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Archive for the ‘Featured Post – Clinical’ Category

Cosmetic Applications of Lasers and Light/Energy-based Devices

Wednesday, August 30th, 2017

By Rutledge Forney, M.D.

Helping children with facial port wine stains was the first cosmetic usage of laser energy. Since then, our understanding of energy in the skin has grown exponentially.

Today, lasers and other light/energy-based devices have dozens of cosmetic applications. From hair to brown spots to wrinkles and much more, demand for non-invasive (non-surgical) procedures has exploded as the baby boomers have aged.

A laser wavelength targets and destroys a specific “chromaphore,” or colored molecule, and can focus at different levels in the skin to minimize damage. Research into tissue temperature sensitivity has brought new ways to tighten skin and “kill” fat. Cosmetic market competition is strong, so these devices have to be effective to replace surgery and older technology. This article will provide an overview and act as a primer for the reader.

Vascular Targets

Pulsed dye and KTP lasers are the gold standards for facial veins and redness. Birthmarks, rosacea, angiomas and sun damage respond well to the 532, 585 and 595 nanosecond wavelengths. Multiple manufacturers make devices with these settings, with the differences being the method of cooling the skin, spot sizes and pulse length.

Leg veins are harder to treat with lasers due to thick skin and pressure in the legs from gravity. 1064 NdYag lasers are marketed to help leg veins, but every lecture I go to on leg veins and lasers confirms that the gold standard for leg veins is still sclerotherapy.

Brown Spots

All brown spots are not created equal! Some are sun damage, some are genetic. Some are superficial, some deep. Some are from hormones, some from acne or trauma. But all brown spots are universally despised. Lasers can help some, not all, brown spots. Lasers can darken brown spots from hormones (melasma).

Many different lasers and light-based devices target brown spots. Classically, intense pulsed light (IPL) – not a laser but a spectrum of light – is used to treat an area of sun damage, principally on the face, neck, chest and arms. Over a few days, obvious and not-so-obvious brown spots disappear. Remaining brown spots may be cleaned up individually with new picosecond lasers and 810 and 1064 wavelengths lasers.

Hair Reduction

The most common use of cosmetic laser therapy today is hair reduction. Dark hair in light skin can be treated effectively. Unfortunately, light hair does not have a “chromophore” to attract a laser, and dark hair in dark skin cannot be “seen” by the laser. Hair reduction wavelengths are commonly 810 in lighter skin, 1064 in darker skin. IPL is used for hair reduction but with a higher risk of hyperpigmentation and blistering due to multiple wavelengths hitting unintended targets.

Skin Texture, Wrinkles and Collagen Refreshment

Aging, primarily sun damage, causes large pores, wrinkles/crinkles and droopy skin. Compare the skin on your lower abdomen or buttocks (which typically has less sun damage) to that of your hands or face. A biopsy of 60-year-old sun-damaged skin compared to young sun-protected skin shows frayed, crinkled collagen and increased elastin. Anyone can tell the difference.

According to The New York Times, collagen production is stimulated by three things. One: laser resurfacing, which gets energy into the dermis where most damaged collagen is found. Two: prolonged use of tretinoin. Three, dermal fillers, which are used to plump thin lips, enhance contours, soften facial creases, remove wrinkles and improve the appearance of recessed scars. Enough said.

In the 1990s, two laser wavelengths were used for full face resurfacing, CO2 and Erbium Yag. They completely removed the epidermis and tightened the dermis. Folks who got a great result were thrilled, but not all got a home run. Poor healing and infection could impair results. It was expensive and usually required general anesthesia. Patients needed to lay low for 3 weeks, keeping the face moist, covered and out of the sun until the epidermis reformed. Scarring and hypopigmentation were not uncommon. Still, the demand for improvement in aged skin motivated research into other options.

In 2005, the fractionated laser was born. It lasered 20 percent, not all of the epidermis and superficial dermis, leaving columns of lasered skin surrounded by normal skin. This assured that the lasered skin was excreted and the damage healed quickly without scarring or hypopigmentation. The original wavelength was 1550; five treatments resurfaced the face for maximum results. Fractionated lasers now include 1550, CO2 and Erbium Yag. Multiple treatments are necessary, with some downtime, but not the risks of non-fractionated lasers.

Skin Tightening

Radiofrequency and ultrasound are now used to tighten skin without surgery. Both go through the epidermis into the dermis without damaging the skin, so they have no downtime. Radiofrequency heat contracts dermal collagen while ultrasound focuses on lower levels of the dermis. Some devices add microneedles to wound the epidermis and deliver focused radiofrequency waves deeper in the skin to tighten both epidermis and dermis.

Fat Destruction and Body Sculpting

Fat is the latest frontier in noninvasive, in-office procedures. Liposuction has been used for decades to remove fat cells in localized fat pockets. Laser-assisted liposuction was developed about 15 years ago to make the process less traumatic and to tighten skin from the inside. Knowledge that fat is temperature sensitive led the developers of the fractionated laser to focus on ways to destroy fat noninvasively. A technique to freeze fat while protecting the overlying skin and underlying muscle was first approved by the FDA in 2010 and is now considered by many to be the gold standard for noninvasive fat destruction. It takes three months to see results; the tradeoff is no cuts, stitches and invasive suction, which is worth it to many.

Cold kills fat, but so do heat and ultrasound! Radiofrequency waves and focused 1064 lasers are used to heat fat. Deep ultrasound is being used to target fat pockets as well.

Tattoo Removal

Tattoo removal is challenging. It involves multiple chromophores (colors), hence multiple wave lengths. The science is that the laser hits the ink and breaks it into smaller pieces, which the body’s macrophages carry away. It typically involves multiple treatments about every 2 months, with eight to 20 total treatments necessary.

A breakthrough in tattoo removal came with the development of a picosecond laser. (All conventional cosmetic lasers are nanoseconds.) This extraordinarily fast laser adds acoustic energy, breaking ink into smaller pieces so it is removed faster, requiring only three to eight treatments.

Obviously, there are many devices and methods that improve the appearance of skin and the body. Young skin reflects light, is smooth and one color. Photo-aging results in dyschromia (multiple colors in the skin: reds and browns of multiples shades), prominent vessels, a rough texture, enlarged oil glands and folds in the skin. The skin is dull with permanent lines from smiling and frowning (motion).

The underlying problems are that collagen and blood vessel walls are damaged by sun and free radicals, and the body’s protective pigmentation eventually cannot be totally removed because the removal processes are tired and worn out.

Not every machine is right for every person. The physician directing treatment must understand the color of the skin. Though operating lasers and other cosmetic devices can be delegated, the devices discussed here require the direction of a physician.

Remember that if one only has a hammer, then everything will look like a nail. Make sure that the physician understands the patient’s goals and that the physician and the patient are sure that the treatment is right for that patient.

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From Office Surgery to Face Lifts

Wednesday, July 19th, 2017

By Elizabeth Morgan, MD PhD FACS

“Can it be done in the office?” and “Do I need a face lift?” are two common questions that cosmetic surgery patients ask us.

Today, short-acting general anesthetics and advanced monitoring make general anesthesia very safe, safer than intravenous sedation — one reason that anesthesiologists prefer this approach. Indeed the dangers of sedation without airway control are such that the American Society of Plastic Surgeons requires members to restrict its use to accredited out-patient surgery centers. But most people dislike the cost of a surgery center, as well as the recovery from general anesthesia, and avoid it if possible.

What can a plastic surgeon today offer the patient who wants the lower cost and faster recovery of a procedure done in the office with local anesthesia, perhaps with one or two light sedative pills at most?

Surprisingly we can offer a lot of safe office operations. This isn’t just our ingenuity but our response to patients wanting solutions to a wider range of cosmetic issues. Today I can safely offer my patients 50 such procedures with continuous monitoring of pulse, blood pressure and pulse oxygenation to ensure the surgery is in fact safe.

Such operations include small-volume liposuction, small-volume fat transfers, lip lifts, lip implants, buccal fat reductions, face lift revisions, skin-only tummy tucks, ear lobe repairs and reductions, chin implants, elbow lifts, buttock lifts, upper lid lifts, lower lid lifts, correction of nipple eversion and inversion, labiaplasties, brow lifts, alar nose reduction, ear setbacks, implant exchanges and much more.

Figure 1A

Figure 1B

Not every patient or problem is suited for local anesthesia surgery, but what can be done is remarkable. Incremental advances in our understanding of local anesthetics and cosmetic surgery have expanded our patients’ options while making these procedures almost painless.

Indeed the pain from many of these operations is much less than for filler, Botox or Kybella injections. For instance, pain from local anesthesia for a lip lift (see Figure 1 A and B) is two spot skin injections or four seconds, compared to the severe pain from Kybella fat injection of the neck (see Figure 2 A and B),which lasts five minutes. This is 75 fold less pain!

Figure 2A

Figure 2B

Indeed the ease and recovery from such procedures makes patients want all cosmetic surgery done this way. The day may come — but it’s not here yet. Why not? Office surgery should take not much more than two hours for patient comfort, cannot be safely done in a hypertensive or hyper-anxious patient or if there is a risk of fluid shifts, unexpected bleeding, unsafe levels of local anesthetic or damage to vital structures. Major surgery with these risks belong in an accredited surgery center.

