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Sclerosing Agents in Ophthalmology

mixing weed and adderall

mixing adderall and weed
Smriti Nagpal, Ruchi Goel, Sushil Kumar, Sonam Garg
Guru Nanak Eye Center, MAMC, New Delhi

Corresponding Author:

Dr. Smriti Nagpa
E-mail : smriti_nagpal@hotmail.com

Published Online: 25-SEP-2013
DOI:http://dx.doi.org/10.7869/djo.2012.73

Abstract
Sclerotherapy is a surgical procedure used for vascular and lymphatic malformations, in all age groups, wherein a sclerosing agent is injected into a vessel to make it shrink. It involves injection of the agent intravascularly intralesionally or topically, under direct vision or under the guidance of radiological imaging. Sclerotherapy has primarily been used in ophthalmology for treatment of arteriovenous malformations like hemangiomas and carotico-cavernous fistulas, and lymphatic abnormalities like lymphangiomas. Sclerosing agents are chemical compounds which cause endothelial injury leading to inflammation and vascular thrombosis. They may be classified into various categories like detergents, hyperosmotic agents, corticosteroids, cytotoxic agents etc. A short description on beta-blockers has also been included in this article, even though beta-blockers are not sclerosants per se. Polyvinyl alcohol, sodium tetradecyl sulphate (STS) and ethanol may be used for arterio-venous malformations, while for lymphangiomas agents like sodium morrhuate, STS, doxycycline and OK-432 are used. In hemangioma patients, corticosteroids and beta-blockers are amongst the first line therapy.
Keywords :

Sclerotherapy is a surgical procedure used for vascular and lymphatic malformations, in all age groups, wherein a sclerosing agent is injected into a vessel to make it shrink. It maybe used alone or as an adjuvant therapy, along with laser, cryotherapy, radiation and surgical excision. The procedure involves injection of the agent intravascularly (inject into the feeder vessel), intralesionally or topically, under direct vision or under the guidance of radiological imaging. Multiple sessions may however be required for complete closure of the abnormal vessels.

 Sclerotherapy has primarily been used in ophthalmology for treatment of AV malformations (AVM) like hemangiomas and carotico-cavernous fistulas, and lymphatic abnormalities like lymphangiomas. They are also used as an adjunctive treatment in large tumors to decrease their blood supply. The procedure is performed on a day-care basis, with minimum patient morbidity and the type of anaesthesia is guided by the lesion and the patient profile. In ophthalmology,sclerotherapy though not popular earlier due to the risk of blindness due to central retinal artery embolisation is now gaining a renewed interest. This may be attributed to the advances in guidewire and microcatheter technology, along with improved digital-subtraction angiography (DSA) and road-mapping techniques, which allow the surgical neuroangiographer to navigate previously unreachable territories with limited risk. It is possible to place microcatheters into the ophthalmic artery distal to the central retinalartery a placement that is a prerequisite to safe embolization.[1]

Sclerosing Agents/ Sclerosants

These are chemical compounds which cause endothelial injury leading to inflammation and vascular thrombosis.[2] An intact endothelium aggressively lyses the thrombus, therefore, vascular fibrosis and obliteration occurs only in response to irreversible endothelial cellular destruction and exposure of the underlying subendothelial cell layer.[2] Sclerosant is diluted with blood as it diffuses away from the site of injection, thus if a strong sclerosant is injected there will be three zones of action.[2](Figure 1)

Types of Sclerosants

Historically various foreign substances have been used for producing venous endothelial trauma. These include, among others, ‘a slender rod of iron', reportedly used by Hippocrates himself and absolute alcohol, introduced in the 1840’s. However, early sclerosing agents caused many deaths from sepsis and from pulmonary embolism, as well as a high incidence of allergic reactions, local tissue necrosis, pain, and failed sclerosis.

Ideal Characteristics of a Sclerosant[2]:
  • No systemic toxicity
  • Effective only above some threshold concentration
  • Require a long period of contact to be effective, hence, more effective in areas of stasis and relatively safer in the deep veins where there is high flow.
  • Non-allergenic
  • Strong enough to sclerose even the largest vessels, yet it would produce no local tissue injury if extravasated
  • Not cause staining or scarring or telangiectatic matting
  • Perfectly soluble in normal saline
  • Painless upon injection
  • Inexpensive
At present, such an agent does not exist.



