Lynda Charters

home

authors

lynda-charters-1

Preventing and treating vitamin A deficiency is the first step in preventing systemic and ocular complications, including xerophthalmia.

, a form of dry eye that results from vitamin A deficiency, was recognized medically as far back as 1520 BC. A treatment was devised that involved cooking beef liver, and then squeezing the “juice” of the liver on the affected eyes, according to 

theorized that the juice from the liver trickled down through the lacrimal sac and was absorbed, entered the blood stream, and ultimately reached the back of the eye.
	
	Dr. Sommer, professor of ophthalmology,

, recounted his experience in 1978 in an Indonesian village during which he witnessed a similar ceremony performed on a child with nightblindness who was treated with goat’s liver and then given the liver to eat, which may be how the vitamin A entered the child’s circulation in the first place.
	
	


	
	A 19th-century treatment that was less humane advised keeping the affected person in a dark room for at least a month, which works temporarily because the retinal pigments have a chance to build up, Dr. Sommer explained. 

 is diagnosed currently by observing a patient’s response to various levels of light, a method that grew out of an observation in malnourished Confederate soldiers during the 

.
	
	The soldiers refused to take night watch because they could not see in the dark, which was confirmed by the lack of a pupillary response when a candle was waved in front of their eyes, Dr. Sommer noted. Another manifestation of xerophthalmia is the presence of Bitot’s spots on conjunctiva, which are comprised of keratin.
	
	“Vitamin A is necessary for development of normal, mucous-secreting conjunctival epithelium,” he explained.
	
	The spots usually develop temporally, but severe cases involve the entire conjunctiva. In the late 19th century, cod liver oil, which is rich in vitamins A and D, was determined to be an effective cure for night blindness and Bitot’s spots.


	
	Dr. Sommer described the case of a child who was vitamin A-deficient and had an unusual form of local necrosis.

“This manifestation often begins with a small ulcerative area that is hard to differentiate from an infection until the clinician realizes that nothing can be cultured from it and it is refractory to antibiotic treatment,” Dr. Sommer said.

 revealed the presence of liquefied corneal stroma over an intact epithelium.
	
	The 

n recommended treatment of the necrosis with water-miscible vitamin A, which was unavailable and required formulation. Dr. Sommer instead administered an oily preparation of vitamin A orally (it was known that it did not work when injected, as had long been taught) until the water-miscible formulation became available.
	
	The new formulation worked well when given intra-muscularly, but no better than the less expensive oily preparation given by mouth. Studies of locally necrotic corneal ulcers in children who died showed them to be strictly demarcated, absent of inflammatory cells, under an intact epithelium, and bordered by normal tissue.
	
	“It did not fit any of the suggestions we had about the mechanism by which sterile corneal melting would develop,” Dr. Sommer said.
	
	Because of the good results Dr. Sommer achieved with the cheap, available orally administered oily vitamin A, he compared it with the more expensive, less readily available water-miscible form administered intramuscularly.
	
	“The rates at which corneal healing occurred were very similar in the two groups,” he said. “We confirmed in 1980 that both the clinical and the biochemical responses were identical in the two groups.”
	
	At six to eight days after administration, the improved/cure rates were 94% and 97%. Early treatment of xerophthalmia is essential before the cornea is completely necrotic. The disease is associated with a mortality rate of about 25% despite hospital care.

Nutrition a priority for dry eye patients


	
	Keratomalacia is the most severe form of xerophthalmia. The association between the corneal deterioration and Bitot’s spot was not recognized until the early 1900s, about the same time as the discovery of vitamin A.
	
	This was a period when it was found that the so-called 

, i.e., fat, carbohydrates, and protein, were insufficient by themselves to sustain life, but, according to Dr. Sommer, life required “accessory factors,” as they were called by Hopkins, or “vital amines” by Funk, and fat-soluble A by McCollum and Davis.
	
	It was not until 1917, that McCollum reported, “We feel confident that these cases of xerophthalmia … should be looked upon as a deficiency disease not hitherto recognized in its true relationship to diet.”
	
	Dr. Sommer described a rat study in which pregnant rats were made vitamin A deficient and the pups were born severely deficient, to facilitate development of xerophthalmia and other manifestations of vitamin A deficiency. The deaths among the pups were charted. The results showed that xerophthalmia developed much later, after a number had died.
	
	This death rate was evident when Dr. Sommer and colleagues studied xerophthalmia in Indonesia and found that children with mild vitamin A deficiency, but with normal looking eyes, died at a third of the rate of those with nightblindness, which was one-sixth the rate of the children with 

.
	
	Further studies, and randomized trials, showed that by giving vitamin A by mouth twice a year to children in the developing world, would reduce childhood mortality by one-third.
	
