to similar studies and our current treatment result in similar outcomes for both treated and untreated cases. In a similar Asian study22 of 80 consecutive patients who underwent treatment for dural CCFs, clinical cure was achieved in 41 patients (51%) and improvement in 30 patients (38%). This result was similar to our study. The authors reported slightly better angiographic outcomes than our study (63% versus 52%). Another case series from the Netherlands9 of 101 cases reported the incidence of ocular signs and symptoms associated with both spontaneous and traumatic CCFs, where the rate of treatment with embolization was lower than in our study (14% versus 78%). A similar trend in this study and our study was that treated CCFs had slightly better outcomes than untreated CCFs. In the Dutch study 100% of treated CCFs recovered or improved versus 82% of untreated CCFs, similar to our study where 87% of treated CCFs recovered or improved versus 76% of untreated CCFs(p40.05). The difference was not however statistically significant and the current CCF treatment in our centre seems to result in similar clinical outcomes for both treated and untreated cases. The presenting VA of worse than 6/60 and the use of anticoagulation or anti-platelet medication was associated with poor outcomes in our patients. This may have useful clinical implications for prognosis.
The resolution of CCFs with treatment or spontaneously was thought to occur as a result of thrombosis of the feeder vessels of the CCF.6,23 Hence anticoagulant or anti-platelet agents may reduce the rate of thrombosis and result in persistent clinical manifestations of the CCF. There have been no previous reports of this association in the literature. In our study there is a low rate of patients on anti-coagulation or anti-platelet medicine and one patient was not treated, which may have contributed to the poor outcome. Larger studies are required to establish the strength of this association. Poor visual acuity related to the CCF complications can include: compressive optic neuropathy, central retinal vein occlusion, proliferative retinopathy and glaucoma. Visual acuity alone however is not a good outcome measure for CCF patients. Significant residual symptoms of orbital congestion (e.g. proptosis, pain and swelling) with complications of raised IOP and diplopia also result in poor outcomes. In our series we had one case (2%) of a central retinal artery occlusion, which is a rare complication of embolization. Another study reported 3/80 (4%) of patients having similar intraoperative complications. The limitations of our study included the retrospective design and limited sample size for direct CCFs; however this study correlates angiographic outcomes with clinical outcomes and compares the clinical outcomes of both treated and untreated CCF cases. Other studies9,10 only briefly report the outcomes of conservatively managed CCFs and difference in the clinical outcomes have not been analysed. The use of anti-coagulation and anti-platelet medication in patients with CCF should be re-considered as this may be associated with a poor clinical outcome. Poor final visual acuity and diplopia may be due to either complications of the CCF itself or subsequent embolisation treatment. Orbit
Carotid-Cavernous Sinus Fistulas
ACKNOWLEDGEMENTS This research received no specific grant from any funding agency in the public, commercial or not-forprofit sectors.
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DECLARATION OF INTEREST No conflicting relationship exists for any author. Dr. Anna C.S. Tan researched data and wrote the manuscript. Mr. Li Xiang did statistical analysis of the data. Dr. Saadia Farooqui and Dr. Tan Yar Li assisted with data collection and contributed to writing the paper. Prof. James Cullen, Prof. Seah LL, Dr. Audrey Looi, Dr. Winston Lim and Dr. Sharon Tow contributed to conception, design, and discussion, in addition reviewed and edited the manuscript. Ethics committee approval: This study was conducted in accordance with the Declaration of Helsinki with ethics approval from the Singapore Central Institutional Review Board. Consent was waived as this was a retrospective review of medical records and no identifying information of any patient was used.
