Irreversible Effects of Previous Cortisol Excess on Cognitive Functions in Cushing’s Disease

10 04 2010

ResearchBlogging.orgApril 8th is Cushing’s Awareness Day. This day has been chosen as a day of awareness as it is the birthday of Dr. Harvey Cushing, a neurosurgeon, who discovered this illness.

Cushing’s disease is a rare hormone disease caused by prolonged exposure to high levels of the stress hormone cortisol in the blood, whereas Addison’s disease is caused by the opposite: the lack of cortisol. For more background information on both see this previous post. Ramona Bates MD, of Suture for a Living, has written an excellent review (in plain language) about Cushing’s Disease on occasion of Cushing Awareness Day at EmaxHealth.

From this you can learn that Cushing’s disease can be due to the patient taking cortisol-like glucocorticoids, such as prednisone for asthma (exogenous cause), but can also arise because people’s bodies make too much of cortisol itself.  This may be due to a tumor on the pituitary gland, the adrenal gland, or elsewhere in the body.

Symptoms of Cushing’s disease are related to the effects of high levels of cortisol or other glucocorticoids on the immune system, the metabolism and  the brain. Symptoms include rapid weight gain, particularly of the trunk and face (central obesity, “moon face” and buffalo neck), thinning of the skin and easy bruising, excessive hair growth, opportunistic infections, osteoporosis and high blood pressure.

Less emphasized than the clinical features are the often very disabling cognitive deficits and emotional symptoms that accompany Cushing’s disease. Cushing patients may suffer from various psychological disturbances, like insomnia, mood swings, depression and manic depression, and from cognitive decline. Several studies have shown that these glucocorticoid induced changes are accompanied by atrophy of the brain, and in particular of the  hippocampal region, leading to hippocampal volume loss and a profound loss of synapses [2]. This hippocampal loss seems reversible [2], but are neurological and psychological defects also restored? This is far more important to the patient than anatomic changes.

If we listen to Cushing patients, who are “cured” and have traded Cushing’s disease for Addison’s disease, we notice that they feel better after their high levels of cortisol have normalized, but not fully cured (see two examples of ex-Cushing patients with longlasting if not irreversible health) problems in my previous post here. [added 2010-04-17)
To realize how this affects daily life, I recommend to read the photo-blog 365 days with Cushing by Robin (also author of Survive the Journey). Quite a few of her posts deal with the continuous weakness (tag muscle atrophy), tiredness (tag fatigue), problems with (short-term) memory (see tag memory)  or both (like here and here).

Scientifically the question is to which extent ex-Cushing patients score worse than other healthy individuals or chronically ill people and, if so, whether this can be attributed to the previous high levels of glucocorticoids.

A recent study by endocrinologists (and one neurologists) from the Leiden University Medical Center assessed the cognitive functioning of patients  after long-term cure of their Cushing’s disease (caused by a ACTH producing pituitary adenoma, that induces overproduction of cortisol (hypercortisolism) by the adrenals [1]. Previous studies had contradictory outcomes and/or were too small to draw conclusions.

The authors first compared a group of 74 Cushing patients (with a previous pituitary tumor) with matched healthy controls (selected by the patients themselves). Matched means that these controls had the same characteristics as the Cushing patients with respect to gender (male/female: 13/61), age (52 yr) and education.
Cushing patients were on average 13 years in remission and were followed for another 3 years (total 16 yrs follow-up). Cushing’s disease  had been established by clinical signs and symptoms and by appropriate biochemical tests. All patients were treated by transsphenoidal surgery (surgery via the nostrils), if necessary followed by repeat surgery and/or radiotherapy (27%). Cure of Cushing’s disease was defined by normal overnight suppression of plasma cortisol levels after administration of dexamethasone and normal 24-h urinary excretion rates of cortisol. 58% of the patients had at least one form of hypopituitarism (deficiency of one or more hormones) and half of the patients needed hydrocortisone replacement therapy.

Long after their cure, 62% of the Cushing patients reported memory problems, and 47% reported problems in executive functioning. The Hospital Anxiety and Depression Scale (HADS)-score (10.5)  indicated no clinical depression or anxiety. Patients with long-term cure of Cushing’s disease did not perform worse on measures of global cognitive functioning. However, these patients had several other cognitive impairments, mainly in the memory domain.
Only a single test result (FAS, measures verbal mental flexibility and fluency) was significantly different between patients with short and long-term remission.