	“This changed the paradigm,” he noted. “Instead of vitamin A deficiency equaling xerophthalmia, as the vitamin A status declines other systemic functions are seriously impacted.”
	
	The ocular manifestations, which had been considered the primary outcomes of vitamin A deficiency, develop relatively late. This recognition led to a program in 50 countries in which large-dose vitamin A capsules are distributed twice annually to all children younger than 5 years. This has been estimated to save about 350,000 lives annually.
	
	

Dr. Sommer has no financial interest in any aspect of this report.

Articles

Centuries of research show treating deficiencies can have dramatic impact

Focusing on xerophthalmia, vitamin A deficiency

This article was reviewed by Scott E. LaBorwit, MD



Practitioners can decrease the treatment burden for patients through the use of available generic and low-cost intraoperative medications that negate the need for patients to purchase medications postoperatively, according to Scott E. LaBorwit, MD.

For example, practitioners can compound antibiotics and steroids and administer them perioperatively via a transzonular or a pars plana approach; however, 

surgeons might not be comfortable with such a procedure. 

Another costly option is steroids that can be deposited in the lacrimal system or under the iris.


Dropless, hands-free regimen key for patients


LaBorwit and Robert Stutman, OD, MBA, conducted a retrospective chart review to identify safe generic or low-cost medications for use at surgery to eliminate patient expenses after surgery.

The sample size was 5400 patients who underwent 

by 1 surgeon from July 2016 to January 2020. The study’s end point was the absence of the need for patient medication purchases after 

The study’s hypothesis was that use of perioperative antibiotic drops, povidone-iodine 5% during the surgical prep, anterior chamber generic moxifloxacin, and sub-Tenon triamcinolone will eliminate the need for preoperative or postoperative drops.

The investigators evaluated the safety outcomes, which included the incidence rates of infection, IOP elevations resulting from steroids, rebound iritis, and cystoid macular edema, LaBorwit recounted.

They used generic moxifloxacin 1 mg/mL from a commercially available bottle (cost, $47.50 per bottle) with 0.3 cc instilled into the anterior chamber; the moxifloxacin was diluted with balanced saline solution in a 1:4 ratio. The cost per patient of this approach was $1.06, LaBorwit noted. 

For the steroid component of the treatment, the investigators injected 0.3 cc of triamcinolone 7 mm posterior to the limbus into the superonasal sub-Tenon space; the dose was later decreased to 0.1 cc. The triamcinolone cost $43 per vial and $1.07 per patient.

Topical moxifloxacin: Best choice before cataract surgery?


No intraocular complications occurred as a result of the medication placement. Endophthalmitis did not develop in any cases. Three corneal ulcers developed that resolved with topical and anterior chamber treatment, LaBorwit explained.

The study results showed steroid-induced elevations in the IOP in 102 patients (1.9%), and these were treated with topical antiglaucoma medications. 

With reduction of the dose from 0.3 to 0.1 cc, the incidence rate of elevated IOP decreased to 0.67%. Nine (0.17%) patients had persistently elevated IOPs that exceeded 30 days postoperatively.

Predictable, branded steroids offer control over surgery

Cystoid macular edema developed in 1.5% of patients for an average of 35 days. All resolved with drops over time. 

Rebound iritis occurred in about 5% of patients, which increased to 6.67% when the steroid volume was decreased, LaBorwit noted.

“The results indicated that generic and low-cost intraoperative medications use is safe and effective and eliminates the need for patients to buy drops postoperatively. The total cost to the surgical center was less than $3 per patient,” LaBorwit concluded.

LaBorwit has no financial interest in this subject matter. Dr LaBorwit is an assistant professor at Wilmer Eye Institute, The Johns Hopkins Hospital, Baltimore, Maryland. Robert Stutman, OD, MBA, is an optometrist in Towson, Maryland.

Options can reduce the treatment burden for patients, leading to improved outcomes


Perioperative medications can eliminate postoperative drops after cataract surgery

Great inventions start with an idea, but only a small fraction moves past that phase through increasingly complicated, work-intensive developmental stages.

Leaders in the field guided investigators through the route their ideas must take to reach fruition. Malik Kahook, MD, professor of ophthalmology, University of Colorado, and Adrienne Graves, PhD, co-founder and co-chair of Glaucoma 360, moderated this discussion.

Considerations when attempting to “grow” an idea into a viable product are the risks involved—emotional, financial, and reputational. 

“These factors seem theoretical until they become real, as people are judging if your approach is sound,” said John Berdahl, MD, who is in private practice at Vance Thompson Vision, Sioux Falls, South Dakota.

The next step is determining if the idea is good (i.e., interesting and important) and can satisfy a marketable need. This stage must be coupled with a high level of motivation to pursue that idea and accomplish the level of work needed to bring it to realization. Finding mentors, performing proof-of-concept science, and being honest with all involved individuals about whether the idea will take off are also mandatory steps.