Although mini-face lifts can be done in the office, surgery tends to be limited and results less durable. So far in my practice, an in-office mini-face lift seems a poorer choice than a well-done standard face lift in a surgery center, which will typically produce good to outstanding durable results with a low risk of complications. (See Figure 3A and B.)

Figure 3A

Figure 3B

This leads to the question — what is a standard face lift? It is a ‘bespoke’ or ‘designer’ lift, based on the patient’s facial changes and the available techniques. Here is how that approach is evolving.

From the early 1910s to 1968, face lifts just tightened skin. By the late 1960s, all of the neck skin and much of the facial skin was being raised off the deep layers beneath. Results could be good but were unpredictable.

In 1968, Tord Skoog, a Norwegian plastic surgeon, introduced his deep layer face lift. By raising and tightening the deep layer of the face — a fascial layer he called the submusculo-aponeurotic system (SMAS) — he improved face lift results and durability. But the SMAS flap was often fragile and hard to suture. Facial nerves travel under the SMAS and could be injured. So face lifting branched in two directions, less and more. Which approach a modern plastic surgeon uses depends on her/his assessment of risk and of the patient’s needs.

Doing less led to SMAS excision or plication — tightening with SMAS without lifting it. Nerve injuries were rarer, and results were very good. This then led to the ‘mini-lift,’ which uses a short incision in front of the ear to tighten just the SMAS. The results are less durable and eventually led to ‘suture’ and ‘thread’ lifts, a recurring ‘face lift’ fad with little durability.

Doing more led to sub-periosteal face lifts, which lifted the facial tissues off the bone, now largely replaced by the composite face lift championed by Dr. Hamra. This procedure leaves the skin attached to the SMAS and extends further into the mid-cheek and lifts the lower lid and brow as well. Results can be superb, but the extent of surgery, longer recovery and greater risk led many surgeons to only incorporate elements of this lift into their face lifts, as needed.

Figure 3

Meanwhile back in the lab, plastic surgeons were dissecting cadaver faces to understand facial aging. Why do our faces age differently from those of all other animals? Faces of the dog and cat, mandrill and camel do not sag as ours do. (See Figure 3.) Here’s what we learned.

First we learned that aging causes loss of facial fat, deflating the face. The advent of fillers, fat injections and soft solid silicone implants allows us to restore some of this youthful facial fullness. But this is only part of a fascinating story.

Another part is that our muscles of facial expression differentiate us from other animals. These muscles lie in the SMAS, kept in place with ligaments that attach skin and SMAS to bone beneath along a line going from lateral brow to angle of the jaw. These ligaments separate the mobile, expressive front of our face from the immobile sides.

In front of each ligament is a ‘potential space,’ a glide plane that allows the muscles to move. We move them constantly! This repetitive motion plus aging and sun damage will stretch the skin, subcutaneous fat and SMAS, causing them all to bulge out over the ligaments, forming the jowls, facial folds, saggy cheeks and bulgy lower lids of “age.”

Further, aging causes thinning, weakening and absorption of tissue in every layer of the face, from skin and fat to periosteum and bone. By our mid-20s, signs of aging are seen in Caucasian women. Because of men’s thicker tissues, these changes are seen later, in the early 30s. Those with even thicker facial tissues have even later visible signs of aging, as is evident in many Americans of Asian and African descent.

But no worries for early agers, right? Now that we know the anatomy in detail, can’t we just tighten those SMAS tissues around the ligaments? Not so fast! The nerves lie in the ligaments. Releasing ligaments can cut those nerves.

But our new knowledge does provide an answer. We now know how to find the glide planes between the ligaments — these are safe spaces where SMAS and skin can be tightened away from ligaments and nerves. This approach provides a limited dissection, less risky composite face lift, an approach being incorporated in face lifts today — yet another important incremental step forward.

Meanwhile, plastic surgeons and others are exploring another avenue: stem cells and other biotechnology to rejuvenate aging tissues. The ultimate irony for plastic surgeons would be if our own research leads to pills, creams or safe injections that restore the face to a youthful appearance permanently without surgery, injections or implants.

While we await this Fountain of Youth, we have ever better face lifts and a panoply of office procedures to offer our patients. It’s astonishing progress from the introduction of general anesthesia in 1844 and local anesthesia in 1888!

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Urology Spotlight

Monday, June 19th, 2017

An interview with Drs. Drew Freilich, Mehrdad Alemozaffar, and John G. Pattaras

By Helen Kelley

Advancing technologies and noninvasive treatments, along with more open communication between physicians and patients, are improving the lives of people with urological conditions and diseases, from incontinence to cancer. Atlanta Medicine recently spoke with specialists who are excited to share their knowledge of the changing landscape of urology.

Minimally invasive procedures for benign prostatic hyperplasia

A growing number of older and younger adults are willing to seek out treatment for chronic conditions that have had a long-term negative impact on their quality of life, says Drew Freilich, M.D., a urologist with Urology Specialists of Atlanta.

“We’re seeing a trend of patients of all ages who are willing to be more aggressive in the treatments they want. They don’t want to continue using catheters and they are more open to accept the risks of undergoing anesthesia for procedures that can help them,” he said. “We’re also finding that cardiologists are more open to clearing older and sicker patients to go into the O.R.”

One example is men who suffer from an enlarged prostate, which causes inability to urinate and often requires them to stay catheterized and/or to take multiple medications. Freilich cites some minimally invasive procedures that are effectively reducing prostate size in cases of benign prostatic hyperplasia (BPH).

Drew Freilich, M.D

“Historically, in cases of benign prostatic hyperplasia, if the prostate grew to a certain size — over 80 grams — open surgery would be performed to remove it. Today, we use a GreenLight laser to remove prostate tissue,” he explained. “The laser technology has been around for several years now. The procedure involves inserting a small fiber into the urethra through a cystoscope and basically ‘vaporizing’ the tissue. The procedure has lower risk of bleeding than previous treatments and improves urinary flow immediately.”

Freilich says two newer procedures — UroLift and Rezūm — are also effective treatments for relieving the symptoms of BPH with minimal risks for the patient.

“UroLift is sort of a ‘glorified stapler.’ We place implants that hold the enlarged prostate tissue out of the way to relieve compression on the urethra,” Freilich said. “Rezūm is an ablation procedure that uses radiofrequency general thermal therapy, or ‘hot steam,’ to destroy the extra prostate tissue that is causing the symptoms.”

Freilich says both procedures quickly improve urinary flow and have minimal side effects.

“UroLift and Rezūm both have good long-term outcomes,” he said. “The low risks and fast recovery time make this procedure popular with both older and younger men.”

Freilich adds that a large part of his practice is comprised of people who have finally sought help after suffering long-term from conditions such as BPH, urinary incontinence and erectile dysfunction.

“Many of them don’t know there is help for their conditions or have been too embarrassed to bring it up,” he said. “As physicians, we must be more proactive about having open discussions so that patients will understand there are options available to them that can improve their quality of life.”

Robotics improve cancer treatments

“Almost every case I’ve done this week has used a scope,” says John G. Pattaras, M.D., Associate Professor of Urology at the Emory University School of Medicine and Chief of Emory Urology services at Emory Saint Joseph’s Hospital. Pattaras, who started the laparoscopic and robotic urologic surgery at Emory 17 years ago, adds that technology has evolved to make a wide variety of surgeries — including those for kidney, prostate and bladder cancers — more effective.

John G. Pattaras, M.D

“Robotics allow us to see better inside the patient. It’s not just diagnostic; it’s changed our ability to do reconstructive surgery,” he said.

Pattaras says that robotic surgery has made treatment of kidney cancer, in particular, more successful.

“In the last several years, we have seen mounting evidence that if we could remove the cancerous tumor from the kidney and spare the organ itself, the patient has a longer life expectancy. For certain size and stage tumors, removing the kidney itself has equal outcomes as far as cancer control. But this is not a good option for people who have only one kidney,” he said. “Robotic surgery gives us the precision to remove tumors, curing the cancer while preventing further deterioration of the kidney.”

For prostate cancer, the surgery that has employed robotics for years, improvements have also occurred as the technology has evolved.

“This is a very compact operation, with a complex reconstruction process to restore urination and erectile function. The robot became popular about 10 years ago as an alternative to open surgery for prostate cancer,” Pattaras said. “With today’s technology, we are able to do bigger surgeries with the same number of small holes and we’re managing more aggressive cancer. Robotics allow less invasive, lower morbidity surgeries.”

New methods for detecting and treating cancer

Mehrdad Alemozaffar, M.D

Mehrdad Alemozaffar, M.D., urologic oncology surgeon and Assistant Professor of Urology, Emory School of Medicine, says there are several recent technologies that now allow urologists to more easily detect and successfully treat various cancers.

“Bladder cancer is a good example of how a new technology is helping us locate and treat cancers more effectively. Sometimes we have difficulty finding tumors in the bladder because they can be very small and might not be readily seen using a standard cystoscope,” he said. “But we now have blue light cystoscopy, which is an enhanced imaging procedure that increases our ability to detect cancers that might be missed under regular light. It involves injecting a fluorescent agent into the bladder an hour before the procedure. The blue light cystoscope then picks up areas where the fluorescence has been taken up, which is preferentially cancerous cells.”

