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ARTICLE
Year : 1953  |  Volume : 1  |  Issue : 1  |  Page : 23-28

Experiences with hyaluronidase


Surat, India

Date of Web Publication15-May-2008

Correspondence Address:
Naumann T Mascati
Surat
India
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Source of Support: None, Conflict of Interest: None


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How to cite this article:
Mascati NT. Experiences with hyaluronidase. Indian J Ophthalmol 1953;1:23-8

How to cite this URL:
Mascati NT. Experiences with hyaluronidase. Indian J Ophthalmol [serial online] 1953 [cited 2020 Oct 28];1:23-8. Available from: https://www.ijo.in/text.asp?1953/1/1/23/40805

Hyaluronic acid, a ,mucopolysaccharide of viscoid consistancy is a definite biochemical entity, first recovered by Meyer Palmer[7] in 1934 from bovine vitreous. They isolated the enzyme Hyaluronidase from pneumococci in 1936[8] . which was proved identical by Chain & Duthie to the spreading factor of Hoffman and Duran-Reveals, obtained from testicular extracts. Enough has been said about the chemical and other properties of Hyaluronidase by various authors, so a description of the bare and pertinent facts regarding this substance is only necessary. By the spreading factor is meant the agent that causes free dispersion of water in the tissues by depolymerization and hydrolysis of the hyaluronic acid. This acid is found in bovine vitreous and aqueous, pig's vitre­ous and skin, bovine and human synovial fluid and in mesenchymal tumour. Other spreading agents are ascorbic acid, glycerine, lecithine and peptones but their spreading activity is lower. According to Hechter,[3] the diffusion rate of hyaluronidase is proportional to the amount of enzyme used. The volume of its solution however, controls the extension. It is non-toxic having no adverse effects on the cardiovascular and renal systems. So far no allergic manifestations have been reported, while it is compatible with procaine hydrochloride, adrena­line hydrochloride and the antibiotics. It is highly soluble in water and normal saline. It is inactivated by blood-serum and heat. The activity of hyaluroni­dase is assessed in Turbidity Reducing Units. (TRU ). Thus one TRU is the amount of hyaluronidase when acting on 0.2 mgms. Of hyaluronic acid for 30 minutes at incubator temperature reduces the turbidity in the test to that given by 0.1mgm. of normally aggregated hyaluronic acid. It is also estimated less frequently in Viscosity Reducing Units ( VRU ), 3.33 of which are equal to I TRU. The product that I have used is Benger's Hyaltironidase, commercially known as ' Hyalase '. A 1000 Benger units of Hyaluronidase arc approximately equal to 450TRU. One ampoule of Hyalase contains a highly purified enzyme product of 1000 Benger Units, which when dissolved in 4.5 ml, of distilled water would give 100 TRU per ml. The solution retains its properties and potency for two weeks under refrigeration. During the past year I have used this pre­paration in more than 350 assorted surgical and other cases, in the following manner, (1) retrobulbar, (2) subconjunctival and (3) local infiltration. 'The retrobulbar injection may be used for (a) anaesthetic purposes and (b) therapeusis.

For infiltration anaesthesia the addition of hyaluronidase to the anaesthetic solution makes a distinct improvement. It not only makes the greater diffusion of the anesthetic agent possible but also helps in prolonging the effect of the latter, by the greater spreading effect of the added adrenaline chloride solution which by constriction of the blood vessels retards the absorption of the anaesthetic solution. The obvious advantages of its use are

1. Less quantity of the anaesthetic solution required when the enzyme is used.

2. Greater diffusion of the anaesthetic solution or am , other drug incor­porated with it.

3. Prolonged effect of the injected solution.

4. .A more efficient method of nerve or ganglion block is available by over­coming any error, through its spreading effect. by near 1 ½ cm . thus making it impossible to miss the desired nerve or ganglion.

5. Less ballooning of the tissues by the injected solution.

6. Injections into the retrobulbur space brings about a more efficient paresis of the extra-ocular muscles and a better anasthesia. There is no proptosis since the contents of the posterior orbit are not appreciably increased by the complete diffusion. The more effective paresis of the muscles brings about a hypotony in conjunction with a possible depolymerization and hydrolysis of the contained hyaluronic acid in the vitreous and possibly aided by the active and extensive constriction of the blood vessels entering the orbit.