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8. Fiore PM, Latina MA, Shingleton BJ, et al. The dural shunt syndrome. I. Management of glaucoma. Ophthalmology 1990;97(1):56–62. 9. de Keizer R. Carotid-cavernous and orbital arteriovenous fistulas: ocular features, diagnostic and hemodynamic considerations in relation to visual impairment and morbidity. Orbit 2003;22(2):121–142. 10. Kupersmith MJ, Vargas EM, Warren F, Berenstein A. Venous obstruction as the cause of retinal/choroidal dysfunction associated with arteriovenous shunts in the cavernous sinus. J Neuroophthalmol 1996;16(1):1–6. 11. Kai Y, Morioka M, Yano S, et al. External manual carotid compression is effective in patients with cavernous sinus dural arteriovenous fistulae. Interv Neuroradiol 2007; 13(Suppl 1):115–122. 12. Meyers PM, Halbach VV, Dowd CF, et al. Dural carotid cavernous fistula: definitive endovascular management and long-term follow-up. Am J Ophthalmol 2002; 134(1):85–92. 13. Kirsch M, Henkes H, Liebig T, et al. Endovascular management of dural carotid-cavernous sinus fistulas in 141 patients. Neuroradiology 2006;48(7):486–490. 14. Yoshida K, Melake M, Oishi H, et al. Transvenous embolization of dural carotid cavernous fistulas: a series of 44 consecutive patients. AJNR Am J Neuroradiol 2010; 31(4):651–655. 15. Harris MJ, Fine SL, Miller NR. Photocoagulation treatment of proliferative retinopathy secondary to a carotid-cavernous fistula. Am J Ophthalmol 1980;90(4):515–518. 16. Grumann AJ, Boivin-Faure L, Chapot R, et al. Ophthalmologic outcome of direct and indirect carotid cavernous fistulas. Int Ophthalmol 2012;32(2):153–159. 17. Thanapura C. Treatment of traumatic carotid-cavernous fistula at the Udon Thani Center Hospital. J Clin Neurosci 2004;11(5):498–500. 18. Liang CC, Michon JJ, Cheng KM, et al. Ophthalmologic outcome of transvenous embolization of spontaneous carotid-cavernous fistulas: a preliminary report. Int Ophthalmol 1999;23(1):43–47. 19. Keltner JL, Satterfield D, Dublin AB, Lee BC. Dural and carotid cavernous sinus fistulas. Diagnosis, management, and complications. Ophthalmology 1987;94(12): 1585–1600. 20. Debrun GM, Vinuela F, Fox AJ, et al. Indications for treatment and classification of 132 carotid-cavernous fistulas. Neurosurgery 1988;22(2):285–289. 21. Suh DC, Lee JH, Kim SJ, et al. New concept in cavernous sinus dural arteriovenous fistula: correlation with presenting symptom and venous drainage patterns. Stroke 2005; 36(6):1134–1139. 22. Preechawat P, Narmkerd P, Jiarakongmun P, et al. Dural carotid cavernous sinus fistula: ocular characteristics, endovascular management and clinical outcome. J Med Assoc Thai 2008;91(6):852–858. 23. Bujak M, Margolin E, Thompson A, Trobe JD. Spontaneous resolution of two dural carotid-cavernous fistulas presenting with optic neuropathy and marked congestive ophthalmopathy. J Neuroophthalmol 2010; 30(3):222–227.