Alemozaffar cites another technology, targeted biopsies, as a very important tool in diagnosing prostate cancer.

“When a patient comes in with an elevated PSA (prostate-specific antigen) level, the only way we can truly diagnose cancer is with a biopsy. Traditionally the way we have done that is to take tissue samples from 12 different areas of the prostate in a somewhat ‘blind’ method,” he said. “Today, we have the ability to target actual lesions seen on an MRI. The MRI determines the probability of cancer using the prostate imaging reporting and data system (PI-RADS). We are then able to see inside the prostate using a combination of the MRI and ultrasound imaging and can zoom in on the targeted area to obtain a much more precise biopsy.”

Alemozaffar adds that the targeted biopsy, which allows him to see three-dimensional images of the prostate lesions, has been a game changer for detecting prostate cancer.

“I’m able to find more clinically significant cancers using this technology than I did in the past with the blind sampling biopsy,” he said.

Fluciclovine PET/CT improves radiotherapy targeting for recurrent prostate cancer

A clinical investigation article in the March 2017 issue of the Journal of Nuclear Medicine demonstrates that the PET radiotracer fluciclovine (fluorine-18; F-18) can help guide and monitor targeted treatment for recurrent prostate cancer, allowing for individualized, targeted therapy.

“This is the first study of its kind demonstrating changes in post-surgery radiotherapy target design with advanced molecular imaging in recurrent prostate cancer, with no demonstrated increase in early radiotherapy side effects,” explains Ashesh B. Jani, M.D., of the Winship Cancer Institute of Emory University.

According to the American Cancer Society, one in seven men will develop prostate cancer in his lifetime. In 2017, more than 161,000 new cases of prostate cancer are expected to be diagnosed in the U.S., and about 26,730 deaths from the disease are anticipated.

For the study, 96 patients were enrolled in a clinical trial of radiotherapy for recurrent prostate cancer after prostatectomy. All patients underwent initial treatment planning based on results from conventional abdominopelvic imaging (CT or MRI). Forty-five of the patients then underwent treatment-planning modification (better defining the tumor-targeted area) after additionally undergoing abdominopelvic F-18-fluciclovine PET/CT. No increase in toxicity was observed with this process.

The Emory researchers determined that the inclusion of F-18-fluciclovine PET information in the treatment planning process leads to significant differences in target volumes (the areas to receive radiotherapy). It did result in a higher radiation dose delivered to the penile bulb, but no significant differences in bladder or rectal radiation dose or in acute genitourinary or gastrointestinal toxicity.

These are preliminary results in a three-year study, which hypothesizes that there will be an increase in disease-free survival for patients in the F-18-fluciclovine-modified treatment group over those in the standard treatment group.

This study could have implications beyond prostate cancer. Jani points out, “Our methodology is readily applicable to other novel imaging agents, and it may potentially facilitate improvement of cancer control outcomes.”

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Diabetic Retinopathy Update

Monday, June 19th, 2017

By Paul Walia, M.D. of Georgia Retina

Diabetic retinopathy affects nearly one-third of all patients with diabetes and is the leading cause of visual impairment and blindness in working-aged adults. The Centers for Disease Prevention and Control (CDC) estimates that currently the healthcare costs associated with the treatment for diabetic retinopathy is around $500 million annually. Projections forecast that from 2010 to 2050, the number of Americans with diabetic retinopathy is expected to nearly double, from 7.7 million to 14.6 million, mirroring trends with obesity and metabolic syndrome.

Diabetic retinopathy often begins without symptoms. It invariably affects both eyes and is usually symmetric. If asymmetric disease is present with one eye having severe changes and the other eye not showing manifestation, the ophthalmologist must be alerted to unilateral hypoperfusion, specifically carotid artery insufficiency or blockage.

Patients may have relatively good and even perfect vision at initial presentation. However as the disease progresses, patients may experience distortion of vision, floaters and decrease of vision from mild diminution to total loss of vision.

The pathophysiology of diabetic retinopathy is complex. Hyperglycemia induces vascular pericyte deficiency, which leads to an increased vascular permeability and leakage and release of pro-inflammatory cytokines. This leads to local ischemia. Clinically, increased vascular permeability is most evident as microaneurysms, cotton-wool spots, intraretinal hemorrhages, the presence of exudates and macular edema. Ischemia is discernible as the presence of neovascularization.

Figure 1: Macular Edema

The two sight-threatening consequences are diabetic macular edema and proliferative diabetic retinopathy.  Diabetic macular edema (Figure 1) affects the macula, and thus the central vision is reduced. Focal laser treatment to photocoagulate the leaking microaneurysms has long been proven an effective therapy. Advances in pharmacotherapy have allowed intravitreal injections of medication to revolutionize the treatment paradigm. (See Figure 2.)

Medications such as anti-VEGF monoclonal antibodies and corticosteroids are vital tools in the retina specialists’ tool chest to treat diabetic macular edema. A challenge with these medications, however, is that they require multiple and ongoing injections at various intervals based on their pharmacokinetics. Promising research is ongoing about other drug-delivery vehicles, such as implantable biodegradable implants, that can allow sustained delivery of medication and reduce the frequency of injections. Additionally, there are several oral medications being studied that in conjunction with intravitreal injections may reduce the treatment burden.

Figure 2: Intravitreal Injection

Proliferative diabetic retinopathy is marked by the presence of neovascularization. (See Figure 3.) The new compensatory vessels that develop in response to ischemia lack structural integrity. They can burst and result in massive vitreous hemorrhage or fibrose and cause traction retinal detachments. Treatment options include intravitreal injection, pan-retinal laser photocoagulation of ischemic retina and vitrectomy to  remove vitreous hemorrhages and delaminate the tractional tissue from the retinal surface. Improvements in vitreoretinal surgery, including small-gauge incisions, improving viewing systems and enhancements to microsurgical instruments, have allowed retina surgeons to achieve superior outcomes.

While specialists who care for retinal diseases have a variety of treatment options to address diabetic retinopathy, prevention remains crucial. Early detection is essential to reducing the devastating consequences that can occur. Estimates suggest that a routine comprehensive dilated eye exam at least once a year can reduce the risk of eye disease by 54 percent to 76 percent and lead to the early detection of eye disease.

Figure 3: proliferative diabetic retinopathy

Of paramount importance in the treatment of diabetic retinopathy is the optimization of hyperglycemia. According to The Diabetes Control and Complications Trial, controlling diabetes and maintaining the HbA1c level in the 6 percent to 7 percent range can  delay the onset or substantially reduce the progression of diabetic retinopathy. Additional risk factors for progression of diabetic retinopathy include male sex, longer duration of diabetes, insulin use and higher systolic blood pressure as well as African-American or Hispanic ethnicity.

As the number of patients with diabetes escalates, all physicians taking care of diabetic patients will be faced with the challenge of managing this chronic disease. With early detection, systemic control and retinal therapeutics, ophthalmologists who focus on retinal care are prepared to handle the fight against diabetic retinopathy.

 

Note- Figures 1 and 3 are courtesy of the Wills Eye Manual.

 

References

Saaddine JB, Honeycutt AA, Narayan KM, et al. Projection of diabetic retinopathy and other major eye diseases among people with diabetes mellitus: United States, 2005–2050. Arch Ophthalmol 2008;126(12):1740–1747.

The Wills Eye Manual : Office and Emergency Room Diagnosis and Treatment of Eye Disease. Sixth Edition. Philadelphia :Lippincott, Williams, and Wilkins. 2012.

King P, Peacock I, Donnelly R. The UK Prospective Diabetes Study (UKPDS): clinical and therapeutic implications for Type 2 Diabetes. Br J Clin Pharmacol. 1999. 48: 643-8.

Nathan D. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Overview. Diabetes Care. 2014. 37: 9-16

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What’s happening in Ophthalmology? More Than the Eye Can See.

Wednesday, May 17th, 2017

By Michael Jacobson, M.D.

Dr. Michael Jacobson

In this edition, we will explore and provide you insight into a wide range of ophthalmology topics. We will start at the front of the eye, the cornea, then delve deeper to discuss the lens and ciliary body. Lastly we’ll finish our eye edition focused on the back of the eye, the retina.

Hold tight onto this issue, as we will give you a whirlwind tour of these wide-ranging and fascinating topics that have meaning for all of us, not just our patients. After all, if you live a long life, you will invariably develop one of these problems.

We will discuss the latest and most exciting developments when it comes to refractive surgery, which gives individuals the opportunity to reduce their dependency on glasses or contact lenses. We’ve come a long way since radial keratotomy (RK) surgery of the 1980s. With the advent of newer techniques like laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK), we now have procedures that permit more consistent, predictable and sustained results.

This field is burgeoning, and the population of people that may be good candidates for some type of refractive procedure is enlarging. Even solutions for presbyopia, or farsightedness caused by loss of elasticity of the lens of the eye that compels most of us over age 40 to turn to reading glasses, is being addressed with surgical options. The future may even be more promising and is likely to surpass the vision correction results that we obtain with LASIK and PRK.

Did you know that 3 million people in the U.S. have glaucoma and that this blinding eye disease progresses insidiously because there are usually no symptoms?? Did you know you can have glaucoma but have normal pressure?