Importantly, the idea must be legally protected with a patent. Entrepreneurs must protect a space to prevent others from developing something similar.

Berdahl also offered a practical tip: develop the intellectual property before starting the company and then license the property to the company for a royalty. Physicians must also learn about how venture deals are structured, executing a business, and staying focused.

Forge pathways through the FDA and reimbursements. Berdahl advised engaging early with the FDA (which provides useful information about achieving approval) and payers to determine what can be reimbursed. Team building is the final and perhaps most vulnerable step to assemble a group of people who are dedicated to making the idea a reality.

“The next step after developing a medical prototype is raising capital,” said Reza Zadno, PhD, CEO of Glaukos. This is easier said than done for novice entrepreneurs. Raising capital also presents questions about who benefits from the product, the patient with better outcomes, the provider with shorter surgical times and better economics, or the payers?

“The most exciting projects for potential investors are those that satisfy everyone—generally high-risk, high-benefit projects,” Zando said. “However, they are also more difficult. A clear path is needed because the patients, provider, payer, and the costs of goods are generally unclear.”

The parties involved evoke myriad questions. For regulators: the FDA history with similar products, regulatory pathways, and is the product paid for by the patient or reimbursed? Have investors lost money with similar products? Are providers interested in new technology?

In some cases, a prototype is not always necessary.

Experience is key to selling the project—with an experienced founder who can define a clear pathway and risk for investors and with experienced capitalists who will ultimately invest in the project.

Every step in the process of developing a new treatment involves establishing and ensuring continuous funding, according to Eugene de Juan Jr, MD, vice chairman of ForSight Labs.

The key to keeping venture capitalists interested in a project is by reducing risk, he noted.

“Entrepreneurs must design, think, [create a] prototype, and test continuously to show that whatever they have is working,” he said.

To ensure the money flow, developers must ask if the product solves a clinical need.

“Human experience is what drives the needle, rather than in vitro and animal models,” de Juan emphasized.

Another consideration is the form. He continued, “Is it attractive? Do patients, doctors, and payers like it?”

Some thoughts for ophthalmologists to live by: Costs increase immensely with decreasing risk as the clinical programs progress. The risks of not progressing through the stage of development increase with each step; failing early can be absorbed by large, not small, companies.

There is a 50% chance of a drug getting through a phase 2 trial. Overall, the success rate from a drug to a clinical approved outcome is about 1 in 100.

The key to not failing late is not to start if failure is in the cards.

The Center for Drug Evaluation and Research ensures that safe and effective products are available for the American public. 

Our goal is to try to approve products that are safe and efficacious,” said Wiley Chambers, MD, deputy director of the Division of Transplant and Ophthalmology Products in the Center for Drug Evaluation and Research of the FDA.

When a product is involved in the approval process, Chambers advises applicants not to do something that they believe the FDA wants them to do when the company and the FDA do not think it is necessary.

The product being tested must have a vehicle that is an acceptable control.

The noninferiority margin is based on multiple previous drug trials. The 95% confidence interval that shows the test product produces the same result as the other products most of the time within 1 mm Hg indicates that within that margin, the drugs are the same, he explained.

In the United States, the generic solutions of timolol, bimatoprost, latanoprost, and travoprost have the same active and inactive ingredients in the same concentrations and these can be used in clinical trials.

The FDA requires comparisons of the peak and trough times of the drug tested and the control, that the measurements are done 2 weeks after treatment onset to be certain of the drug’s effect, and measurements are performed at 12 weeks because drugs that work then continue to be efficacious after that time. The FDA also wants drugs to be studied bilaterally as long as the eyes are within 5 mm Hg. “There are reasons behind everything the FDA asks for,” he said. “If you don’t know the reason, please ask.”

If considering a start-up, Thomas A. Mitro, president and chief operating officer of Aerie Pharmaceuticals Inc., advised hiring the best, most experienced people, who are not necessarily the most affordable, to lead the company through start-up turmoil.

In line with that, he also advised that they be paid well and not in stock options, before another company scoops them up.

Virtual start-up companies (and departments within those companies)—although very attractive—are difficult to build and establish the company culture and repertoire among employees scattered across the United States and globally.

To combat the negative aspects of having a company with multiple sites worldwide, Aerie Pharmaceuticals brings all employees together at 1 location for an annual meeting. The company also encourages immediate decision making by employees.

“Quick start-ups are encouraged and in like manner, fail as quickly as possible. Long exits waste time and money,” Mitro said.

He advised companies not to fall prey to failures by other companies in the industry that are attempting similar start-ups.

Finally, Mitro advised building relationships, not enemies; other companies should be considered competitors who are treated with respect.