With this adjuvant, 1 have operated upon 350 cases out of which I am giving a report of 200 cases which have been followed up to date. 100 cases of lens extraction, 40 cases of glaucoma. 8 cases of discission, 4 cases of capsulectomy, 3 cases of replacement of vitreous. 5 cases of enucleation of the eye ball. 2 cases of eviscertaion, 3 cases of muscle surgery. 4 cases of retinopexy, 12 cases of surgery of the lacrymal sac, and 19 cases of plastic surgery of the eye lids.

The retrobulbar injection I employ, consists of 1.5 c.cm. of a 4% solution of novocaine to which are added 2 drops of adrenaline chloride solution 1 : 1000. To this I add 50 TRU of hyaluronidase. The whole is injected into the muscle cone in the usual way with a 3 cm. long needle from the infero-lateral orbital margin. A post injectional massage of the eye ball accelerates the diffusion. O'Brien's akinesia is done with a 2% solution of novocaine, 5.00 c.c. of this solution with 100 TRU of hyalase are injected. The immobilization of the eye lids and the eye ball is perfect.

Total independence from the cooperation of the patient is the key to case and confidence in operating which every surgeon desires in eye surgery. Hyaluronidase appears to be the answer to this desire.

My experience with the use of hyalase in 100 cases of cataract ext actions of all kinds including cataracts with glaucoma may here be stated. Hypotony is desirable in the sense that the ease of instrumentation is far greater. The capsule forceps or the erisiphake can be easily and dexterously manipulated. Freedom from the risk of over application of pressure minimises the fear of , prolapse of vitreous. The insertion of corneo-scleral sutures is simplified by the perfect immobility of the eyeball and the hypotony. Cataracts with glau­coma were extracted in one sitting without mishaps. In cases where one feels a little more hypotony has resulted than is needed, a little pressure on the specu­lum rectifies the same.

My experience with hyalase in surgery of glaucoma covers 40 cases, 16 acute and 24 chronic, with all varieties of operations including introduction of glass seton of Beck and carbon dioxide freezing of the ciliary body.

Out of 12 cases of after-cataracts discission was done in eight cases and capsulectomy in four. I would here like to draw attention to a useful observa­tion. It would not seem worth while to give a retrobulbar anaesthesia for a seemingly simple procedure like needling. By giving a retrobulbar injection with hyaluronidase, the resultant hypotony obtains a sinking of the vitreous posteriorly, with the result that the vitreous face or the hyaloid membrane can actually be seen through a magnifying loup to have receded considerable below the plane of the iris. The remnants of the capsule could be seen to be separated from it by an optically empty space. The adhesions, if any, between the capsule and the hyaloid membrane can also be visualised. This sinking of the vitreous facilitates the introduction of a knife needle in the posterior chamber and in the space between the capsule and the vitreous without any risk of injury to the latter and its herniation forward. The capsule can be incised with perfect freedom of manipulation and can be freed from the iris as well as the hyaloid membrane. I believe this would be of advantage while using the method recommended by Sato[10] with his special capsulectomy knife.

Out of four- capsulectomy cases, in two the capsule was freed from adhesions with a knife needle which was then withdrawn without collapsing the anterior chamber and a sharp iris hook introduced instead which entangled the capsule in its fine point and was withdrawn with the capsule material. The remaining two cases were operated upon by opening the eye ball with a keratome-scissors incision and preplaced corneoscleral sutures. The capsule was dissected off completely from the incarcerated points, from the posterior face of the cornea to which it was plastered and also from the iris and removed en masse, with most gratifying results. This would demonstrate, how confidently and without the slightest risk, surgery of the interior of the eye ball is possible.

This statement would be borne out further by the next series of three cases of vitreous replacements which were done under the same anaesthesia, for a completely turbid vitreous in one case after a massive haemmorhage with residual large vitreous floaters. In the second case, vitreous was replaced in an aphakic eye which had been myopic and had a degenerated vitreous with posterior synechia of the iris with the hyaloid membrane and the capsule. The third case was for a couched lens extraction. wherein a loss of vitreous was anticipated. In these three cases the vitreous was replaced with the patient's own preobtained cerebrospinal fluid, to which 10,000 units of penicillin were added.