ORIGINAL ARTICLE
Ocular Manifestations and the Clinical Course of Carotid Cavernous Sinus Fistulas in Asian Patients Anna C. S. Tan1,2, Saadia Farooqui1, Xiang Li3,5, Yar Li Tan1, James Cullen1, Winston Lim4, Seah Lay Leng1,2,3, Audrey Looi1,2, and Sharon Tow1,2,3 Singapore National Eye Centre, Singapore, 2Singapore Eye Research Institute, Singapore, 3National University of Singapore, Singapore, 4Interventional Radiology Department, Singapore General Hospital, Singapore, and 5 Department of Statistics and Applied Probability, National University of Singapore, Singapore
ABSTRACT Purpose: To study the clinical course with regard to both the angiographic and visual outcomes of carotid cavernous fistulas (CCFs). Background: Carotid cavernous sinus fistulas (CCFs) are conditions which often present with ocular signs and symptoms. The clinical presentation of CCFs is varied according to the anatomy, haemodynamics and size of the CCF. CCFs causing significant symptoms or vision loss should be treated with embolization. Methods: This is a retrospective review of the medical records of all CCF cases seen in the Singapore National Eye Centre from September 2002 to December 2011. Results: 45 patients who had confirmed CCF on conventional cerebral angiography were included. Anterior draining CCFs presented with orbital congestion while posterior draining CCFs presented with pain, diplopia and cranial nerve palsies. Mild residual symptoms were still present in 85% of treated direct CCFs despite complete angiographic closure however 52% of treated dural CCFs had complete resolution of symptoms despite only half of those achieving angiographic closure. Treated and untreated dural CCFs had similar outcomes (87% versus 76% recovered or improved (p40.05)). Poor outcomes can result from residual diplopia or vision loss from complications of the CCF itself (e.g. compressive optic neuropathy, glaucoma, retinopathy) or complications from CCF embolization treatment (e.g. central retinal artery occlusion). Conclusion: Presenting symptoms and signs are related to the angiographic drainage of CCFs. Angiographic outcomes after embolization treatment may not always correlate with clinical outcomes. Keywords: Carotid-cavernous sinus fistulas, neuro-ophthalmology, orbit
INTRODUCTION
have an acute presentation with orbital congestion and ophthalmic symptoms. Dural arteriovenous fistulas on the other hand, result from connections between the cavernous sinus and branches of the meningeal arteries arising from the internal and/or external carotid artery. Those that drain posteriorly into the petrosal sinuses can be asymptomatic or present with painful, isolated cranial nerve palsies sometimes in the absence of orbital congestion.3,4 Posterior draining dural CCFs with cerebral vascular drainage can sometimes cause mortality through brainstem congestion and rarely intra-cranial haemorrhage.5 Posterior dural CCFs may
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1
A carotid cavernous fistula sinus (CCF) is an abnormal communication between the cavernous sinus and carotid arterial system. Classifications of CCF types can be divided by (1) anatomy; direct versus dural fistulas1 or posterior versus anterior draining fistulas2 (2) haemodynamic properties; high flow versus low flow (3) cause; spontaneous versus traumatic. Direct CCFs arise from a direct connection between the cavernous sinus and the cavernous portion of the internal carotid artery. Direct CCFs are usually associated with trauma and due to their high flow
Received 28 January 2013; Revised 7 September 2013; Accepted 30 September 2013; Published online 6 November 2013 Correspondence: Anna Tan, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751. E-mail: [email protected], [email protected]
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46 Tan et al. be difficult to diagnose and if left to progress may lead to a change in the drainage pattern. If the drainage becomes anterior, patients will then develop orbital congestion associated with ocular complications. Proptosis, lid swelling, conjunctival injection and chemosis and corkscrew vessels are all clinical signs associated with anterior draining dural CCFs. Ophthalmoplegia may be due to both orbital congestion and cranial nerve palsies. Pain and discomfort are common symptoms. Raised intra-ocular pressures (IOP) can occur from a raised episcleral venous pressure or an angle closure mechanism when venous congestion in the iris and choroid causes the lens iris diaphragm to move forward.6–8 When a patient presents with clinical signs and symptoms suggestive of CCF, investigations such as computed tomography scanning (CT) or magnetic resonance imaging (MRI) with angiography (MRA), Doppler and other ultrasound imaging may help confirm the diagnosis. However the gold standard diagnostic test is still cerebral catheter angiography. Angiography should be done to confirm the presence of the CCF and