From direct comparison with healthy controls it is not clear what causes these cognitive alterations in Cushing patients.

Therefore the cognitive function of Cushing patients was compared to that of patients previously treated for non-functioning pituitary macroadenomas (NFMA).
NFMA patients were chosen, because they have undergone similar treatments (transsphenoidal surgery (100%), with repeat surgery and/or radiotherapy (44%) as the Cushing patients. They also shared hypopituitarism and the need for hydrocortisone substitution in half of the cases. NFMA patients, however, have never been exposed to prolonged excess of cortisol.

Cushing patients could not be directly compared to NFMA-patients, because these patient groups differed with regard to age and gender.

Thus Cushing patients were compared to matched healthy controls and NFMA to another set of healthy controls, matched to these NFMA patients (Male/Female: 30/24  and mean age: 61 yr).

To compare Cushing patients with NFMA patients the Z-scores* were calculated for each patient group in relation to their appropriate control group. A general linear model was used to compare the Z-scores.

Overall Cushing patients performed worse than NFMA patients. In the memory domain, patients cured from Cushing’s disease had a significantly lower MQ measured with the Wechsler Memory Scale compared with patients with NFMA in the subscales concentration and visual memory. On the Verbal Learning Test of Rey, patients cured from Cushing’s disease recalled fewer words in the imprinting, the immediate and delayed recall trials. Furthermore, on the Rey Complex Figure, patients with cured Cushing’s disease scored worse on both trials when compared with NFMA patients. In tests measuring executive function, patients cured from Cushing’s disease made fewer correct substitutions on the Letter-Digit Substitution Test and came up with fewer correct patterns on the Figure Fluency Test compared with treated NFMA patients.

These impairments were not merely related to pituitary disease in general and/or its treatment, because these patients with long-term cure of Cushing’s disease also revealed subtle impairments in cognitive function compared with patients previously treated for NFMA. These are most likely caused by the irreversible effects of previous glucocorticoid excess on the central nervous system (because this is the main difference between the two).

Sub-analysis indicated that hypopituitarism was associated with mildly impaired executive functioning** and hydrocortisone dependency** and additional radiotherapy were negatively associated with memory and executive functioning, whereas the duration of remission positively influenced memory and executive functioning.

The main point of criticism, apparently raised during the review process and discussed by the authors, is the presentation of the data without adjustments for multiple comparisons. When more than one test is used, the chance of finding at least one test statistically significant due to chance increases. As the authors point out, however, the positive significant results were not randomly distributed among the different variables. Furthermore, the findings are plausible given the irreversible effects of cortisol excess on the central nervous system in experimental animal and clinical studies.

Although not addressed in this study, similar cognitive impairments would be expected in patients having continuous overexposure to exogenous glucocorticosteroids, like prednison.

* Z-scores: The z score for an item, indicates how far and in what direction, that item deviates from its distribution’s mean, expressed in units of its distribution’s standard deviation. The z score transformation is especially useful when seeking to compare the relative standings of items from distributions with different means and/or different standard deviations (see: http://sysurvey.com/tips/statistics/zscore.htm).

** This makes me wonder whether Addison patients with panhypopituitarism have lower cognitive functions compared to healthy controls as well.

Hattip: Hersenschade door stresshormoon lijkt onomkeerbaar (2010/04/08/) (medicalfacts.nl/)

References

  1. Tiemensma J, Kokshoorn NE, Biermasz NR, Keijser BJ, Wassenaar MJ, Middelkoop HA, Pereira AM, & Romijn JA (2010). Subtle Cognitive Impairments in Patients with Long-Term Cure of Cushing’s Disease. The Journal of clinical endocrinology and metabolism PMID: 20371667
  2. Patil CG, Lad SP, Katznelson L, & Laws ER Jr (2007). Brain atrophy and cognitive deficits in Cushing’s disease. Neurosurgical focus, 23 (3) PMID: 17961025 Freely available PDF, also published at Medscape
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Changing care (for Addison patients)

19 10 2008

This post is inspired by the theme for this weeks Grand Rounds at PalliMed, a Hospice and Palliative Medicine Blog: “Changing Goals of Care”. According to Christian Sinclair, M.D. of Pallimed:

It can be changing the goals in any direction, not just the curative towards palliative route, although I expect that is a common touchstone for many in the medical field.

