Exogenous Cushing’s syndrome considered as the visible sign of a Corticosteroid Use Disorder

Background:

 

The definitions of dependence, habituation, addiction and abuse have been refined significantly since the introduction of corticosteroids as an accepted treatment for inflammation related diseases and autoimmune disorders. While the terms of addiction and abuse are no longer considered clinically correct, and have both been replaced with the term “substance use disorder”, they will be further refined to interpret older studies. There is a paucity of information and research on many of the adverse side effects of corticosteroids within the literature including vascular damage and as the basis for substance use disorder.  

 

Corticosteroids were introduced during the middle of the last century, and Prednisone is the most commonly prescribed corticosteroid today, and its usage has risen from being the fifteenth most commonly mentioned prescription drug in 1981[i] with 5.6 million mentions to the fifth most prevalent prescription drug in 1993[ii] with 7.8 million mentions. Since their introduction, many significant and serious adverse side effects have been noted, including cognitive impairment, Cushing’s Syndrome, Diabetes Mellitus, Osteoporosis and many others including neurological issues. Despite these significant issues, corticosteroids were seen as lifesaving medications worth the risk because of their ability to reduce inflammation. Addictions have been noted within the literature since near the beginning of their usage.

 

Definitions:

 

Dependence: the point at which the patient would risk adrenal crisis to abruptly discontinue using corticosteroids. This has been documented to occur in a very short amount of time[i] with respect to the times that patients have been documented as having some form of addiction or abuse, and certainly much shorter than the visibly obvious signs of Cushing’s Syndrome.

 

Addiction and Abuse: More correctly identified as a substance use disorder, as defined by the DSM V pages 581-582 under Other (Corticosteroid) Substance Intoxication, with the reward pathway primarily that of freedom from either the objective or subjective withdrawal symptoms and generally, at least a partially psychoactive response including a decrease in anxiety and/or an increase in energy to qualify as addiction, and with the reward pathway primarily that of mainly psychoactive response without underlying medical basis for its use to qualify as abuse.

 

Neurocognitive Disorder: Medication (Corticosteroid) Induced Neurocognitive Disorder as an impairment of at least one of the six cognitive domains as referenced in the DSM V pages 591-595 that is based on the effects of corticosteroids known in the literature. For the purposes of this paper will include Steroid Dementia and steroid delirium.

 

Cushing’s syndrome: Cushing’s syndrome is hypercortisolism, while exogenous refers to having a pharmaceutical basis outside the body and endogenous refers to having a naturally occurring basis inside the body, and both are clearly associated with neurocognitive decline.[ii] The visual appearance of well-defined Cushing’s Syndrome is obvious and includes facial obesity referred to as moon face (82%) that is frequently plethoric (reddish) in appearance, truncal obesity (96%) with distinctive striae, and supraclavicular fat pads that are an unusual fat deposit between the shoulder blades commonly referred to as a buffalo hump (74%)[iii], with most notably, thin arms and legs, skin atrophy and bruising (62%), edema (18%), polydipsia and/or polyuria (10%)[iv], fungal infections (6%).[v] Typically more women than men exhibit exogenous Cushing’s syndrome because more women suffer from autoimmune issues that require prolonged corticosteroid therapy. Women will also tend to exhibit alopecia, hirsutism (72%). The visual appearance on MRIs will show a notable smaller volumetric hippocampal volume.[vi] While these are the outward appearances of exogenous Cushing’s Syndrome, they are only a small part of the cumulative damage including Diabetes (80%), gonadal dysfunction (74%), high blood pressure (68%), muscle weakness (64%), mood disorders (58%), osteoporosis (38%) that prolonged supraphysiologic doses of corticosteroids do to the patient where after fifteen years of continuous corticosteroid therapy the damage resulting from the medication used to treat the underlying disease is greater than that of the underlying disease itself.

 

Addiction Other (Corticosteroid) Substance Intoxication:

 

The Diagnostic Criteria on the basis of the DSM V (ICD10 F19.929):

 

Threshold for substance use disorder is set at two or more criteria.[vii]

 

 

  1. The development of a reversible substance-specific syndrome attributable to recent ingestion of (or exposure to) a substance that is not listed elsewhere or is unknown.

Mood swings, depression, psychosis, and hallucinations are well documented and attributed to Prednisone in both the literature and on the label itself.

  1. Clinically significant problematic behavioral or psychological changes that are attributable to the effects of the substance on the central nervous system (e.g., impaired motor coordination, psychomotor agitation or retardation, euphoria, anxiety, belligerence, mood lability, cognitive impairment, impaired judgement, social withdrawal) and develop during, or shortly after the use of the substance.