Increased pressure in the eye leads to blindness, and eye drops are usually the first line of treatment. New drug classes, each with a unique mechanism, has led to a diversity of eye drop options that we have used for the past 3 decades without any big developments. However there is a new drug class awaiting FDA approval which you can read more about in this issue.

Compliance has been a major obstacle in treating glaucoma patients with drops. Innovative sustained drug delivery devices may lead to improved outcomes, and these are addressed.

For those in whom drops are not enough, laser therapy remains effective to increase outflow or decrease inflow, but there have not been new big breakthroughs here. A momentous advance in glaucoma treatment has been the discovery that cataract surgery lowers pressure. This has been very good news for glaucoma patients as that can sometimes be enough of a drop in pressure to make a difference.

If that is not thought to be enough pressure reduction, then the opening of the eye during cataract surgery now affords the opportunity to insert micro-incisional devices to facilitate the drainage of fluid out of the eye. Our authors have been involved in their development. Additional novel approaches in this micro-incisional surgery arena will be highlighted.

More advanced glaucoma damage requires larger scale, macro surgery. These procedures create a pathway – essentially a hole – from inside the eye to a bleb (a fluid-filled bump) on the ocular surface, and they can achieve profound pressure reduction. Alternate fluid pathways procedures continue to evolve year by year now. If patients undergo frequent eye exams as they grow older as recommended and when necessary, and we use the aforementioned treatments, we can hopefully prevent blindness from this terrible disease.

A cataract is formed as the lens of the eye becomes dense and opacified with age. Less light is able to enter the eye, causing diminished light perception, dulling of colors and blurry vision. Light becomes diffracted, resulting in glare. As the No. 1 cause of reversible vision loss worldwide, a great deal of time and effort has been spent on developing a safe, efficient and accurate surgical treatment.

The evolution of cataract surgery to become the operation it is today is one of the most interesting stories in all of medicine, and that journey is what the authors will share with you, taking you from ancient couching to incisional surgery where the entire cataract was removed.

The invention of intraocular implants allowed the “Coke bottle” glasses of your great grandparents to disappear. Techniques advanced allowing partial removal of the lens. Then ultrasonic dissolution and aspiration evolved to permit smaller and smaller incisions.

Very recently, a unique laser has enhanced and “simplified the surgical technique whereby the laser can make precise computer-designed incisions and dissolve the cataract. Incision size can be as small as 2mm (less than 1/10 inch), still large enough to remove the old cataract and insert a foldable lens implant substitute. Anesthesia has evolved from required general anesthesia to retrobulbar shots and now simply topical. That makes it infinitely safer for all patients.

While risks of surgery exist, this surgery offers very high levels of postoperative satisfaction. Astigmatism-correcting intraocular lenses (IOLs), refractive multifocal IOLs and presbyopia-correcting ones are available. Models have improved rapidly particularly over the past decade, and there is an excellent chance of finding a precise internal vision correction that makes the patient much less eyeglass-dependent. Essentially, a patient with healthy retina can request and choose crisp near vision or crisp distance vision. If that is not the desired endpoint, then there are multifocal IOL options that try to achieve a hybrid of both. The authors explain how cataract surgery of 2017 should preserve one’s active lifestyles like never before.

Diabetic retinopathy (DR) affects nearly one-third of all patients, and diabetes is the leading cause of blindness in our working-age population. This disease is epidemic, particularly here in Georgia.

A retina specialist will provide you with a succinct understanding of how this condition is managed. He emphasizes how all of us need to work collectively to get our patients motivated to not only achieve good A1c levels, but to address the other factors that accelerate this disease, particularly hyperlipidemia, hypertension and tobacco use.

All of us now know that what was considered an acceptable A1c of 8 in the past is not acceptable and the postponement of nephropathy, neuropathy and retinopathy depend on true tight control. Today he will report that compliant patients seldom end up blind, thanks to more tools in the retinal surgical tool box (small gauge surgery, improved pre-op pharmacology).

I recall during my fellowship and will never forget that one of my friends, in the midst of his neuroradiology fellowship, developed Type I diabetes mellitus. He diagnosed himself. It was ironic that he came down with this, given that his father, a professor of endocrinology, was also the president of the American Diabetes Association. Initially, he went into a deep depression concerned that he ultimately would lose the ability to read X-rays and catastrophizing how his life was doomed. Today such thinking hopefully is truly a thing of the past.

Age-related macular degeneration (AMD) is a very big deal because the aggressive forms of the disease lead to legal blindness (20/200 vision). This represents a severe handicap to our aging population who will lose the ability to drive, read or recognize faces.

Unless you are a pediatrician, you will encounter these visually handicapped patients. Now over 9 million people here in the U.S. have AMD, but 18 million people will have this condition by 2050. That is staggering! Knowing that QALY surveys find that people would rather have AIDS or advanced congestive heart failure than face the prospect of blindness, I am pleased to report that we have made great strides in managing this horrific condition, and a retinal specialist will share the good news with you and what we hope to achieve tomorrow.

No longer are ophthalmologists serving like psychiatrists trying to help these patients cope with their depression that such visual loss brings. Intravitreal injections of anti-VEGF drugs remain the standard of care for wet AMD. Yes, shots directly into the eye. Ninety percent of patients benefit, and of those, almost half experience some vision improvement. Considering 10 years ago when we relied on laser, we could only help 10 percent of patients, this is a revolutionary breakthrough. However, there is still room for improvement in AMD treatments since only the minority of patients experience significant visual gains and the treatment burden of frequent injections is high.

Breakthroughs for patients blinded by retinitis pigmentosa (RP) may include a retinal prosthetic device akin to a cochlear implant, called the Argus. In a different direction, we soon may be able to repopulate compromised/degenerated retinal cells using stem cell replacement, injected under the retina. 3-D printers using living cells placed on a substrate may even build networks of retinal cells that mimic the complex retinal hierarchal structure. Gene therapy provided by a viral vector (adeno-associated virus) has been recently used successfully in Leber’s Congenital Amaurosis (LCA), a blinding eye disease of children, and now may be modified to insert enhanced cells that may suppress natural VEGF production and allow our body to better defend against the onset of wet AMD.

As a consequence of the human genome project, each day more single-nucleotide polymorphisms (SNPs) of DNA are being investigated to find their relationship to eye disease. These discoveries will allow us to explore how we can synthesize protein inhibitors or promoters to prevent or cure disease.

Such research is robustly underway, including biotech company Spark Therapeutics, which is screening large populations to attack some rarer but devastating blinding eye disease such as choroideremia, RP and LCA. Enjoy the this eye edition.

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The Changing World of Hysteroscopy

Wednesday, August 31st, 2016

By Carla Roberts, M.D., Ph.D.

Hysteroscopy is the inspection of the uterine cavity by endoscopy with access through the cervix. It allows for the diagnosis of intrauterine pathology and serves as a method for surgical intervention, also called operative hysteroscopy.

Although the first reported uterine endoscopy was in 1869, the modern-day hysteroscopy did not become popular until the 1970s, when technology yielded more practical and usable instruments. The use of liquid distention media became routine by the 1980s, and many new hysteroscopic procedures, including endometrial ablation, were developed.

hysteroscopy

Figure 1: Diagram depicting a hysteroscopic procedure.

By the mid-1980s, hysteroscopic procedures had nearly replaced dilation and curettage (D&C) for diagnosing intrauterine pathology. They are now routinely used for diagnosis and treatment for abnormal bleeding, infertility evaluation, proximal tubal cannulation, transcervical sterilization, difficult removal of IUDs, intrauterine polyps, submucosal myomas, intrauterine adhesions and correction of müllerian anomalies.

Over the past few decades, refinements in optic and fiberoptic technology and inventions of new surgical accessories have dramatically improved visual resolution and surgical techniques. Many hysteroscopic procedures have replaced old, invasive techniques. As instruments become smaller, office hysteroscopy is replacing operating-room procedures. One of the most recent hysteroscopic procedures approved by the U.S. Food and Drug Administration (FDA) is female sterilization (Essure, Conceptus, Incorporated, Mountain View, Calif), which can be performed in the gynecologist’s office.

Hysteroscopes and Instruments

The telescope consists of 3 parts: the eyepiece, the barrel and the objective lens. The focal length and angle of the distal tip of the instrument are important for visualization (as are the fiberoptics of the light source). If not a solitary unit, a sheath is required to allow for inflow and outflow of distension media. Angle options include 0°, 12°, 15°, 25°, 30° and 70°. A 0° hysteroscope provides a panoramic view, whereas an angled one might improve the view of the ostia in an abnormally shaped cavity.

5 mm Rigid Hysteroscope

Figure 2: 5 mm Rigid Hysteroscope

Rigid hysteroscopes are the most common, and they are available in a wide range of diameters for both in-office and complex operating-room procedures. Of the narrow options (3-5 mm in diameter), the 4-mm scope offers the sharpest and clearest view. It accommodates surgical instruments but is small enough to require minimal cervical dilation. In addition, patients tolerate this instrument well with only paracervical block anesthesia.

