In support of Rare Disease Day, the CSRF held a National Cushing’s Patient Education Day on Feb. 23, 2013 in Boston, MA. Approximately 80 patients were in attendance and covered a wide spectrum from those still undergoing testing, to post-treatment, to those who have been in recovery for many years.

This year’s speakers included from left to right, Dr. Biller, Dr. Vance, Dr. Swearingen, Dr. Woodmansee, Dr. Laws, Dr. Findling

Dr. Biller, Massachusetts General Hospital, led off the morning with an Introduction to the Pituitary Gland. Dr. Biller stated that meeting’s such as this are “terrific in that the best thing a physician can have is educated patients and support groups.” She then went on to discuss how the pituitary glands functions, using an analogy of the pituitary gland being the “conductor of the endocrine orchestra” that controls the levels of many different hormones. In the case of Cushing’s Disease, the pituitary produces too much ACTH, which causes the adrenal glands to make too much cortisol. In adrenal Cushing’s, the adrenal makes too much cortisol and suppresses ACTH. Dr. Biller stressed that Cushing’s presents in many different ways and that she has evaluated patients referred from almost every medical specialty, eg orthopedic, ophthalmologists. Thus the diagnosis of Cushing’s is not like a heart attack, which has well defined symptoms. She also pointed out the importance of change over time and how useful old pictures can be.

The next talk by Dr. Woodmansee, Brigham and Women’s, covered the steps of Diagnosing Cushing’s. She again stressed that Cushing’s is one of the hardest disorders to diagnose and that the evaluation stage can be time consuming and frustrating for the patient. She discussed one of her early cases where because a person did not appear to have Cushing’s, some physicians believed that she could not have Cushing’s, however tests showed she did. In another case, the patient had numerous Cushing’s symptoms but after repeated testing over a number of years, was found not to have Cushing’s. The Endocrine Society Guidelines can serve as a guide for determining who and how to test. A careful clinical evaluation, lab tests and imaging are required to establish a correct diagnosis.

In the next talk, Dr. Swearingen, Massachusetts General Hospital, discussed Pituitary Surgery as well as some of the history of Cushing’s. He emphasized that if Cushing’s is not treated, it can be deadly, but that with cure, survival of past Cushing’s patients is equal to the general population. Dr. Swearingen discussed a variety data regarding cure rates, which in general, with very experienced surgeons, are about 90%. He also discussed that cure rates are higher for microadenomas compared to macroadenomas and that cure rates are higher if tumors can be seen on an MRI (95%) versus those that cannot be seen (89%), thus future improvements in imaging could lead to increased remission rates. He also discussed the surgical technique, possible complications and second surgeries. Dr. Swearingen stressed that endocrine follow up is required for many years as the recurrence rate for microadenomas is 10% at 5 years, 15% at 10 years and 20% at 15 years. He also stressed that recovery from Cushing’s symptoms takes much longer than recovery from surgery.

In the next talk, Dr. Laws, Brigham and Women’s, discussed the Options for Treatment of Unsuccessful Pituitary Surgery and Recurrent Cushing’s. The goal is to normalize cortisol and preserve normal pituitary function. The options include re-operation, radiosurgery, bilateral adrenalectomy, or medical treatment. Dr. Laws stressed that the choice of which of these options to pursue is dependent on the individual patient. If a patient is relatively stable, there may be time to utilize radiation or control the cortisol with medicines. With a very ill patient an immediate solution such as bilateral adrenalectomy might be required. Dr. Laws discussed studies in monkeys that showed only 15% of the normal pituitary volume is needed to preserve normal function. Thus, normal function can be retained even with removal of a significant part of the pituitary. Remission rates following Radiosurgery (Gamma Knife or Proton Beam) were 50%-60% within 1-1/2 years and approximately 30% of patients experienced hypopituitarism. Patients are usually placed on medications to control cortisol levels while they are waiting for the radiation to take effect. Dr. Laws stressed that patients should go to an experienced center for Radiotherapy as complications are less than with an inexperienced center. Bilateral adrenalectomy (BLA) is a viable option, particularly in a very ill patient, but requires life-long replacement medications and there is a risk of Nelson’s syndrome (an increase in tumor size and aggressiveness following BLA). Dr. Laws also mentioned that they are exploring the genetics of all of the tumors that are removed in an effort to identify potential new targets for medications.