    While this can occur on relatively short courses, it typically occurs during prolonged use and is described in more detail under the discussion of Criteria C of Medication (corticosteroid) Induced Neurocognitive Disorder.[viii] Mild naturally occurring perturbations in the neurobiology in the natural glucocorticoid, dopamine, and oxytocin systems have been identified as having roles in these types of behaviors. Supraphysiologic doses of Corticosteroids are also implicated in these behaviors.

  2. The signs and symptoms are not attributable to another medical condition, and are not better explained by another mental disorder, including intoxication with another substance.

    It would be necessary to investigate the neurological presentation of the underlying disease for which the Prednisone was prescribed to control. Long courses including lifetime courses are known to be prescribed for autoimmune conditions such as systemic lupus erythematosus, and the possibility of antibodies directly affecting the patient’s brain in the form of neuropsychiatric systemic lupus erythematosus would need to be considered.

 

Nine of the eleven features of addiction as identified in the DSM V are common in patients that are on chronic corticosteroid therapy. The two features that are typically rare would include virtually all of the patient’s daily activities revolving around corticosteroids, and withdrawal from family activities and hobbies in order to use the substance. In the case of corticosteroid use disorder, these features would be more typically attributed to the underlying illness rather than the medication prescribed to control it. An extreme example of Corticosteroid Intoxication was the subject of a legal proceeding, where two charges for attempted murder (filicide) were dropped on the basis involuntary intoxication of a Prednisone based oral asthma medication.[ix] This clearly shows support for Prednisone, the most commonly prescribed corticosteroid, as a medication capable of producing intoxication.   

 

Neurocognitive disorder – Medication (Corticosteroid) Induced Neurocognitive Disorder (ICD10 F19.188 & F9.288):

 

The Diagnostic Criteria on the basis of the DSM V:

 

  1. The criteria are met for major or mild neurocognitive disorder.

 

Individual neurocognitive testing of the patient in question would be a requirement in order to fully meet the criteria, and refusal to test in the face of a Cushingoid appearance would be considered suspect. Neurocognitive testing itself has grown over the last 65 years, including the Withers and Hinton test, the WAIS test, the MMS, and more recently automated computer testing such as CNSVS[x] [xi]. Testing variability such as choice of testing, subjectivity, familiarity and degree of validation of the testing procedure can provide questionable results in mild cases while more profound impairments become more obvious in test results.

 

  1. Persistence: The neurocognitive impairments do not occur exclusively during the course of a delirium, and persist beyond the usual duration of intoxication and acute withdrawal.

Nils Varney had identified Steroid Dementia as a reversible dementia in six patients because it was noted that their dementia like impairments diminished over time subsequent to the discontinuation of exogenous corticosteroids. The memory and IQ tests clearly showed persistent impairment as did the discussion of the six case studies.[xii] Dr. Owen Wolkowitz reported on a twin case study that continued 38 months beyond the discontinuation of corticosteroids administered to one twin. Academic, developmental and social disparities arose concurrent with the onset of corticosteroid therapy and showed improvement but remained upon the discontinuation of treatment.[xiii] In this work, Dr. Wolkowitz refers to a prior work in which he refers to four cases of persistent cognitive impairment comorbid with an appearance of Cushing’s syndrome.

 

 

 

  1. Capability: The involved substance or medication and duration and extent of use are capable of producing the neurocognitive behavior.

 

Starkman and coworkers[xiv]  found cognitive deficits in several domains in patients with Cushing’s disease, including verbal intellectual skills, learning, and memory. The largest decline in cognitive function in this study was found in measures of the verbal intelligence quotient and verbal learning and recall.[xv] These impairments are consistent with the clinical cognitive complaints reported by patients with Cushing’s disease.[xvi] Chronic exposure to supraphysiologic levels of glucocorticoids in Cushing's syndrome is associated with an increased prevalence of sleep disturbances, mood alterations, Psychiatric diseases, cognitive impairment, and anatomical brain changes.[xvii] The results of the study by Khiat et. al. clearly demonstrate that the patients under Prednisone therapy for many years display a cerebral alteration analogous to that observed for patients suffering from endogenous Cushing’s Syndrome.[xviii] Sibel Guldiken and Baburhan Guldiken suggest in their work that increased glucocorticoids may be responsible for subclinical Cushing’s Syndrome that lack many of the usual stigmata particularly especially those with risk factors including obesity, hypertension and diabetes mellitus and rapidly deteriorating cognitive functions.[xix] Finally, the label[xx] of the most popularly prescribed corticosteroid Prednisone includes a Cushingoid state, delirium, psychosis, dementia, emotional instability, hallucinations, impaired cognition and others that clearly place this medication into the category of being able to produce both neurocognitive impairment and Cushing’s syndrome. The following additional capabilities are noted for patients inclined towards chronic, or lifetime courses of corticosteroids for underlying autoimmune conditions such as systemic lupus erythematosus.