Rigid scopes larger than 5 mm in diameter (commonly 7-10 mm) require increased cervical dilation for insertion. Therefore, they are most frequently used in the operating room with intravenous sedation or general anesthesia. Large instruments include an outer sheath to introduce and remove media and to provide ports to accommodate surgical instruments. The most widely used surgical instruments include scissors, biopsy forceps, graspers, rollerball, loop electrode, vaporizing electrode and the morcellator.

Instruments for the rigid hysteroscope

Figure 3: Instruments for the rigid hysteroscope. Top to bottom: biopsy forceps, tissue graspers and scissors.

The flexible hysteroscope is most commonly used for office hysteroscopy. It is notable for its flexibility, with a tip that deflects over a range of 120-160°. Its most appropriate use is to accommodate the irregularly shaped uterus and to navigate around intrauterine lesions. It is also used for diagnostic and operative procedures. During insertion, the flexible contour accommodates to the cervix more easily than a rigid scope of a similarly small diameter.

Recent improvements in specific operating instruments for the hysteroscope incorporates a suction channel and a pump to aid in removing pieces of tissue during resection. This improves visibility and decreases time spent emptying the pieces from the endometrial cavity. Another recently available instrument is a hysteroscopic morcellator, which may reduce myomectomy and polypectomy time by morcellating and removing tissue in one movement under direct visualization. These come in a variety of diameters from 6 to 9 mm. While these require cervical dilation, the smaller diameter morcellators may be useful in the office setting.

A variety of energy sources have been employed with the hysteroscopic technique, including monopolar and bipolar electricity as well as fiber optic lasers including potassium-titanyl-phosphate (KTP), argon, and Nd:YAG lasers. They all have different wavelengths, though the KTP and argon lasers have similar properties.

Distension Media

Table 1 compares the various types of media used to distend the uterine cavity, aid in the visualization of intrauterine pathology and provide an appropriate operative field. There are pros and cons to each type.

Table 1 (click to enlarge)

Table 1

Pre-Operative Evaluation. Appropriate procedure should be proceeded by accurate history taking, physical examination, and careful workup of the suspected pathology. In preparation for hysteroscopic procedures, the following may be useful: CBC, electrolytes, β-hCG, Pap smear, cervical cultures, endometrial biopsy and imaging such as a hysterosalpingogram (HSG) or CT/MRI.

Antibiotic prophylaxis is not indicated unless the patient has clinically significant valvular disease or a history of tubal occlusion due to pelvic inflammatory disease.

Office Hysterosocpy. Office hysteroscopy offers many benefits and is becoming more acceptable among patients and gynecologists for both diagnostic and operative procedures. Despite clear advantages, many gynecologists remain hesitant to perform in-office procedures out of fear that the patient, who is generally awake, will experience significant discomfort.

The success of diagnostic and operative hysteroscopic procedures with minimal and acceptable levels of patient discomfort in the office depends, therefore, on multiple factors. Procedural factors affecting the outcome of hysteroscopy include the size of the instrument used, the type and length of the procedure, the use of preprocedure anesthesia or analgesia, and a vaginoscopic approach.

The skill of the surgeon also affects the hysteroscopic experience and outcome. In addition, patient variables such as menopausal status, anatomic distortion (eg, cervical stenosis) and anxiety may adversely affect the patient’s experience.

Future Uses of Hysteroscopy

In 1869, Pantaleoni used a modified cystocope lit with reflected candlelight to examine the uterine cavity of a patient with post menopausal bleeding. Although Pantaleoni blindly used silver nitrate to cauterize the observed bleeding polyps, the ability to treat intrauterine pathology by direct visualization has been ever expanding.

Since that time, the technology surrounding hysteroscopic surgery has continued to expand to meet both physicians’ and patients’ demands for safe, cost-effective and minimally invasive treatments. We can expect to see smaller and smaller instruments with improved visualization to enable more procedures to be done comfortably in the office setting.

In the future, combining hysteroscopy with tissue sampling of the fallopian tubes to test for abnormal pathology may revolutionize ovarian cancer prevention. To be able to do this in an office setting with minimal to no anesthesia would be a development that is beneficial to all of our female patients.

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When Does My Patient Need a Medical Geneticist?

Monday, December 21st, 2015

SanchezBy Rossana Sánchez, M.D.

Medical Genetics is a vast and rapidly advancing field. With an estimated 20,000 to 25,000 genes in the human genome, mutations in these genes give rise to many disorders. The scope of practice of a geneticist is necessarily broad, encompassing inpatient and outpatient consultations for inherited conditions and congenital malformations, for genetic counseling and risk assessment, for treatment of genetic diseases and prevention of complications, as well as for ordering genetic and genomic testing1. The focus of genetics as a science is not solely on the patient, either, but also the patient’s family.

Preconception and Prenatal

The need for a medical geneticist may arise very early, sometimes even prenatally. As the science advances, mothers-to-be are offered special screening options for genetic conditions, such as the first and second trimester screen and the newer noninvasive prenatal testing (NIPT)2. These tests are designed to screen for aneuploidies (abnormal chromosomal numbers) of select chromosomes in the fetus via maternal blood. Common disorders caused by aneuploidies are trisomy 21 or Down syndrome, trisomy 13 and trisomy 18. It is common to offer this testing to mothers who are over 35 years of age, which is called “advanced maternal age.” The reason this age was originally chosen as an ideal screening time is because the risk of having a baby with Down syndrome was comparable to the risk of having a miscarriage as a result of an invasive procedure like amniocentesis to confirm this same diagnosis.

Usually, a certified genetic counselor explains all testing to parents and discusses age-related chromosomal problems when presenting results. If any of the screening tests are positive, then the mother should be offered confirmatory testing via amniocentesis. If an aneuploidy is diagnosed, then she and her partner will receive further genetic counseling so they have adequate information about the disease and understand their options. Confirmatory testing may also be offered if there are any fetal abnormalities seen in the ultrasound, including abnormal nuchal (posterior neck) translucency. Prenatal testing via amniocentesis or chorionic villus sampling (CVS) can also be offered for other genetic conditions that are present in the family if the mutations for a disease are known. Antenatal testing may also be offered to couples who have a family history of a disorder and wish to know if they are carriers and to couples with multiple (more than two) miscarriages or multiple stillbirths.

Some couples may also need preconception genetic testing. This is known as carrier testing or a carrier screen3. Most people are carriers of genetic disorders that are recessive, and females can be carriers of X-linked disorders. Carriers do not usually have any signs or symptoms; however, if both partners in a couple are carriers for the same recessive condition, then the chances of a child being affected are 25 percent for each pregnancy. If a mother is a carrier of an X-linked disorder, then males have a 50 percent chance of being affected, and females have a 50 percent chance of being carriers.

Ethnicity may also affect the chances of being carriers of certain disorders. For example, cystic fibrosis is well known to be more common in Caucasians, Tay-Sachs is more common in the Jewish population, and sickle cell disease is more common in African Americans. This is why initiatives like the Jewish Screen, or JScreen, started. It initially screened for common mutations in genes that caused diseases in this population, but it has now expanded to include more genes and full gene sequencing to detect mutations in other populations, becoming a pan-ethnic carrier screen.

Couples who are carriers of a known genetic disorder and whose mutations are known also have a chance to deliver healthy children via pre-implantation genetic diagnosis, or PGD4. This is a procedure used to screen embryos made via in vitro fertilization for genetic conditions, and then only unaffected embryos are implanted in the mother.

Neonatal

After birth, if any malformation is noted in a baby, a geneticist should be consulted. Common birth defects include cleft lip and palate or a congenital heart defect, which may be isolated and nonsyndromic, meaning it is not related to other findings. These defects may also be seen as part of other disorders. A geneticist might recognize patterns that lead to a specific diagnosis or suggest a need for testing. It is common to order a chromosomal microarray test when there are multiple congenital anomalies that are not explained by maternal exposures or deformations in utero5. This test helps uncover missing or extra copies of genetic material, known as deletions and duplications, respectively, which may explain the myriad of symptoms a baby has. If a diagnosis is confirmed, then there will be counseling with the family to discuss the diagnosis, possible complications and risks of recurrence.

In the neonatal period also comes the challenge of positive newborn screens. In the state of Georgia, we currently screen for more than 40 conditions. The false-positive rate tends to be high, so we must follow many children until confirmatory testing is complete. Some of the babies who are true positives appear clinically ill, even before the screen is back. Thus, inborn errors of metabolism should be considered in cases of suspected sepsis, seizures, lethargy, hyperammonemia or an anion gap acidosis, amongst other findings. In all these cases, a biochemical geneticist and metabolic nutritionist should be contacted and brought into the team treating the patient. If a metabolic condition is diagnosed, then the patient will be followed by geneticists throughout his or her lifetime.

Infancy and Childhood

During infancy and childhood, common reasons to refer to a geneticist include developmental delay or developmental regression and autism or pervasive developmental disorder (PDD). Developmental regression tends to be a more ominous sign but can be seen in many different disorders, including some inborn errors of metabolism like Tay-Sachs, neurological conditions like neuronal ceroid lipofuscinosis or Rett syndrome6,7,8. Developmental delay may be fairly nonspecific and ubiquitous in many disorders. A thorough history, physical exam and pedigree can help focus the diagnosis and target the testing strategy. Moreover, autism and PDD may have an underlying genetic cause, and genetic testing is warranted in the initial stages of evaluation8.