to plan subsequent treatment. Most direct CCFs have usually rapidly progressing orbital congestion and ocular symptoms requiring treatment. However 20–50% of dural CCFs close spontaneously despite presenting with significant orbital congestion. This closure of the CCF and resolution of the clinical symptoms can occur days or years after presentation.5,8 Treatment of a CCF is considered when the patient experiences significant ocular symptoms or complications. Vision loss in CCF is a serious complication and can result from orbital congestion causing compressive optic neuropathy and glaucoma. Progressive proptosis may lead to lagophthalmos and exposure keratopathy. In cases where there is either spontaneous or post-treatment thrombosis in the superior ophthalmic vein, a central retinal artery occlusion or ischaemic optic neuropathy can occur. Chronic ischaemia can lead to anterior segment ischaemia, neovascular glaucoma and proliferative retinopathy with vitreous haemorrhage. Other posterior segment complications include central retinal vein occlusion, retinal detachment, choroidal effusion and choroidal folds. In cases of CCFs related to trauma, traumatic optic neuropathy must also be considered if visual loss is present.8–10 Treatment of CCFs can be divided into conservative (e.g. observation or external manual ipsilateral carotid artery compression),11 radiological or surgical. Endovascular embolization and gamma knife surgery have achieved high rates (480%) of CCF closure.12–14 Local treatment of ocular complications is required if they are severe, but the treatment of the underlying CCF should be a priority. Lubricants or tarrsorraphy for exposure keratopathy can be considered. Topical glaucoma medications have a limited effect and
glaucoma surgery should only be considered if intra-ocular pressure is still elevated despite CCF closure. Pan retinal photocoagulation can be performed for proliferative retinopathy from ocular ischemia.8,15 A successful outcome of CCF treatment in most studies has been defined as anatomical closure of the fistula.14 More recent studies9,12,16 have also reported clinical resolution of symptoms which may not necessarily correlate to the anatomical closure of the CCF. In Asia, many case series14,17,18 have been small and details of ocular signs, symptoms and rates of visual complications have not been fully described.
METHODS Study Design This was a retrospective review of the medical records of all CCF cases seen in our centre from September 2002 to December 2011. All hospital, outpatient charts, angiographic and imaging studies were analysed. History of potential risk factors and the medication use was obtained from medical records. The angiographic outcome was determined at the end of the last treatment and the clinical outcome was assessed at the last follow-up visit.
Definitions and Classifications Poor visual acuity was defined as worse than 6/60. Proptosis was defined as more than 2 mm difference between the Hertel’s exophthalmometer measurement in unilateral cases, and a measurement of more than 20 mm in bilateral cases. Raised intraocular pressure was defined as more than 21 mmHg measured with Goldmann tonometry.
Outcomes Outcomes were divided into anatomical and clinical outcomes. Anatomical outcomes of the CCFs were determined on follow up imaging after treatment and were classified as completely closed, partially closed, open or recurrent. Clinical outcomes taken at the last follow-up visit were divided into (i) complete resolution, (ii) stable with residual mild symptoms still acceptable to the patient or (iii) poor outcomes where patients still had significant residual symptoms.
Statistical Analysis Statistical analysis was performed using R version 2.15.2 (R Development Core Team, Vienna, Austria, Orbit
Carotid-Cavernous Sinus Fistulas 2012). Characteristics of the study population were examined using proportions or means and standard deviation (SD). Wilcoxon’s Rank Sum test, McNemar’s test or Fisher’s exact test was performed to test the difference in distribution of potential risk factors between direct and dural CCFs and the difference in the incidence of various poor clinical outcomes. The Mann–Whitney U-test was used to test the association between two ordinal anatomical and clinical outcome variables. The association between clinical outcome and potential risk factors was assessed by using age-gender adjusted logistic regression.
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RESULTS Forty-five patients who had confirmed CCFs on conventional cerebral angiography were included in this study (Table 1). There were 8 (18%) direct CCFs and 37 (82%) dural CCFs, 16 (36%) were anterior draining, 8(17%) were posterior draining, 20 (44%) were both anterior and posterior draining and for 1 patient the drainage pattern was not available. Angiographic drainage pattern of the CCF affects the initial clinical presentation (Figure 1).