Classification of Sclerosants

1. Detergents

This class of drugs came into use in the 1930’s. They work by a mechanism known as protein theft denaturation, in which an aggregation of detergent molecules forms a lipid bilayer in the form of a micelle, which then disrupts the cell surface membrane and may steal away essential proteins from the cell membrane surface leading delayed cell death.

Determinants of activity of detergent solutions:
  1. Concentration: Micelle formation occurs only above a threshold concentration called the Critical Micellar Concentration (CMC), below which the agent causes no injury.
  2. Temperature: Detergent molecules are much more soluble in cold solutions than in hot ones. Hence, their sclerosing effect is higher at warmer temperatures.
  3. Mixing: The surface area of lipid bilayer structures is maximized when the solution is shaken and because it is the surface of these structures that causes protein theft denaturation, a solution that has been shaken will be a more effective. Unfortunately, foamy bubbles that are injected into the veins, run the risk of causing air embolism.
Currently available detergent agents:
  • Sodium morrhuate
  • Ethanolamine oleate
  • Sodium tetradecyl sulphate (Sotradecol)
  • Polidocanol
  • Scleremo
2. Hypertonic and Ionic Solution (Osmotic Sclerosants)

These solutions were thought to cause endothelial death by osmotic cellular dehydration. But recent evidence suggests that these agents probably work by causing conformational denaturation of cell membrane proteins in situ. Like the detergents, they can be diluted to the point where they have no further cellular toxicity. These include:
  • Hypertonic saline
  • Sclerodex
  • Polyiodinated iodine
3. Cellular Toxins

They probably act by a direct or indirect chemical toxicity to endothelial cells. Such agents are less useful since they are also toxic to other body cells and also they remain toxic to some degree even after extreme dilution, so that there is no real threshold below which injury will not occur. These include:
  • 5 Fluorouracil
  • Bleomycin
4. Corticosteroids

5. Others Include

Ethibloc, Alcohols ( polyvinyl alcohol, ethanol)

OK-432, doxycycline, fibrin glue, cyanoacrylate glue and beta blockers**

** Although these agents are not classified as sclerosing agents, yet they are now being widely used in the treatment of infantile hemangiomas.

Sclerotherapy of some common ophthalmic pathologies

6. Arteriovenous malformations

Polyvinyl Alcohol (PVA): PVA is used as a suspension form. The particles are mixed in a combination of saline and contrast. PVA has a tendency to flocculate or settle out of solution. Hence, immediately prior to injection, the material should be resuspended so that uniform injection can be obtained.PVA has been used as an add-on treatment in orbital AVM’s.[1,3]
 
Ethanol (95% to 98% conc.)[4]: Firstly, high flow lesions are excluded using various imaging techniques. Then under ultrasound guidance, the AVM is cannulated and ethanol is injected. The volume depends upon size of the lesion. It’s left in place for 5-10 mins and then aspirated out. Repeat sessions may be needed several weeks apart. The volume of ethanol that can be injected should be small (0.5–1 mL/kg) to minimize systemic complications and is, therefore, often ineffective. Max upto 60 ml may be used at one time. Having a low viscosity, it passes readily through arteriovenous shunts making it suitable for embolisation of AVM in conjunction with supra-selective catheterization of the nidus.

STS: 1.2 ml intraarterial injection was used in a study. It was injected into the ophthalmic artery, with the cannula just beyond the central retinal artery.[1]

Fibrin glue can also be combined with different sclerosing agents to aggregate the drugs and increase the time of pharmaceutical effect.[5]

7. Lymphangiomas

The endothelial lining of lymphangiomas is vulnerable to infections and chemical irritants, and spontaneous infection of lymphangiomas can lead to total regression of the lesion. However it is essential to exclude coexisting venous or arteriovenous malformations, since intravascular injection of sclerosing agents could damage normal vessels. Hence, hemodynamic assessment of deep orbital lesions is necessary pre-treatment.

Sodium morrhuate 5%[6]: It should be used only in superficial orbital lymphangiomas because of the potential for severe deep orbital inflammation and fibrosis. For this intralesional sodium morrhuate 5% can be injected under direct visualization or under radiographic guidance. The lesions regress in 1 to 6 injections of 0.2 to 2.1 ml sodium morrhuate 5%. Reported complications are orbital hemorrhage and transient keratopathy.