Dr. Findling, Medical College of Wisconsin, presented the next talk on Medical Therapy for Cushing’s. Dr. Findling stressed that surgery is always the initial treatment of choice, but what do you do when that is not successful? In some cases, medications can be used to control cortisol levels. Medications that effect ACTH output include cabergoline and the newer medication, pasireotide. Cabergoline has been used for many years to control prolactin excretion and is effective in normalizing cortisol in about 20% of Cushing’s Disease patients. The newer pasireotide (not yet available in the US) targets receptors on the pituitary tumor and while it decreases cortisol in most patients, cortisol is normalized in about 25% of patients. In a clinical trial, blood pressure decreased and patients lost weight, however blood sugar was increased in 70% of patients. Ketoconazole is often used to decrease steroid production from the adrenal glands and normalizes cortisol in about 50% of patients, but the response is usually not sustained over long periods of time. Mitotane and metyropone are other medications that could be used, but have side effects and are not generally available in the US. Another medication, mifepristone, was approved in 2012 for the treatment of Cushing’s and works at the receptor level to block the action of cortisol, thus cortisol levels remain high, or can even increase. This is a similar approach to blocking the effects of estrogen using Tamoxifin in women with estrogen responsive breast cancer. Clinical trials reported improvement in metabolic and neuro/cognitive symptoms in 80% of patients. Side effects include vaginal bleeding and low potassium levels. In some cases, the medication may cause an increase in tumor size, but with small tumors, this may allow the tumor to be seen on an MRI. Dr. Findling presented a very interesting case where this indeed was the case and the patient underwent a successful pituitary surgery.

The next talk titled What to Expect During Recovery, Tapering and Follow up, was given by Dr. Mary Lee Vance, University of Virginia. Dr. Vance stressed that recovery takes time. Patients are evaluated 8 weeks following successful pituitary surgery for all hormones produced by the pituitary. Also at 8 weeks, a patient holds their replacement dose for 2 days and ACTH and cortisol are measured to determine if the axis has recovered. If not, tests are repeated every 2 months while the patient remains on replacement medication. There is no way to tell how long an individual patient will require replacement. Most are able to discontinue in 2-9 months, but others take much longer. Dr. Vance discussed the various symptoms of Cushing’s, again stressing that it takes time to recover. Blood pressure usually improves, but may not come back to normal. Diabetes also improves, with the need of less medication, but sometimes does not resolve completely. Depression also improves, but again it takes time and continuation of anti-depressants for 3-4 months can be useful. For weight loss, it can take some work, but decreased calories and increased activity pays off. Osteoporosis also improves but it takes time. Kidney stones generally don’t recur. With Cushing’s, blood clotting factors are abnormal so precautions need to be taken to prevent clotting during Cushing’s and for a time after Cushing’s. Birth control pills should be stopped as they increase the chance of clot formation. The aches and pains associated with steroid withdrawal will improve and Dr. Vance suggests anti-inflammatories, acetaminophen and water exercises to manage this. Memory and cognition also improves, but it can take a substantial period of time. There are no magic bullets for recovery and every patient is different. Recovery from Cushing’s is not like gallbladder surgery, where recovery is well defined. With Cushing’s, it takes time, everyone is different and it also depends on the severity of the Cushing’s.

The next talk on the Effects on Cushing’s on the Brain and Brain function was presented by Dr. Laws and Dr. Moodmansee. Dr. Laws explained that Cushing’s influences many psychological and cognitive functions including mood, depression, anxiety, apathy and sleep. Almost all of his patients complain of difficulties remembering names, difficulty performing their job function and an inability to concentrate. Dr. Laws showed some MRI’s of patients with Cushing’s that illustrated that the brain decreases in size during Cushing’s. The MRI of a 35yo female Cushing’s patient was approximately equivalent to an 85 yo man. After treatment, brain size and function can greatly improve, although it may not return to 100% of normal. Why does this happen? Dr. Laws said that the mechanism is largely unknown at this point, but studies in rats show decreased blood flow to the brain and functional MRI’s show a big difference in connections within the brain. Dr. Woodmansee then discussed that the hippocampus, an area of the brain important for learning and memory is greatly affected by Cushing’s. The same occurs in prolonged exposure to stress. Studies done in patients cured from Cushing’s show some prolonged subtle differences in some cognitive areas, but the longer the remission, the more improvement. The status of other hormone replacement is also important for this improvement. So while, some subtle differences may remain, psychological and cognitive functions vastly improve following cure.

In the last talk of the day, Dr. Mary Lee Vance discussed Cushing’s and Quality of Life. Dr. Vance pointed out that in the medical literature there are many surgical series that report high cure rates for Cushing’s patients. While that is good news, what that literature doesn’t cover, is what the patient actually experiences in terms of quality of life. Dr. Vance stressed that while she can talk to patients and know that their quality of life has been impacted, the question is how to measure that. Quality of life includes physical, emotional and psychological aspects and if one looks at the symptoms of Cushing’s, it is immediately apparent that all of the Cushing’s symptoms can greatly impact quality of life. There are a variety of standardized tests that are used to measure quality of life in different diseases compared to the quality of life of the normal population. When these tests are used to study Cushing’s patients, the results clearly show that active Cushing’s greatly reduces every aspect of quality of life. Studies after cure show very good improvement, however not all patients will return to 100% of their pre-Cushing’s quality of life. Recovery takes a long time and the more severe the symptoms, the longer it appears to take for recovery. Also, younger patients and children tend to recover more rapidly than older patients.

The day also included panel discussions. In the Patient Panel, Louise and Ellen discussed their experiences with Cushing’s and numerous attendees made comments as well. All of the speakers were involved in a panel discussion and the audience asked some very good questions (see the article on page 8). In addition to the speakers, we were also thankful to have Dr. Roy Phitayakorn, an endocrine adrenal surgeon from Massachusetts General Hospital, participate in the discussion.