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Radiological and Clinical Outcomes of Treated and Untreated CCFs In our study 7 patients (87%) with direct CCFs were treated and 1 patient (13%) was observed. 29 (78%) patients with dural CCFs were treated and 8 (22%) of patients were observed. Indications for treatment include reduced visual acuity, raised IOP, significant orbital congestion and diplopia. No further imaging was performed for the observed patients and hence no angiographic outcomes were available for these patients. Fewer patients had raised intra-ocular pressure (34% versus 9%), significant proptosis (42% versus 11%) and diplopia (56% versus 19%) after treatment when compared to initial clinical presentation (Table 2A). The number of patients with visual acuity loss was more after treatment than before (9% versus 6%).The reasons for poor visual acuity are summarised in Table 4. The angiographic and clinical outcomes of treated direct and dural CCFs (Table 2B and 2C) and the clinical outcomes between treated and untreated dural CCFs were compared (Table 2D). The numbers of direct CCFs were too small for any meaningful statistical analysis (Table 2B). There was no significant association with angiographic outcomes and the incidence of poor clinical outcomes (Table 2C).
TABLE 1. Baseline characteristics for direct and dural CCFs.
Average age Gender Male Female Race Chinese Malay Indian Others Laterality Right Left Both Mean follow-up time in months (range) Mean time to presentation in months (range) Mean time to treatment in months (range) Trauma Hypertension Hyperlipidemia Diabetes Intervention Treated Observed
Direct CCF (n = 8)
Dural CCFs (n = 37)
41(18–54)
58(31–82)
5(62%) 3(38%)
11(30%) 26(70%)
4(50%) 0 0 4(50%)
33(89%) 2(5%) 1(3%) 1(3%)
p 50.01 0.11
0.01
0.01 4(50%) 3(38%) 1(12%) 12.4(2–53)
3(8%) 20(54%) 17(46%) 37.0(1–166)
0.01
2.9(0–9)
2.5(0–12)
0.81
2.9(0–10)
4.6(1–16)
0.23
A significantly higher percentage of patients on anticoagulant or anti-thrombotic medications had a poor clinical outcome (50% versus 3% p50.05) (Table 3). Presenting visual acuity less than 6/60 was also associated with a poor clinical outcome (33% versus 3%, p50.05). There was no association between ischaemic risk factors such as hypertension, hyperlipidemia and diabetes or the type of CCF (direct versus dural) and a poor clinical outcome in both treated and
TABLE 2A. The comparison of clinical characteristics of treated CCFs before and after treatment (n = no. of available results). Clinical characteristics of CCFs
7(88%) 0 1(13%) 1(13%)
2(5%) 15(41%) 17(46%) 8(22%)
50.01 0.04 0.12 1.00
7(87%) 1(13%)
29(78%) 8(22%)
1.00
p Value based on Fisher’s exact test or Wilcoxon’s Rank Sum test. !
Risk Factors for Poor Clinical Outcomes in Direct and Dural CCFs
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Visual acuity of worse than 6/60 (n = 33) Before treatment After treatment p
Intra-ocular pressure Significant 421 proptosis* Diplopia (n = 32) (n = 28) (n = 32)
2(6%)
11(34%)
12(42%)
18(56%)
3(9%)
3(9%)
3(11%)
5(16%)
0.56
50.01
p Value based on McNemar’s test. #2 patients were seen only after treatment.
0.01
50.01
48 Tan et al. untreated groups. Five (17%) patients with treated dural CCFs had poor outcomes with significant residual symptoms despite treatment (Table 4).