For deep lymphangiomas adjunctive intraoperative injection of sodium morrhuate 5%, under direct visualization into lymphangioma channels prior to surgical excision is performed. Because injected tissues are partially excised shortly after injection, deep orbital sclerosis and inflammation are lesser. Furthermore, the sclerosing agent remains in residual lymphangioma tissue, causing further sclerosis and involution. Because lymphangiomas lack communication with surrounding tissues, residual sclerosing agent remains within the lesion and mostly spares normal tissues. This leads to maximal debulking of the lymphangioma mass, with minimal deep inflammation. In the orbit, incremental volumes of 0.2 ml can be injected beneath the tumor surface, turning the surface dark from clotting. Injected tissues are then excised. Cycles of dissection, injection, and excision can be repeated until the majority of tumor bulk is removed.

STS: It is a widely used, safe and effective solution for destroying unwanted veins. Several authors reported good results after intralesional injection into orbital lymphangiomas.[7] The lesions are punctured directly under CT guidance and 3% STS is injected intralesionally. One to three injections in total, spaced at least 3 months apart, with each injection involving a volume of 1.5–2 ml of STS can be administered.[7] After the injection, the patients are given intravenous dexamethasone (0.3 mg/kg) and cloxacillin (50–100 mg/kg) divided into 4 doses, followed by oral prednisolone (1 mg/kg/per day) and oral cloxacillin (50–100 mg/kg) for 1 week.[7]

Polidocanol: Jain et al[8] achieved a volume reduction of 96% to 100% in 3 patients with lymphangiomas after sonographically guided percutaneous injection of 1% polidocanol 1-6 ml, depending on the size of the lesion.

Ethanol: Sclerotherapy can be affected using CT-guided technology, under sedation or general anesthesia, using <1.0 ml/kg of body weight.

Shiels et al[9] reported good results after dual-drug chemoablation (sequential intracystic sodium tetradecyl sulfate [STS] and ethanol) of macrocystic lymphangiomas. They hypothesized that STS effectively releases transmembrane lipoproteins from the lymphangioma cell membrane and leads to increased membrane permeability and, therefore, allows greater membrane penetration of ethanol. Bleomycin has also been used in lymphangiomas, mostly in combination with surgery.

Doxycycline (5-20 mg/ml): Available as a powder that can be suspended in saline or contrast medium. Since the injection is very painful, use of general anaesthesia may be preferred. The effect is usually seen after 4 to 6 weeks. An alternative application of doxycycline in cases of massive lymphangiomas is an irrigation of the lymphangioma via a drainage catheter.

Ethibloc and OK-432 are also used.

8. Haemangiomas[10]

 Since most capillary hemangiomas undergo spontaneous involution, treatment is reserved for patients at risk for permanent visual impairment, which maybe due to amblyopia, compressive optic neuropathy or proptosis with exposure keratopathy. Drug therapy is also indicated for mixed hemangiomas, proliferative hemangiomas, and hemangiomas that affect vital organs or are lifethreatening. Several treatment modalities exist, used depending on the lesion location and size and the potential adverse effects of intervention.

Corticosteroids: are the most commonly used agents.
  • Systemic: are generally considered first-line treatment, especially helpful in diffuse or deep orbital lesions. Effectiveness depends on the dose used. The best results are seen at <6 months of age. Oral prednisolone is more effective than intravenous injection of methylprednisolone. Oral prednisolone (2.0–5.0 mg/kg) is used, every other morning for 6-8 weeks and then tapered. The treatment can be repeated for 2 or 3 cycles if needed, at 4-6 week intervals. Rebound growth after corticosteroid discontinuation can prolong treatment. leading to increased systemic side effects.
  • Intralesional: A combination of short- and long-acting intralesional corticosteroids (1:1 mixture of triamcinolone acetate @ 1-2mg/kg to a max of 60 mg, 40 percent and betamethasone sodium phosphate or acetate 6 mg/ml) often results in an initial rapid regression, followed by a sustained response over the next 6-8 weeks. Posterior sub-Tenon’s injection has also been used for cutaneous, anterior and focal orbital hemangiomas.[3] Local complications include dystrophic periocular calcifications, skin hypopigmentation and fat atrophy, eyelid necrosis, central retinal artery occlusion (CRAO) and adrenal suppression.
  • Topical (clobetasol propionate 0.05 percent): Are best used as adjunctive therapy. They are most effective in superficial cutaneous lesions and have significantly fewer side effects, although adrenal suppression can occur when used in large doses over a prolonged period.
Immunomodulators. They may be especially effective for lesions with an orbital component.
  • Vincristine has been moderately successful in treating the diffuse visceral hemangiomas of Kasabach- Merritt syndrome.
  • Cyclophosphamide (10 mg/kg/day) has been used as monotherapy or in combination with systemic corticosteroids. Long term use may lead to myelosuppression and hepatotoxicity.
  • Interferon alfa-2a is less commonly used due to its neurotoxic side-effects (spastic diplegia).
In an effort to shorten the treatment period, a recent retrospective case series used a combination of cyclophosphamide (10 mg/kg/day for three days, then every two weeks) and interferon alfa-2a (3 million U/m2/day subcutaneously). Treatment was limited to maximum 6 months, with fairly good results.
  • Imiquimod can be used for small and intermediate-sized hemangiomas[6] located in inconspicuous sites, with alternate day topical application, for a cycle of 3 to 5 months. (Advantages: easy to use, safe, and no local irritation or systemic effects. Disadvantage: may cause hyperpigmentation).
Bleomycin: Administered intralesionally in complicated cutaneous hemangiomas[13] and in proliferative hemangiomas which respond poorly to steroids and/or laser therapy. Technique: 8 mg is dissolved with 2% lidocaine and then mixed with normal saline and dexamethasone (5 mg/1 mL). The injection in?ltrates evenly within the lesion until the surface of the lesion appears pale and is followed by compression for 15 to 30 minutes. The injection can be repeated every 2 to 3 weeks; each dosage is not more than 8 mg.