Another concern at this age is muscle weakness or hypotonia; again, this may be due to a number of different disorders, and it is important to rule out spinal muscular atrophy, Prader-Willi syndrome, and muscular dystrophy, amongst other disorders9. A simple CPK screen can help differentiate a muscular dystrophy from other disorders, but it is not always abnormal.

Abnormal growth patterns may also indicate a genetic disorder. Such patterns include both short and tall stature or failure to thrive10. Many skeletal dysplasias present with disproportionate short stature, so measuring a patient’s limbs and obtaining the height of other family members are recommended. Overgrowth syndromes, such as Sotos syndrome, are also seen and usually present with increased weight, height and head circumference that may be present from birth11.

Evidence of congenital or early-onset blindness or deafness warrants a genetics consult. It is important to rule out syndromic causes for these and assess for family history of potentially inherited conditions. One common autosomal dominant trait, for instance, is congenital cataracts. When signs and symptoms of an unknown disease follow a Mendelian pattern of inheritance or there is a family history of a known condition, patients should also be referred to genetics.

Adolescence and Adulthood

We customarily see patients during adolescence who have abnormal growth patterns. Patients with tall stature and other findings of common disorders like Marfan syndrome or Klinefelter syndrome should be assessed by a clinical geneticist11. Many of these patients present with other findings, and the work-up may be started by the primary care physician. If, for instance, a diagnosis of Marfan syndrome is considered, then an eye exam and an echocardiogram could be ordered. Another common reason for referral is abnormal sexual maturation. It is important in these cases to rule out disorders of sex development or intersex conditions12. Chromosomes should be analyzed for both growth abnormalities and sexual maturation anomalies.

In this age group, it is also common to receive referrals for a strong family history of cancer or when the types of cancer are rare. Usually, these patients are seen by a certified counselor in the Cancer Genetic Counseling Clinic who obtains a family history and orders testing for known cancer syndromes13. Depending on which genes are found to have mutations, the risks for different cancers increase in different percentages, and follow up with counselors is warranted to explain recurrence risks, practice guidelines and to offer testing to other relatives at risk.

We commonly receive referrals for mutations in the MTHFR gene, which has been linked to mildly elevated homocysteine levels in blood. Hyperhomocysteinemia has been associated with increased risk of developing cardiovascular disease and venous thrombosis14. That said, a person with the common polymorphisms in the MTHFR gene, even in the homozygous state, but with a normal homocysteine level does not require management or referral to genetics. All women regardless of MTHFR status should take folic acid supplements preconceptionally and during pregnancy to lessen the risk for neural tube defects at the recommended daily allowance of folate (0.4 mg/day) 15.

Table 1. Indications for Medical Genetics Referral

Medical Geneticist

 

 

Abbreviations: AFLP: Acute fatty liver of pregnancy. US: Ultrasound. IUGR: Intrauterine growth restriction. FTT: failure to thrive. PDD: Pervasive developmental delay.

* Table adapted from Reference 16.

References:

  1. Scope of practice: a statement of the American College of Medical Genetics and Genomics (ACMG). ACMG Board of Directors. Genetics in Medicine (2015)17,e3.
  2. Carmen J. Beamon et al. A single center’s experience with noninvasive prenatal testing. Genetics in Medicine (2014) 16, 681 – 687.
  3. Wayne W. Grody et al. ACMG position statement on prenatal/preconception expanded carrier screening. Genetics in Medicine (2013) 15,482–483
  4. Harvey J. Stern. Clin. Preimplantation Genetic Diagnosis: Prenatal Testing for Embryos Finally Achieving Its PotentialMed. 2014, 3, 280-309.
  5. Jay W. Ellison et al. Clinical Utility of Chromosomal Microarray Analysis. PEDIATRICS (2012) Vol. 130 No.5.
  6. M A Cleary, A Green Developmental delay: when to suspect and how to investigate for an inborn error of metabolism. Arch Dis Child 2005;90:1128–1132.
  7. Anita Rauch et al. Diagnostic Yield of Various Genetic Approaches in Patients with Unexplained Delay or Mental Retardation. AJMG Part A 140A:2063-2074.
  8. Judith H. Miles. Autism spectrum disorders-A genetics review. Gentics in Medicine (2011) Vol 13, No.4.
  9. N. Prasad, C. Prasad. Genetic evaluation of the floppy infant. Seminars in Fetal & Neonatal Medicine 16 (2011) 99 – 108.
  10. M. Wit, W. Kiess, P. Mullis. Genetic evaluation of short stature. Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 1
  11. G.Kant, J.M. Wit, m.H. Breuning. Genetic Analysis of Tall Stature. Horm. Res 2005;64:149 – 156.
  12. Ieuan A. Hughes. Disorders of Sex Development: a new definition and classification. Best Practice & Research Clinical Endocrinology & Metabolism Vol. 22, No. 1, pp. 119–134, 2008.
  13. Jill E. Stopfer. Genetic counseling and clinical cancer genetic services. Seminars in Surgical Oncology 2000: 18:347 – 357.
  14. Hickey et al. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genetics in Medicine (2013)15,2.
  15. Clarke R, Bennett DA, Parish S, et al. Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. PLoS Med 2012;9:e1001177.
  16. Beth A. Pletcher et al. Indications for genetic referral: a guide for healthcare providers. ACMG Practice Guideline. (2007) Vol 9. No.6.

 

 

 

 

 

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Ovarian Cancer In The Future Perfect Tense

Tuesday, August 25th, 2015

Benedict BenignoNOTES FROM AN INSIDER
By Benedict B. Benigno, M.D.

Ovarian cancer is an avaricious tumor, and its domain is nothing less than the entire abdominal cavity. It can extend from the deepest part of the pelvis up to the diaphragm and to the right and left of the colon and everything in between. It can appear after a few weeks of the mildest symptoms, and by then it has already declared open season on the body of a woman. It is fiendishly difficult to treat and unrelenting in its destructive ambition. It is a modern day scourge, casting a narrow and selective net, forever changing the lives of its victims.

The initial symptoms of ovarian cancer are vague and frequently present as gastrointestinal disorders. The ovary is the only organ in the body that has its functioning cells facing the interior of the abdomen, so long before a tumor actually forms, cells detach and implant on the undersurface of the diaphragm, the capsule of the liver, and most important, on the surface of the bowel.

Hundreds of nodules accumulate on the serosal surfaces of the large and small bowel, impeding the smooth flow of intestinal contents, and cause, along with the production of ascites, the cramping distention of the abdomen, which is the hallmark of ovarian cancer. The presentation is actually an intermittent, partial small bowel obstruction and represents a stage 3 cancer at the time of diagnosis. The finding of a stage 1 cancer is usually a serendipitous event – the surgeon is operating for some other reason, and a small nodule on an ovary is discovered.

Despite what you may have been told, there is no way to screen for ovarian cancer. CA-125 is a protein that has been around since 1981 and is merely a test for inflammation. It is by no means specific for this cancer. In fact, the CA-125 blood test is negative in 20 percent of patients with advanced cancer.

My lecture on ovarian cancer contains a slide with the heading, Is It Possible To Screen For Ovarian Cancer? The remainder of the slide contains the word no in 41 languages. Many laboratories are involved in the discovery of a diagnostic test for ovarian cancer that would approach 100 percent accuracy. Such a test would be one of modern oncology’s Holy Grails!

The Ovarian Cancer Institute was founded in 1999, and its work is centered in the McDonald Laboratory in the Department of Biology at The Georgia Institute of Technology. For the past 15 years, we have been investigating the genetic and molecular structure of ovarian cancer in the hope that a highly accurate diagnostic test might one day emerge.

Tissue and serum samples are immediately flash-frozen in my operating room at Northside Hospital and transported to the lab at Georgia Tech. They are stored in the minus 80 degree Celsius freezer, rendering them “eternal.” These specimens can be as accurately studied 100 years from now as they would be on the day they were collected. We now have one of the largest serum, tissue and data banks for ovarian cancer in the world.

This work is unfortunately expensive. Several years ago the Institute paid $250,000 for a laser capture dissection microscope. This device allows us to outline precisely the tissue we wish to analyze and then detach it from the specimen. The DNA from this tissue is extracted, thus allowing for precision analysis. The DNA is not contaminated by stroma or connective tissue but represents the epithelium of the ovarian cancer. The DNA is then transported to a microarray analyzer. This unit allows us to identify genes that are aberrantly expressed in ovarian cancer tissue.

Years ago, if researchers were interested in studying the genetic morphology of a cancer, they would have to proceed one gene at a time. Today, the microarray analyzer prints out the entire genetic composition of a cancer in quadruplicate on a microchip the size of a thumbnail.

The Ovarian Cancer Institute is very fortunate to be located at Georgia Tech, where there are so many departments working in areas related to ovarian cancer research, including bioengineering, bio-informatics and nanotechnology. There are many ways in which basic science research may eventually impact the way in which patients with cancer of the ovary are treated, but for now, the Ovarian Cancer Institute is focusing on three areas.
1) The Diagnostic Test

If only it were as simple as it is with cancer of the cervix. A pap smear is positive, a biopsy directed with the colposcope shows a CINIII lesion and a LEEP conization is done in the office under local anesthesia completing treatment and preserving the uterus.