The performance of enucleation with buried plastic implants in 5 cases and of evisceration in 2 cases were done with perfect absence of pain or post­operative oedema of the lids or chemosis of the conjunctiva. The use of hyalu­ronidase in muscle surgery also is of great advantage. The injected muscle or Tenon's capsule does not balloon up to distort the field of operation nor is there any post operative chemosis.

Some surgeons[1],[5] advocate against the use of hyaluronidase in cases of retinal separation operations because of the resultant hypotony which in their opinion would make surgery more difficult. I have operated upon eight cases of retinal separations with large tears and dialysis, under this anesthesia, four of which I include in these observations. It is true that injection of hyaluroni­dase would yet bring, down the already subnormal intraocular tension, but one trust not forget that the tension rises after electro-coagulation of the sclera. which shortens and shrinks in the process. The consequent rise in tension slay reach 70 mm. of Hg. Schiotz, when the surgery is done under general anaesthesia, and 50mm Hg. with the usual retrobulbar injection. Therefore. the excessive hypotony of hyaluronidase is in fact beneficial rather than of adverse consequence.

The spreading, effect of hyaluronidase added to the anesthetic Solution in the surgery of the lacrymal sac and for plastic surgery obtains obvious advan­tages for the operator.

Having, studied the use of hyaluronidase in retrobulbar and local infiltra­tion anaesthesia. let me mention some very useful observations made by way of retrobulbar therapy. In post-operative and persistent collapse of the anterior chamber, excluding, any obvious leakage, an injection of novocaine with adrenaline and hyaluronidase will help restoration of the collapsed chamber.

In cases of spasm of the central artery of retina and its branches in malign­nant hypertension and also in cases where one aims at improving the retinal circulation, the employment of vaso dilators is imperative. I have with very gratifying, results used priscol to Which hyaluronidase was added, retrobulbarly. The diffusion by hyaluronidase of the contained vasodilator perhaps aids absorption of the chug over a more extensive area.

The incorporation of hyaluronidase with retrobulbar injection of the anti­biotics for the intraocular and extraocular Saturation Would certainly help its dispersion of the antibiotics over a wider surface.

Now let its consider the possibilities of the application of hyaluronidase by subconjunctival route in certain affections of the anterior Segment of the eyeball. In cases of hypopyon, a Subconjunctival injection of 20 TRU of hyaluroni­dase helps the hypopyon to either completely get absorbed or to cause it to regress to the limbal level in about 10 hours.

I have used 30 TRU of hyaluronidase at intervals of four days in cases of recent corneal superficial opacities, the latter base. strange as it may seem. dis­appeared permanently. This is most probably due to the improved metabolism and nutrition of the cornea through the increased permeability all round the Iimbus.

I have had some cases of postoperative ruptures of the hyaloid membrane with consequent herniation of the nitrous in the anterior chamber. Subcon­junctival injection of 50 TRU of hyaluronidase twice a day for a couple of days cleared the anterior chamber of the vitreous humor. In cases of chemosis of the conjunctiva due to any cause, a sub-conjunctival injection of 20 TRU of hyaluronidase would flatten the swelling.

A striking action of the spreading factor is demonstrated in cases of iritis With aqueous flare, 30 TRU of hyaluronidasc injected subconjunctivally would clear the turbid aqueous and lessen the risk of a secondary glaucoma due to blockage of the filtering angle.

Finally I must mention a very good and permanent result of the action of hyaluronidase in cases of pannus. The regression or rather ablation is something bordering on the marvellous. I have started on this recently and have no com­plete follow tips, but the results hate been encouraging. Lebensohhn[5] speaks highly of his trials.


  Discussion Top


As reported by Hoffman et al. the testicular extracts containing hyaluroni­dase. stimulate cell growth in vitro as also of Roes sarcoma ( chicken tumour I. ) One can infer from this that adverse results with pathological cell proliferation may be expected front the prolonged use of the drug, but not with a single injection. On the other hand we know that to stimulate cell proliferation sulf­hydryl is essential which in conjunction With ascorbic acid definitely regenerates, replaces and stimulates cell growth. Thus vitamin C is essential for the main­tenance and production of the intercellular cement substance through its action on the supporting tissue. There intercellular substances so maintained arc the collagens of all fibrous tissues. Matrix of bones, dentines and Cartilages and all known epithelial cement substances even including those of vascular endot­helium which all contain hyaluronic acid. We may therefore hypothesize that a strict and intimate relation exists between ascorbic acid and hyaluronic acid in as much as the former produces and maintains the intercellular substance while the latter is an important constituent of the intercellular cement sub­stance. imprisoning the water in the interstitial spaces, holding the cells together in a jelly like matrix which obstructs diffusion. Hyaluronidase destroys hyalu­ronic acid and thus breaks the barrier to diffusion.