Vincristine: It is used for hemangiomas that are unresponsive to steroids or rebound after steroids.[14] 0.5 to 1.0 mg/ kg is given i.v. once a week for 6 weeks. This cycle may be repeated if necessary.

In cases with fulminant life-threatening platelet consumptive coagulapathy, diluted ethanol embolotherapy was reported to be very effective.

Commonly Used Agent
  1. Sodium morrhuate (conc 5%, pH 9.5, iv use only)
    • Mixture of saturated and unsaturated fatty acids, derived from cod liver oil.
    • Contraindications: Allergy, DVT, vasculitis, uncontrolled DM, thyrotoxicosis, TB, neoplasms, asthma, sepsis, blood dyscrasias, acute respiratory or skin disease and in bedridden patients. Use with caution in pregnant/lactatating mothers.
    • Extravasation may cause extensive tissue necrosis
    • Side effects: Aching or burning sensation at injection site with discolouration, redness, swelling or ulceration; allergic reactions. Pulmonary embolism and anaphylaxis have been documented. (test dose of 0.25-1 mL recommended).
  2. Sotradecol (Sodium Tetradecyl Sulphate (STS), 0.1-3%)
    • Synthetic long chain fatty acid.
    • Adverse Effects: Nausea, vomiting, cough, shortness of breath; pulmonary embolism; pruritus; redness of conjunctiva; injection site problems (hyperpigmentation, ulcer or necrosis following extravasation); hypersensitivity reaction and anaphylaxis (test dose of 0.5ml of 1% solution is recommended).
    • Contraindications: hypersensitivity, pregnancy, thrombophlebitis, hyperthyroidism. Acute infections, TB, prolonged recumbency, cardiac insufficiency, uncontrolled diabetes, arterial disease and asthma.
  3. Polidocanol (1%, max upto 2mg/kg/day, iv use only)
    • Synthetic long-chain fatty alcohol.
    • Advantages: Painless upon injection, does not produce necrosis, and has been reported to have a very low incidence of allergic reactions.
    • Side effects: Injection site problems (hematoma, irritation, discolouration, pain, pruritus, thrombosis, ischemia); neovascularization; anaphylaxis and cardiac arrest have been documented
    • Contraindications: Hypersensitivity and acute thromboembolic disease
    • Pregnancy Category C, Lactation: caution advised.
  4. Polyvinyl Alcohol (Foam particles, 50-2000 microns)
    • PVA is utilised predominantly for tumor embolisation as well as pre-operative devascularisation of other lesions.
    • Aggregation of PVA particles may result in occlusion of the delivery catheter or a more proximal vascular occlusion than intended.
    • MoA: Direct mechanical obstruction as well as induction of a foreign body type granulomatous reaction. Over time this reaction subsides and the vessel may recanalise.
  5. Ethanol (95%-98%, @0.5–1 mL/kg, max upto 60ml)
    • Complications: nerve injury, skin necrosis, and systemic effects (hypotension, respiratory depression, cardiac arrhythmias, CNS depression, seizures, pulmonary hypertension and hypoglycaemia)
    • There is an intense sclerotic reaction, and easy passage into normal adjacent vessels causing damage.
    • Impractical in small children due to high risk of systemic toxicity.
    • MoA: Denaturation of endothelial proteins, results in immediate thrombosis.
  6. Doxycycline
    • Broad spectrum antibiotic
    • Relatively nontoxic, hence, large volumes can be used in a single session.7
    • The exact MoA is unknown, but an in?ammatory process causing ?brosis and involution of cysts is speculated.12 Also causes inhibition of MMP’s and suppression of vascular endothelial growth factor (VEGF)-induced angiogenesis and lymphangiogenesis.
    • Side Effects: local erythema and pain. Systemic absorption may cause long-term effects on tooth and skeletal development in children.
Beta-Blockers[10]