Researchers must weigh emotional, financial, and reputational considerations

Developing a new therapy: Where do we go from here?


	
	Upper eyelid blepharoplasty (UEB) is the most frequently performed invasive facial esthetic procedure, according to

. The procedure can remove excess skin, muscle and sometimes fat from the upper or lower eyelids. It is performed for either functional or cosmetic indications. UEB may be performed in a traditional fashion, using stainless steel instruments, or may be modified with radiosurgery incisional techniques or laser incisional techniques.
	
	Following UEB, the visual fields can improve by as much as 26.2%. Dr. Tovilla-Canales, director, 

Orbit and Oculoplastics Department, Instituto de Oftalmologia, Mexico City, Mexico

, enumerated his pearls for performing a successful UEB. “The surgery is usually considered a simple procedure, but there are key points that must be adhered to before surgery to avoid adverse events,” he said. Dr. Tovilla-Canales offered several key points to consider for successful UEB procedures:

The procedure is not a recipe. Each patient will have different anatomic landmarks, and, therefore, have different surgical needs.

The brows and the different amounts of skin to be excised must be considered.

Understand the anatomy. Knowledge of the anatomy is essential to perform an appropriate technique for each patient.

The preoperative assessment is one of the most important steps before surgery is even undertaken. The physician must obtain a history and perform a complete examination, discuss expectations with the patient, select the appropriate technique, and discuss potential complications.

Patients must be instructed to stop taking aspirin and anticoagulants before surgery.

 Physicians also should obtain preoperative photographs in the event that patients question the postoperative outcome.

Another consideration in the preoperative assessment is determining whether just skin or skin and fat are to be removed.

“Watch the eyebrow,” Dr. Tovilla-Canales said, pointing out that the eyebrows are always considerations when performing UEB. He demonstrated cases with the preoperative presence of upper lid ptosis, a droopy eyebrow, fat pads in the lateral aspect upper lids disguised as upper lid ptosis and bulging of the upper lids caused by supraobicularis fat, indicating that these must be addressed to achieve an appropriate UEB.

Perhaps the most important surgical factor is marking the incisions, according to Dr. Tovilla-Canales.
	
	“With the patient supine, I create the crease in the patient’s natural crease, usually 10 millimeters from the lid margin in women and a little lower in men,” he explained, demonstrating the pinch test, performed using forceps with the patient sitting and with eyes closed, to determine the amount of skin to remove.
	Dr. Tovilla-Canales said he uses a guideline of 20 millimeters from below the incision to above the incision as a safe amount. When it comes to anesthesia, Dr. Tovilla-Canales advises administering intravenous sedation preoperatively and a small amount of local anesthesia.
	
	The incision, skin and fat removal also are important, and Dr. Tovilla-Canales said his preference is to create incisions using a blade rather than a CO2 laser because of the possibility of wound dehiscence related to the laser. Once the incision is created, Dr. Tovilla-Canales performs electrocautery. When removing the orbicularis, he said he prefers to remove only skin and preserve as much orbicularis as possible.
	
	When removing fat, he extracts the least amount possible to avoid hollowing of the eye. Typically, he removes only the medial fat pad. Dr. Tovilla-Canales also emphasized the importance of identifying lacrimal gland prolapse, which also can mimic the appearance of fat pads; his procedure of choice in such cases is to reposition the lacrimal gland with sutures.
	
	The procedure is not simply one of removing skin and/or fat, but recognition of structural issues such as ptosis. “Surgeons must be very conservative with the amount of skin, fat, and orbicularis muscle that is left postoperatively,” he said.
	
	During wound closure and crease formation, the wounds can be closed with interrupted 6-0 or 7-0 nylon or Prolene sutures. In some cases, a crease may need to be created. Dr. Tovilla-Canales said he takes a small bite of the orbicularis muscles, a bite of the aponeurosis where it joins the tarsus and finally another bite of the orbicularis muscle in the upper incision.
	
	While UEB appears to be a simple procedure, complications can occur. This can include asymmetry, ptosis, lagophthalmos, ocular motility disorders, scarring, hematoma, retrobulbar hemorrhage, and lymphedema.
	
	“UEB is usually a safe and effective procedure,” Dr. Tovilla-Canales concluded. “Complications can be prevented by performing an adequate preoperative assessment, understanding the patient’s expectations, obtaining meticulous measurements for skin markings, and proper surgical technique.”

Dr. Tovilla-Canales has no financial interest in any aspect of this report.

No cookie-cutter procedure, UEB can improve patients’ visual fields by more than 25%

Author | Lynda Charters

Articles

Perioperative medications can eliminate postoperative drops after cataract surgery

Developing a new therapy: Where do we go from here?

Pearls for upper eye lid blepharoplasty

Focusing on xerophthalmia, vitamin A deficiency