The pap smear, unfortunately, is useless in the diagnosis of cancer of the ovary. A positive pap smear has led me to the diagnosis of this cancer only three times in my career. A diagnostic test for ovarian cancer must approach 100 percent accuracy, otherwise cancers will be missed or women will undergo unnecessary surgery.

Our initial attempts at the discovery of a diagnostic test at the Ovarian Cancer Institute involved the study of proteins. These are large and cumbersome structures that produced inaccurate results. We eventually started using mass spectrophotometric analysis of metabolites found in our serum samples. This instrument is amazingly accurate in separating out peaks in similar metabolites from the many samples studied.

We published our results several years ago and reported a nearly 100 percent accuracy. The only time that we found a positive result in a patient with a benign tumor was in someone whose mother and grandmother had died of ovarian cancer. The justifiable criticism of this paper concerned the fact that there were so few samples from stage 1 cancers. No one wants a diagnostic test that is positive only in advanced disease. We then purchased 90 serum samples from patients with stage 1 disease and found that our test picked up every one of them. The data analysis is complete, and we are about to publish our results. It should be noted that the test will be run on a single drop of serum and cost only a few dollars.
2) Targeted Gene Therapy

Very little has changed since Sidney Farber ushered in the modern age of chemotherapy in the mid-1940s. Newer drugs have been developed, dosage has changed as have routes of administration. One thing, however, has remained constant – the pineal gland gets as much of the drug as does the nucleus of the cancer cell.

This is most unfortunate since chemotherapy is a poison, and the dose and the interval between treatments is directly related to the body’s ability to withstand repetitive poisoning. It would be wonderful to be able to deliver the chemotherapy drug to the cancer cell and only to the cancer cell. This would allow the use of a dosage unthinkable today.

Modern genetic profiling identifies specific genes disrupted in a cancer. It is estimated that only 10 percent of mutated genes in a cancer are druggable at the protein level, which is the level at which drug therapy is currently focused.

Targeted gene function at the RNA level is preferred because all malfunctioning genes in a cancer can be targeted at the RNA level. The problem resides in the inability to deliver these RNA-inhibiting drugs directly to the cancer cell. It is important to remember that DNA is the same in every cell, but RNA codes for specific function. In collaboration with the nanotechnologists at Georgia Tech, we are developing a new class of nanoparticle delivery vehicles for this purpose. These technologies are being tested in animals and, if successful, will lead to phase 1 trials in humans.

 

3) Personalized Medicine

Carboplatin and Paclitaxel are chemotherapy drugs that are used as first-line therapy for ovarian cancer around the world. However, because of a significant incidence of platinum resistance, there are patients who fail this regimen. Few things are more disconcerting to a gynecologic oncologist then to spend six hours in the operating room removing the last remnant of ovarian cancer only to watch it return after several cycles of chemotherapy.

The choice of a chemotherapy regimen is sometimes the roll of the dice – a prediction based merely on experience and not science. Several companies are involved in choosing the right drug for the precise genetic aberration in a particular person’s particular cancer. It is time to stop approaching cancer based on the organ or origin; rather, we must choose treatment based on individual molecular structure. We are learning that the molecular structure of an ovarian cancer may have more in common with the molecular structure of certain pancreatic cancers than it does with other ovarian cancers.
Personalized medicine in oncology simply refers to treatment based on the structural idiosyncrasies of an individual’s cancer. Once this is nailed down, we should remember that the initial regimen might not be the proper treatment should the cancer return. This recommendation is based on the work of the Ovarian Cancer Institute published a few years ago. We used the microarray analyzer to compare the structure of the primary ovarian cancer with that of the recurrent cancer expecting them to be identical. To our surprise they were frequently quite disparate.

In collaboration with the College of Computer Science at Georgia Tech, we are developing computational algorithms that can accurately predict drug responsiveness of patients based on genomic/gene expression profiles. This approach uses learning algorithms, which are much more accurate than current methods employed by commercial firms such as Foundation Medicine etc.

This development is being coupled with genomic studies (DNA/RNA sequencing analyses) on ovarian cancer primary, metastatic and recurrent tumors all collected from the same cohort of patients. Further studies aim to validate these predictions in current patients by establishing primary cell lines from patient tumor samples. By submitting the patient sample to genomic profiling, we will be able to predict drug responsiveness and hopefully delete chance from the equation.
In reflecting over a 40-year career devoted to the care of women with ovarian cancer, I find myself consumed with the sheer barbarity of it all. A sharp knife opens the abdomen from the pubic symphysis to the xiphoid process to remove cancerous cells, there’s six rounds of chemotherapy, a recurrence and then more surgery and chemotherapy, etc.

I would like to envision the next generation of oncologists sending a newly diagnosed patient to an interventional radiologist to have some cells sucked through a skinny needle passed into the tumor under CAT scan guidance. These cells would be easily grown in the cell culture laboratory, then a geneticist would create the exact antidote to the nuclear protein in the cancer cell.

This material would then be injected into the patient at 10 in the morning, killing every cancer cell without harming a hair on her head and seeing to it that she is not late for her 2 p.m. tennis match. I would call this designer therapy – Giorgio Armani constructs the cancer treatment. Maybe one day we will see this idea come to fruition.

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Anterior Cruciate Ligament Injuries

Monday, March 16th, 2015

By Ryan Chen, M.D.

From ATLANTA Medicine, Vol. 86, No. 1

ACL 1“A-C-L”is the three-letter word that no athlete wants to hear. The anterior cruciate ligament is critical to stability of the knee and is the primary restraint to anterior tibial translation. Every year, professional athletes such as Tiger Woods, Tom Brady and Lindsey Vonn sustain season-ending ACL ruptures. These high-profile athletes are among the 400,000 patients who undergo ACL reconstructions annually in the U.S.

Risk

Various factors influence the incidence of ACL tears. Risk of ACL injury varies depending upon the sport, with a higher incidence in sports such as football, soccer and basketball. Several studies have reported a higher rate of football-related ACL injuries on artificial surfaces compared to grass. ACL injuries occur up to 10 times more frequently in games than practices. In recent years, ACL tears have been on the rise in pediatric patients due to increased participation in competitive sports at younger ages.

Female athletes have up to a three to eight times higher rate of ACL tears compared to males in high-risk sports such as soccer and basketball. The higher risk of ACL tears in the female athlete has been attributed to differences in neuromuscular control, lower extremity alignment and ligament size. Further, females tend to land from a jump with more of a valgus moment, which places the ACL at risk for rupture. Some studies have suggested an association between risk of ACL tears and the menstrual cycle.

ACL 2Diagnosis

The classic presentation for an ACL rupture involves a sudden deceleration, a “pop,” immediate swelling and inability to continue play. Approximately two-thirds of ACL injuries are non-contact pivoting injuries.

A physical exam is sufficient to diagnose most ACL tears. An effusion is typically present, and an aspiration in the acute setting will typically reveal a hemarthrosis. The most sensitive physical exam maneuver to diagnose an ACL tear is the Lachman test. Additionally, the anterior drawer and pivot shift can help to confirm the diagnosis.

It is imperative to assess for associated ligamentous injury such as tears to the medial collateral ligament (MCL), posterior cruciate ligament (PCL), lateral collateral ligament (LCL) and posterolateral corner (PLC). Evaluation of axial alignment (varus or valgus deformity) is critical, as malalignment can predispose to surgical failure.Plain radiographs in the setting of an ACL tear assess for preexisting degenerative changes as well as associated fracture or dislocation. A Segond fracture represents an avulsion fracture of the lateral aspect of the tibial plateau and is often associated with an ACL tear. A tibial spine avulsion, which is typically seen in the pediatric population, represents an ACL avulsion and requires more urgent surgical intervention.

Magnetic resonance imaging (MRI) is often ordered to confirm the diagnosis and evaluate for concomitant intra-articular pathology. Classic bone bruises associated with an ACL tear are present at the mid aspect of the lateral femoral condyle and posterior aspect of the lateral tibial plateau. These contusions represent the bony injury that occurs during the so-called pivot shift.

The differential diagnosis for ACL injury includes patellar instability, meniscus tear, chondral injury or injury to other knee ligaments. An MRI is helpful to assess for these conditions. Meniscus tears are present in approximately half of all ACL ruptures. Associated ligament pathology can influence timing and approach to ACL treatment.

Treatment

The natural history of the ACL-deficient knee is one of recurrent instability with subsequent injury to the menisci and articular cartilage. This can result in accelerated arthritis in the knee.

ACL injuries can be treated with or without surgery. Nonoperative treatment is an option in low-demand or sedentary patients who are willing to modify their activities and avoid cutting, pivoting and jumping activities. Patients who choose not to have surgery are treated with rehabilitation and functional bracing.

The recommended surgical management of ACL tears is reconstruction. Simple repair is no longer advised. ACL reconstruction consists of replacing the ruptured ACL with graft tissue, which will then become a new ACL through a process called ligamentization. ACL reconstruction is indicated in active patients who are experiencing functional instability. Skeletally immature patients are increasingly being considered candidates for surgery, as compliance with nonoperative treatment in this age group is typically poor.