DISCUSSION
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Older studies19,20 quote 70–90% of all CCFs are direct CCFs but in our study, there was a significantly lower percentage of direct CCFs (18%). This may be a result of lower rates of head trauma due to improved safety regulations (e.g. increased helmet usage, stricter traffic regulations). An increase in the diagnosis of spontaneous dural CCFs by high resolution routine imaging and angiography may be another reason for a larger percentage of dural CCFs. Angiographic outcomes did not correlate with clinical outcomes
(Table 2B and 2C) and there was no significant difference in the clinical outcomes of treated and untreated dural CCFs. CCF is an evolving disease and the initial angiographic outcomes may not reflect the eventual clinical outcome. Similarly the improvement of symptoms in non-treated dural CCFs may be due to spontaneous thrombosis. The risk factors on presentation which were statistically significantly associated with a poor clinical outcome were the use of anti-coagulation or antithrombotic medication and a presenting visual acuity of 56/60 (Table 3). Classification of CCFs by their angiographic drainage pattern had a good correlation with the initial clinical presentation.2,6,21 In our study more dural CCFs had complete clinical resolution of symptoms than direct CCFs (52% versus 0%), however more direct versus dural
TABLE 2B. The association between anatomical and clinical outcomes of treated direct CCFs (n = 7). Poor clinical outcomes of CCF after treatment Anatomical outcomes after final treatment
Visual acuity of worse than 6/60
Intra-ocular pressure 421
Significant proptosis*
Residual diplopia
1 0 0
0 0 0
0 0 0
1 0 2
Completely closed CCF (n = 3) Partially closed CCF (n = 1) Partially closed initially then completely closed after 1 year (n = 3) Sample size too small for meaningful statistical analysis.
TABLE 2C. The association between anatomical and clinical outcomes of treated dural CCFs (n = 29). Poor clinical outcomes of CCFs after the final treatment Anatomical outcomes after final treatment
Visual acuity of worse than 6/60
Closed CCF (n = 10) Partially closed CCF (n = 12) Partially closed initially then completely closed after 1 year (n = 4) Recurrent CCF(n = 1) Result unavailable (n = 2) p
Intra-ocular pressure 421
Significant proptosis*
Residual diplopia
Anyy
1 1 0
1 1 0
0 1 1
2 1 0
3 2 1
0 1 0.57
0 1 0.52
0 1 0.19
1 0 0.91
1 2 0.92
p Value based on Mann–Whitney U-Test. yAny defined as any one of the four poor clinical outcomes of CCFs.
TABLE 2D. The comparison of clinical outcomes between treated and untreated dural CCFs (n = 37). Poor clinical outcomes of CCFs after the final treatment
Treated dural CCF(n = 29) Untreated dural CCF(n = 8) p
Visual acuity of worse than 6/60
Intra-ocular pressure 421
Significant proptosis*
Residual diplopia
3(10%) 1(13%) 1
3(10%) 2(25%) 0.29
2(7%) 0(0%) 1
5(17%) 1(13%) 1
p Value based on Fisher’s exact test. *Based on a difference of 42 mm in unilateral cases and 420 mm in bilateral cases on Hertel’s exophthalmometry measurement. Orbit
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TABLE 3. Risk factors for poor clinical outcome in direct and dural CCFs. Clinical outcome Overall (n = 43)