Contrary to its action when given extraocularly intravitreal injections of the enzyme hyaluronidase would cause a conspicuous inflammatory reaction from the inner coats of the eye. It has been proved[6] that the introduction of the enzyme in animal experimentation into the anterior chamber brings about clouding of the cornea and inflammation of the iris. We know that in inflam­mation of the anterior segment of the eye, hypopyon is the product of reaction. Similarly in inflammation of the posterior segment vitreous is affected. The vitreous receives and stores the byproducts of retinal and choroida1 metabolism, Which possibly contain the enzyme. In inflammatory conditions of the chorio­retina accumulation of this enzyme overcomes the normal hyaluronic acid con­tent of the vitreous Which shows reaction change by becoming store liquified.

Since the enzyme liquefies the vitreous from a gel to sol, is it possible that introduction of hyaluronic acid would again restore the viscosity of the fluid vitreous. There have been many promising reports on the therapeutic value of Vitamin C in myopia where We know the vitreous is deranged and as men­tioned above probable ascorbic acid is a precursor of hyalurouic acid. Pixie[9] observed that after an intravitreal injection of hyaluronidase in rabbits the depolymerization was complete in 4 hours, the humour being completely liquified,regaining its normal viscosity after six weeks. This would prove that the pro­duction of hyaluronic acid is a continuous process. Is there then, a hyaluronic acid deficiency rather than an avitaminosis C in myopes ?Further research would reveal.


  Summary Top


The action properties and standardization of hyaluronidase are described. A review of 200 assorted operated cases is given which shows the advantages of the preparation when used with an anaesthetic agent retrobulbarly, subconjunc­tivally and by local infiltration. Observations also have been reported upon the use of the enzyme therapeutically in various affections of the anterior segment of the eye. The technique and the preparation used by the author are ex­plained. . In the discussion the author presents his ideas about the intimate relationship of vitamin C and hyaluronic acid and speculates on the possibility of a hyaluronic acid deficiency in myopes which is responsible for the liquification of the vitreous in the myopic eye.[10]

 
  References Top

1.
Atkinson W. S. "Use of Hyaluronidase in Ophthalmology", Arch. Ophth. 42: 1949, p. 628.  Back to cited text no. 1
    
2.
Chain E. and Duthie E. S. " A Mucolytic Enzyme in Testis Extracts." Naturem 144: 1939, p. 977.  Back to cited text no. 2
    
3.
Hechter O. " Importance of Mechanical Factors in Hyaluronidase Action in Skin. J. Exp. Med. 85: 1947, p. 77.  Back to cited text no. 3
    
4.
Hoffman D.C. and Duran-Reynals, F. "The Influence of Testicular Extract on Intradermal Spread of the Injected Fluids and Particles. J. Exp. Med. 52: 1931, p. 38.  Back to cited text no. 4
    
5.
Lebensohn J. E. "Hyaluronidase in Ophthalmology ". Am. J. Ophth. 33: 1950, p. 868.  Back to cited text no. 5
    
6.
Linn J. G. and Ozment, T. L. Some Effects of Injections of Hyaluronidase into the Anterior Chamber. Am. J. Ophth. 33: 1950, p. 33.  Back to cited text no. 6
    
7.
Meyer K., and Palmer, J. W. " The Polysaccharides of the Vitreous Humour ", J. Biol. Chem. 107: 1934, p. 629.  Back to cited text no. 7
    
8.
Meyer et al. " Action of the Lytle Principle of Pneumococcus on Certain Tissue Polysaccharides ". Pro. Soc. Exp. Biol. Med. 34: 1936, p. 816.  Back to cited text no. 8
    
9.
Pirie A. " The Effect of Hyaluronidase Injection on the Vitreous Humor of the Rabbit." Brit. J. Ophthal. 33: 1949, p. 878.  Back to cited text no. 9
    
10.
Sato T. "New Surgical Treatment for Post-operative Cataract". Am. J. Ophth. 34: 1951, p. 1136.  Back to cited text no. 10
    




 

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