The recent accidental discovery of accelerated involution of infantile hemangioma induced by propranolol (nonselective beta-blocker) and acebutalol (beta1-adrenoreceptor blocker), has resulted in a significant paradigm shift in the treatment of proliferating infantile hemangiomas. Propranolol is now the preferred treatment for the same.

MoA: Unknown. Their effects on beta-receptor stimulation, down-regulation of angiogenic growth factors, reduction in expression of MMP’s and induction of apoptosis have been suggested.

Propranolol is used as a 2-3mg/kg/day dose in two to three divided doses,over 6 weeks to 7 months. Acebutolol is used in doses of 8-10 mg/kg/day.The optimal duration of treatment remains to be determined. Topical beta-blockers (eg. Timolol maleate 0.5% BD or as a gel preparation with BD local application) have shown promising results.

Although beta-blockers are relatively safe, they should be used with caution, especially in premature babies and normotensive infants. The potential adverse effects of propranolol include bradycardia, hypotension, and hypoglycaemia.

Conclusion

 Sclerotherapy is a treatment modality for management of various ophthalmological lesions like hemangiomas, caroticocavernous fistulas, lymphangiomas, tumors etc. which is based on the principle of vessel regression following injection of sclerosing agent intravascularly, intralesionally or topically and oral administration.

References
  1. Borden NM, et al. Endovascular treatment of orbital lesions. Barrow Quarterly. 1996, volume 12, number 4.
  2. Mechanism of action of sclerosing agents and rationale for selection of a sclerosing solution. Dr. Craig Feied, American Vein and Aesthetic Institute, http://www.medrehab.com/sclerosing_solutions.php
  3. Razavi ME, Nekooei S, Afzaly S. Iranian J. Intraorbital Arteriovenous Malformation Treated by Transcatheter Embolization; a Case Report. Ophthalmic Res 2006; 1: 125-8.
  4. Crawford EA, Slotcavage RL, King JJ, Lackman RD, Ogilvie CM. Ethanol Sclerotherapy Reduces Pain in Symptomatic Musculoskeletal Hemangiomas. Clin Orthop Relat Res 2009; 467:2955–61.
  5. Zheng JW, Zhou Q, Yang XJ, et al. Treatment guideline for hemangiomas and vascular malformations of the head and neck. Head Neck 2010; 32:1088-98.
  6. Kahana A, Bohnsack BL, Cho RL, Maher CO. Subtotal excision with adjunctive sclerosing therapy for the treatment of severe symptomatic orbital lymphangiomas. Arch Ophthalmol  2011; 129:1073-6.
  7. Poonyathalang A, Preechawat P, Jiarakongmun P, Pongpech S. Sclerosing therapy for orbital lymphangioma using sodium tetradecyl sulfate. Jpn J Ophthalmol 2008; 52:298–304.
  8. Jain R, Bandhu S, Sawhney S, Mittal R. Sonographically guided percutaneous sclerosis using 1% polidocanol in the treatment of vascular malformations. J Clin Ultrasound 2002; 30:416–23.
  9. Shiels WE II, Kang DR, Murakami JW, Hogan MJ,Wiet GJ. Percutaneous treatment of lymphatic malformations. Otolaryngol Head Neck Surg 2009; 141:219–24.
  10. Itinteang T, Withers AH, Leadbitter P, Day DJ, Tan ST; Pharmacologic therapies for infantile hemangioma: is there a rational basis? Plast Reconstr Surg 2011; 128:499-507.

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Nagpal S, Goel R, Kumar S, Garg SSclerosing Agents in Ophthalmology.DJO 2013;23:221-226

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Nagpal S, Goel R, Kumar S, Garg SSclerosing Agents in Ophthalmology.DJO [serial online] 2013[cited 2023 Jan 29];23:221-226. Available from: https://www.djo.org.in/articles/23/3/sclerosing-agents-in-ophthalmology.html