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Age Gender Female Male Hypertension No Yes Diabetes No Yes Hyperlipidemia No Yes Anticoagulation/ Anti-platelet No Yes Trauma No Yes Proptosis No Yes Presenting IOP Presenting visual acuity Presenting visual acuity of less 56/60 No Yes CCF Direct Dural
55.62 (13.47), n = 43 n = 43 28 (65.1%) 15 (34.9%) n = 43 29 (67.4%) 14 (32.6%) n = 43 34 (79.1%) 9 (20.9%) n = 43 26 (60.5%) 17 (39.5%) n = 43
Poor (n = 6) 56.81 (16.7), n=6 n=6 5 (83.3%) 1 (16.7%) n=6 4 (66.7%) 2 (33.3%) n=6 5 (83.3%) 1 (16.7%) n=6 5 (83.3%) 1 (16.7%) n=6
Good (n = 37) 55.43 (13.13), n = 37 n = 37 23 (62.2%) 14 (37.8%) n = 37 25 (67.6%) 12 (32.4%) n = 37 29 (78.4%) 8 (21.6%) n = 37 21 (56.8%) 16 (43.2%) n = 37
p Value 1 0.551
Reference 3.01 (0.41, 61.33)
0.34
Reference 1.25 (0.16, 11.93)
0.834
Reference 1.63 (0.21, 34.38)
0.68
Reference 4.39 (0.53, 96.73)
0.225
Reference 0.02 (0, 0.28)
0.008
1
0.376
0.006
36 (97.3%) 1 (2.7%) n = 37 31 (83.8%) 6 (16.2%) n = 36 22 (61.1%) 14 (38.9%) 20.19 (6.76), n = 36 0.26 (0.34), n = 36
0.889 0.089
n = 43
n=6
n = 37
0.047
36 (97.3%) 1 (2.7%) n = 37 6 (16.2%) 31 (83.8%)
0.933
1
3 (50%) 3 (50%) n=6 4 (66.7%) 2 (33.3%) n=5 4 (80%) 1 (20%) 19.8 (6.61), n = 5 0.89 (0.88), n = 5
4 (66.7%) 2 (33.3%) n=6 1 (16.7%) 5 (83.3%)
1 (0.93, 1.06)
p Value 2
0.403
39 (90.7%) 4 (9.3%) n = 43 35 (81.4%) 8 (18.6%) n = 41 26 (63.4%) 15 (36.6%) 20.15 (6.67), n = 41 0.34 (0.47), n = 41
40 (93%) 3 (7%) n = 43 7 (16.3%) 36 (83.7%)
OR (95% CI)*
0.308 Reference 0.2 (0.02, 2.07)
0.161
Reference 2.81 (0.31, 63.29) 1.07 (0.91, 1.29) 0.05 (0, 0.54)
0.405 0.423 0.061
Reference 0.04 (0, 0.58)
0.028
Reference 1.46 (0.06, 16.36)
0.769
0.636
1
p Value 1 based on Wilcoxon Rank Sum test or Fisher’s exact test. p Value 2 based on age-gender adjusted logistic regression. *OR represent the ratio in odds between patients with good clinical outcomes and patients with poor clinical outcomes (reference). Statistically significant p-values 50.05 in bold. TABLE 4. Complications and reasons for poor outcomes in direct and dural CCFs. Complications of CCF Direct CCF (treated) 1 Left compressive optic neuropathy Dural CCF (treated) 1 Residual bilateral CN VI palsies and orbital congestion 2 Central retinal vein occlusion with orbital congestion with raised IOP 3 Cranial nerve VI palsy Dural CCF (untreated) 4 Cranial nerve III palsy and glaucoma 5 Left central retinal vein occlusion with laser and left macular scarring
Angiographic closure
No. of treatments
Residual symptoms
Presenting VA
Final VA
Closed
1
Poor final visual acuity
N/A
NPL
Recurrent CCF
1
Diplopia, tinnitus and headache
R: 6/12 L: 6/6
R: 6/9 L: 6/6
Open CCF (partially closed after 3rd treatment) Partially closed
3
Poor final visual acuity
6/18
6/120
4
Diplopia
6/6
6/6
Poor final visual acuity Poor final visual acuity
CF
HM
CF*
6/30
Untreated
N/A
Untreated
N/A
R = right eye, L = left eye, CF = counting fingers closely, HM = hand movements, NPL = no perception of light. !
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50 Tan et al.
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FIGURE 1. Presenting signs and symptoms of CCFs according to their pattern of angiographic drainage (p40.05 unless stated).