‘Goals of Care’ is a subject that is outside of my area of professional expertise, being a medical biologist and an information specialist.

But as a consumer and patient I can easily see how I would like health care to change.

  • affordable healthcare for everyone who needs it
  • More personal and personalized care
  • And -indeed- more attention for palliative healthcare (my mother in law has a bearable life, since low doses morphine were prescribed)

But those issues can be better addressed by persons in the field. I just simply want to restrict to “changing care in a very specific area, adrenal diseases, simply because I’m a hands-on expert, having secondary Addison’s Disease (Sheehan’s syndrome)”.

Main conclusions:
Healthcarefivers look (and act) beyond your specialty! Try to be a good generalist as well. Please adapt protocols if it suits the patients. Take the patient seriously.

Diagnosis
Primary Addison (damage or destruction of the adrenal cortex) as well as secondary Addison (absent pituitary signal(s)) often have a slow onset and are difficult to diagnose.
In theory this may be different for Sheehan’s Syndrome. According to Google Knol:

Sheehan’s syndrome (…) is a condition in which the pituitary gland is injured as result of heavy blood loss during complicated childbirth. This heavy loss of blood deprives the pituitary gland of oxygen and other nutrients and leads to necrosis (death) of pituitary tissue and therefore pituitary failure (hypopituitarism). Failure to produce breast milk after delivery (due to lack of the pituitary hormone prolactin) may be a presenting sign of Sheehan’s syndrome. Fortunately, Sheehan’s syndrome is now rare cause of pituitary failure, particularly in developed countries as a result of improved obstetric care.

Looking back I’m stunned that Sheehan was not directly diagnozed by the gynecologists themselves.
And perhaps even more surprised why it happened to me in the first place, being hospitalized in Europe, and having a previous cesarean. (For good reason it is: “Once a cesarean, always a cesarean” According to present protocols I had many negative predictors for success (no prior vaginal birth, short stature, age >40, induction of labor, gestational age almost 43 weeks, failed second stage), but worst of all they didn’t take me serious when I said I didn’t feel well and got a sudden neck pain. When standing up I fainted. So I have every reason to believe all this could have been prevented).

I lost more than 3 litres of blood (and had puerperal fever as well), developing all signs of Sheehan (and Addison crisis) in the days that followed: breast milk “disappearing”, loss of appetite, severe muscle pain, fatigue, headache, lethargy, extreme nausea, diarrhea & vomiting and finally speaking with double tongue, feeling like I fell when lying down, sensitive to cold etc. But nurses pressed to try to give breastmilk (till bleeding), reprimanded me in presence of other patients (you have to break the circle, please do your best (!) and eat something; you have to take care of your child, come on!) and a psychiatrist was being ordered. Finally (after 10 days), when I plead them to check whether I was not dehydrated, they did some tests and found out my blood Natrium was dangerously low (106; normal 140), and could apparently not be corrected by giving saline transfusion. I “missed’ this part, but when I woke up the internist told me proudly he found out I had Sheehan (practically no cortisol or any other hormones under regulation of the anterior hypophysis). Normal natrium levels were achieved after giving cortisol-replacement.

I’m by no means an exception. Addison’s disease is often missed or diagnosed late. That early diagnosis can be a challenge is frequently addressed in the medical literature and many poignant examples can be read on patient forums. In fact I know very few prompt and swift diagnoses.

For instance (from the Newsletter of “The Canadian Addison Society”, issue 27, 2002

After being admitted and discharged what seemed to feel like every weekend, I was finally admitted for bronchitis that affected my asthma. I went on Prednisone* to treat the infection. I felt much better to my surprise. After being “cured” of bronchitis, back in the hospital I went. The pain was unbearable; doctors were questioning if I was anorexic, I saw a psychiatrist who put me on Paxil because I “appeared” to be depressed. Demerol became my new best friend and was the only thing that put me at ease.
My mother continued to stay by my side the entire time. Whether it be stroking my hand, brushing my hair, or encouraging me to walk just a few steps a day. This felt like a marathon to me; in reality it was only a few steps.
After every “possible” test was completed my internist had suggested performing one more test. The results had come back positive! Addison’s Disease….**

(*Prednisone is a glucocorticosteroid that can replace cortisol; this patient also had pigmented handpalms, specific for primary Addison.)

well-ville.com/images/adrenalQA2.jpg

The same is true for other adrenal diseases. Cushing’s Disease (excess of cortisol) is often mistaken for (manic) depression. See for instance wrongdiagnosis.com or here (Dutch).