Grafts that are available to surgeons can be divided into autografts harvested from the patient or allografts obtained from cadaveric donors. Autograft reconstruction is often considered in young patients who engage in high-risk sports. The two most common autografts include bone-patellar tendon-bone (BTB) and hamstring.

Bone-patellar tendon-bone autograft has historically been considered the “gold standard.” Bone-to-bone healing results in less laxity on stability testing and faster incorporation compared to soft tissue grafts. However, there is significant morbidity to BTB autografts, such as kneeling pain and patella fracture.

Hamstring autograft is a desirable graft for several reasons. Quadruple hamstring grafts have very strong tensile load compared to the native ACL. There is typically less kneeling pain and better cosmesis compared to BTB. In addition, hamstring autograft is indicated in the skeletally immature patient secondary to less risk of physeal bar formation and angular deformity.

There are several disadvantages of hamstring autografts. Hamstring grafts are entirely soft tissue and do take longer to incorporate than BTB grafts. Hamstring weakness can also result, but postoperative hamstring strength is typically 90 percent of normal.

Allografts have become a popular choice for reconstruction secondary to technical ease and absence of graft harvest morbidity. In recent years, allografts have come under scrutiny secondary to a higher failure rate, particularly in young active patients.

The reasons for the higher failure rate are likely multifactorial. Sterilization with gamma irradiation weakens the biomechanical properties of the graft. Although allografts take longer to incorporate compared to autografts, athletes treated with allograft feel less pain and may return to sport prematurely. This can predispose to graft failure. Another disadvantage of allografts is the small potential risk of disease transmission. Allografts may be suitable for the older recreational athlete who needs to return to sedentary work more rapidly.

Several concomitant injuries may require treatment with the ruptured ACL. MCL tears often occur at the same time as ACL tears. These typically can be treated nonsurgically with a period of relative immobilization prior to ACL reconstruction. For meniscus tears, partial meniscectomy versus repair are options. Meniscus repair at the time of ACL reconstruction has a higher healing rate compared to isolated meniscus repair and should be attempted for tears that are amenable to repair.

Most surgeons release athletes to full unrestricted sports 6 to 12 months after ACL surgery, depending on graft selection and surgeon preference.

Potential Outcomes

ACL surgical failure has historically been less than 5 percent. Failure can result from inappropriate graft selection, inaccurate graft placement, inadequate graft fixation or tensioning, reinjury, overly aggressive rehabilitation or a premature return to sport.

Failure to address associated pathology can compromise ACL surgical outcome. Excessive malalignment or associated ligament injury, such as a posterolateral corner injury, that was not addressed at the time of the initial surgery can result in graft failure. Concomitant meniscus tears or chondral injuries can also lead to symptoms postoperatively.

Although ACL reconstruction is generally considered a successful operation, only two-thirds of NFL players undergoing ACL reconstruction will return to their previous level of play. Furthermore, while repetitive instability from an ACL deficiency can lead to degenerative changes in the knee joint, studies have yet to show that ACL reconstruction prevents the development of arthritis.

Prevention

Neuromuscular training programs in female athletes have been shown to prevent ACL injuries. These programs have done so by teaching proper technique for jump landing and emphasizing core and lower extremity strengthening.

Functional bracing may provide a proprioceptive benefit to athletes postoperatively. However, there is no evidence that functional bracing after ACL reconstruction will prevent reinjury, except in the setting of downhill skiing.

The treatment of ACL tears has evolved substantially over the last few decades. Fortunately, abundant research has been dedicated to improving outcome and a return to function after this devastating injury.

References

Ajuied et al. Anterior Cruciate Ligament Injury and Radiologic Progression of Knee Osteoarthritis: A Systematic Review and Meta-analysis. AJSM. 2014. 42 (9). 2242-2252.

Massini et al. ACL Bracing Update. Sports Medicine Update. Nov-Dec 2011. 2-6.

Herring et al. Consensus Statement on the Adolescent Athlete. Sports Medicine Update. Jan-Feb 2009. 7.

Balazs et al. Risk of AnteriorCruciateLigament Injury in Athletes on Synthetic Playing Surfaces: A Systematic Review. AJSM. Aug 2014.

Hewett et al. Clinical Sports Medicine Update: Anterior Cruciate Ligament Injuries in Female Athletes: Part 1, Mechanisms and Risk Factors. AJSM Feb 2006. (34) 299-311.

Frank et al. Anterior Cruciate Ligament Injuries in the Skeletally Immature Athlete: Diagnosis and Management. JAAOS.2013; 21:78-87.

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Advances in Orthopaedic Trauma

Thursday, February 19th, 2015

By Douglas W. Lundy, M.D., MBA, FACS

From ATLANTA Medicine, Vol. 86, No. 1

Ortho TraumaOrthopaedic surgery is a diverse specialty comprised of multiple subspecialties focused on anatomic areas or pathologic processes (degenerative disease, developmental or trauma). Although the origins of orthopaedic surgery stem from treatment of children affected by polio, a tremendous portion of orthopaedic surgery throughout the world today involves the treatment of injuries to the bones, joints and surrounding tissues of the musculoskeletal system. Orthopaedic trauma surgery has advanced significantly over the last 50 years, with massive strides in the understanding of injury and the techniques to successfully return these patients to a functional level of living.

The subspecialty of orthopaedic trauma is an underrepresented discipline in orthopaedic surgery that has benefited greatly from the conflict in Iraq and Afghanistan. It is a very unfortunate truth that the treatment of injury always increases greatly in the time of war. It is especially unfortunate that many young American men and women must be injured in battle for funding to become available for these very important initiatives.

Through the aggressive lobbying efforts of orthopaedic surgeons, hundreds of millions of dollars have been directed by Congress to fund research on the treatment of extremity injuries during war. The valuable lessons learned from the suffering of American combatants will further improve the treatment of American citizens now and in the years to come.

Trauma continues to be a major problem in the state of Georgia. Although trauma is the No. 1 killer of Georgians between the ages of six months to age 44, the state continues to underfund efforts to improve the trauma system and establish a truly effective trauma network.

Trauma costs this country $406 billion a year, including both healthcare costs and lost productivity. Studies by the Georgia Trauma Care Network demonstrate that fatality rate from motor vehicle crashes doubles as the distance from a verified trauma center increases.

At 13.2/100,000, the death rate in Georgia from trauma is higher than the national average of 11.3. Nonetheless, when Georgia Trauma Care Funding, Amendment 2, an effective constitutional amendment to fund trauma care in the state, was placed on the ballot four years ago, the initiative was defeated 52.6 percent to 47.4 percent. Ironically, the sections of the state that would have benefitted the most from this funding actually voted en masse to defeat the effort.

Mangled extremityTreatment of Mangled Extremities

Significant improvement techniques and a better understanding of severe extremity trauma has occurred over the last several years. The use of vacuum-assisted devices in the treatment of severe soft tissue trauma has dramatically decreased the morbidity of the treatment of these injuries. Improvements in the surgical and pharmacologic care of these injuries have resulted in lower rates of infection and other complications. Once again, much of this learning resulted from the horrific injuries sustained by our soldiers as they served valiantly in Iraq and Afghanistan.

The Lower Extremity Assessment Project (LEAP) was a tremendous effort by orthopaedic trauma surgeons to better understand the outcomes and ideal treatment of mangled extremities. I contributed some of the patients to this study during my fellowship 15 years ago, and this project resulted in over three dozen publications describing best practices in patients with these injuries.

The main findings of this study were sobering. Patients with severe lower extremity injuries did equally poorly whether their extremities are reconstructed or amputated, and the worse news is that the patients actually deteriorated in function between two and seven years after injury. This finding highlights that although we can reconstruct the bone structure and often gain healing, the extent of the soft tissue injury often determines the eventual functional outcome of the patient. Even though we have made significant strides in the treatment of these injuries, we still have a long way to go.

Pelvic and Acetabular Fractures

Pelvic and acetabular fractures with their associated injuries are some of the most catastrophic injuries affecting patients injured from motor vehicle crashes or falls. Increased understanding of the mechanisms leading to hypovolemic shock and death from pelvic injuries has resulted in a decrease in death rates and improvements in surgical techniques and functional outcomes. Minimally invasive techniques have resulted in faster returns to work and decreased morbidity for these badly injured patients.

Damage Control Orthopaedic Surgery

One of the biggest advances in orthopaedic trauma is the increased understanding of the contribution of major fractures to the overall stability of badly injured patients. With increased collaboration of orthopaedic surgeons with trauma surgeons and the trauma service, critically injured patients that would have died not too long ago now survive to live productive lives. Carefully timed and tactical emergent treatment of femoral and pelvic fractures, compartment syndromes and mangled extremities help optimize the patient’s condition during the critical hours after injury. After the patients have stabilized, we then return to surgery to anatomically reduce and stabilize articular fractures and accomplish definitive stabilization.

Advances in the care of patients with severe extremity injuries continue to develop, and these patients are enjoying much greater functional outcomes than they would have in the not too distant past. Although there is still much to accomplish in the care of these patients, we have come a long way. Atlanta has fellowship-trained orthopaedic trauma surgeons on staff at Grady Memorial Hospital, Kennestone Hospital, North Fulton Hospital and Gwinnett Medical Center trauma centers ready to care for patients presenting with severe injuries.

 

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