CCFs achieved complete angiographic closure (86% versus 52%). Despite complete angiographic closure of a direct CCF, one patient had residual diplopia with compressive optic neuropathy and subsequent permanent poor visual acuity. This poor clinical outcome may be related to a more severe initial clinical presentation that may result in irreversible damage to orbital and ocular structures despite subsequent treatment and complete anatomical closure of the fistula. Overall, both our angiographic outcomes and clinical outcomes were comparable to similar studies and our current treatment result in similar outcomes for both treated and untreated cases. In a similar Asian study22 of 80 consecutive patients who underwent treatment for dural CCFs, clinical cure was achieved in 41 patients (51%) and improvement in 30 patients (38%). This result was similar to our study. The authors reported slightly better angiographic outcomes than our study (63% versus 52%). Another case series from the Netherlands9 of 101 cases reported the incidence of ocular signs and symptoms associated with both spontaneous and traumatic CCFs, where the rate of treatment with embolization was lower than in our study (14% versus 78%). A similar trend in this study and our study was that treated CCFs had slightly better outcomes than untreated CCFs. In the Dutch study 100% of treated CCFs recovered or improved versus 82% of untreated CCFs, similar to our study where 87% of treated CCFs recovered or improved versus 76% of untreated CCFs(p40.05). The difference was not however statistically significant and the current CCF treatment in our centre seems to result in similar clinical outcomes for both treated and untreated cases. The presenting VA of worse than 6/60 and the use of anticoagulation or anti-platelet medication was associated with poor outcomes in our patients. This may have useful clinical implications for prognosis.
The resolution of CCFs with treatment or spontaneously was thought to occur as a result of thrombosis of the feeder vessels of the CCF.6,23 Hence anticoagulant or anti-platelet agents may reduce the rate of thrombosis and result in persistent clinical manifestations of the CCF. There have been no previous reports of this association in the literature. In our study there is a low rate of patients on anti-coagulation or anti-platelet medicine and one patient was not treated, which may have contributed to the poor outcome. Larger studies are required to establish the strength of this association. Poor visual acuity related to the CCF complications can include: compressive optic neuropathy, central retinal vein occlusion, proliferative retinopathy and glaucoma. Visual acuity alone however is not a good outcome measure for CCF patients. Significant residual symptoms of orbital congestion (e.g. proptosis, pain and swelling) with complications of raised IOP and diplopia also result in poor outcomes. In our series we had one case (2%) of a central retinal artery occlusion, which is a rare complication of embolization. Another study reported 3/80 (4%) of patients having similar intraoperative complications. The limitations of our study included the retrospective design and limited sample size for direct CCFs; however this study correlates angiographic outcomes with clinical outcomes and compares the clinical outcomes of both treated and untreated CCF cases. Other studies9,10 only briefly report the outcomes of conservatively managed CCFs and difference in the clinical outcomes have not been analysed. The use of anti-coagulation and anti-platelet medication in patients with CCF should be re-considered as this may be associated with a poor clinical outcome. Poor final visual acuity and diplopia may be due to either complications of the CCF itself or subsequent embolisation treatment. Orbit
Carotid-Cavernous Sinus Fistulas
ACKNOWLEDGEMENTS This research received no specific grant from any funding agency in the public, commercial or not-forprofit sectors.
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DECLARATION OF INTEREST No conflicting relationship exists for any author. Dr. Anna C.S. Tan researched data and wrote the manuscript. Mr. Li Xiang did statistical analysis of the data. Dr. Saadia Farooqui and Dr. Tan Yar Li assisted with data collection and contributed to writing the paper. Prof. James Cullen, Prof. Seah LL, Dr. Audrey Looi, Dr. Winston Lim and Dr. Sharon Tow contributed to conception, design, and discussion, in addition reviewed and edited the manuscript. Ethics committee approval: This study was conducted in accordance with the Declaration of Helsinki with ethics approval from the Singapore Central Institutional Review Board. Consent was waived as this was a retrospective review of medical records and no identifying information of any patient was used.
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