After years of non-recognized Cushing one of my fellow patients was treated by many specialists. One expert (being an orthopedic, I believe) totally missed the Cushing, because she fixated on other causes of the severe osteoporosis and didn’t notice the patient’s bruises, mania, belly fat, striae to name just a few other symptoms, typical for Cushing. Missing her diagnosis means she is mostly in a wheel chair now, and not able to do the things she liked to do (for those interested and able to read Dutch she has written a book about it: “Aftakelen and Ophijsen”)

Action (in case of a crisis)
With hormone replacement therapy, most Addison patients disease are able to lead normal lives. However extreme stress can precipitate an Addison crises, which is a medical emergency. Patients therefore often wear alert bracelets or necklaces, so that emergency personnel can identify them as having adrenal insufficiency and provide stress doses of steroids in the event of trauma, surgery, or hospitalization.

Luckily I don’t seem very vulnerable to crises (still producing aldosterone), but the one time I had something like it (presumably due wrong capsules, thus more insidious), family physicians reacted inadequatly. One gave me a lab form emphasizing twice that lab tests should ONLY be done when I was really, really ill. Very stupid, because determining Natrium costs nothing compared to hospitalization, and my pride prevented me taking the test, afraid that I made a fool of myself. My own physician said a few weeks later that I should consult a endocrinologist, because he found Addison “much too difficult”. I thought that wasn’t bad, but my endocrinologist didn’t agree, because “he would have been too late in case of a real emergency”. (I had a Na of 123, but was hospitalized, because my endo (a wonderful female doctor) found I behaved differently and wasn’t ok – I also lost >18 pounds in 2 months)

But there are far more upsetting stories of other Addison crises. Even in this era there are unnecessary deaths due to  inadequate intervention. What is also worrying is that paramedics often miss the alert bracelets. A Dutch paramedic wrote on the bulletin board of our patient’s association, that paramedics don’t even look at it, because they aren’t allowed to do anything going beyond first aid and stabilization. However, if my husband may give me an intramuscular injection of corticosteroids, why can’t a paramedic? It is the most essential emergency measure that can and should be taken. He advised that we would bundle our forces with other patient groups to change the protocols of the ambulance personnel. Paramedics won’t do anything when they are not legally entitled to.

I also hear from many Addison patients that it takes ages before there is adequate action. Apparantly routine tests have to be performed first. A nurse even told me that glucose is tested first, because it is such an easy and fast test. O.k. an addison crisis is often accompanied by low blood glucose. So what? Get those corticosteroids in!!! Intravenous injection is often difficult, because of the low blood pressure. It often takes too long and often fails, at least that is what I hear from other patients.

Iatrogenic Cushing and Addison

Apart from natural causes, Cushing and Addison’s disease can have a iatrogenic cause (unintended harmful effects by a physician’s activity, manner, or therapy). It is well known that longlasting treatment and/or high doses of corticosteroids can give Cushing-like symptoms as well as Addison-crises in case of sudden withdrawal (because of feedback mechanisms the body can’t make cortisol any longer).
Laurens Mijnders has developed long lasting Addison’s Disease because of his asthma treatment. His letter in Contrastma, a paper of a Dutch Asthma Foundation (Astma fonds) evoked many responses of patients who had used high doses corticosteroids (up to 50 mg/day Prednison per day). The reactions showed that doctors had given little or no information about adverse effects of corticosteroids and had never warned against a possible Addison crisis (see here).
An endocrinologist revealed at a meeting that they still regularly see Addison crises in patients who received high-dose steroids for their asthma, rheuma, dermatologic or other inflammatory condition
Of course some of these diseases can only be controlled by corticosteroids, but the treating physician should try to sail safely between Scylla and Charybdis, and prepare the patient for any (anticipated) danger.

Wasn’t it: “Primum non nocere” (Latin for “First, do no harm”)?!

Thus physicians, look beyond the border of your specialty and always take patients seriously, please?

Addison's disease info (nvacp)