Psychiatric side effects have included psychoses, behavioral changes, and pseudotumor cerebri.[xxi]

  1. •Psychological problems •Irritability

  2. •Agitation, psychosis

  3. •Euphoria/depression (mood swings)

  4. •Insomnia[xxii]

    Brain atrophy was seen in 18% and focal lesions in 8% of patients. This suggests that the brain may be affected early in the course of SLE, even before the diagnosis of SLE is made, and while perhaps worsened by high cumulative corticosteroid dose and NPSLE events, is not dependent for their development.[xxiii] Disease duration, total corticosteroid dose and greater number of CNS manifestations were associated with hippocampal atrophy in patients with SLE. A significant progression of hippocampal atrophy related to total corticosteroid dose and number of CNS events was observed.[xxiv]

    Psychiatric adverse effects during systemic corticosteroid therapy are common. Two large meta-analyses found that severe reactions occurred in nearly 6% of patients, and mild to moderate reactions occurred in about 28%. Although disturbances of mood, cognition, sleep, and behavior as well as frank delirium or even psychosis are possible, the most common adverse effects of short-term corticosteroid therapy are euphoria and hypomania. Conversely, long-term therapy tends to induce depressive symptoms. Dosage is directly related to the incidence of adverse effects but is not related to the timing, severity, or duration of these effects. Neither the presence nor the absence of previous reactions predicts adverse responses to subsequent courses of corticosteroids.[xxv]

     

  1. Timing: The temporal course of the neurocognitive deficits is consistent with the timing of substance or medication use and abstinence (e.g., the deficits remain stable or improve after a period of abstinence.)
    1. Corticosteroid-induced symptoms frequently present early in a treatment cycle and typically resolve with dosage reduction or discontinuation of corticosteroids. In severe cases or situations in which the dose cannot be reduced, antipsychotics or mood stabilizers may be required. This review offers an approach to identifying and managing corticosteroid-induced psychiatric syndromes based on the type of symptoms and anticipated duration of corticosteroid treatment.[xxvi] This is also supported by the previously mentioned works of Drs. Varney and Wolkowitz.

 

 

  1. The neurocognitive disorder is not attributable to another medical condition or is not better explained by another mental disorder.

 

An investigation of what other conditions might be comorbid in a particular patient would certainly be in order. There is truly a paucity of reference in the literature to the vascular impairments secondary to prolonged corticosteroid use[xxvii] [xxviii] but there is enough to consider that Steroid Dementia may have both reversible and irreversible components. Cushing’s syndrome has been linked with this condition.[xxix] The reversible components well described by both Drs. Varney and Wolkowitz, but the irreversible component that I speculate exists has yet to be fully explored as vascular dementia. Prednisone is known to not only treat vasculitis, but according to the label, to cause it as well. The challenges of identifying the pathogenesis for drug induced vasculitis is discussed in the work by Radic and Kaliterna[xxx]as is the discussion of its comorbidity with systemic lupus erythematosus, and while it discusses corticosteroid treatment for vasculitis, it fails to consider corticosteroids among the causes of vasculitis. It is known to cause vasomotor dysfunction and high blood pressure, and it is known to cause coagulopathy as discussed in the work of Fardet and Feve which also linked these conditions to Cushing’s syndrome.[xxxi] While other disorders ought to be ruled out, it is within reason to consider any cerebral vascular impairment as being possibly caused by the corticosteroids used to treat the patient. It is even more likely that when there is cerebrovascular impairment that is minimized by treatment with corticosteroids comorbid with emotional and cognitive impairment as a result of the adverse side effects of a prolonged course of corticosteroids on the patient’s brain, that they become trapped in a U shaped corticosteroid dosage constraint where they may be unable to be removed from corticosteroid therapy.

 

Discussion:

 

Cushing’s syndrome is associated with the dependence/addiction/abuse spectrum in the literature on table 1. The literature clearly supports dependency being developed well within the time frame of chronic therapy defined as being greater than a 90 day course and is therefore omitted from further discussion. Kligman et. al. describes dependence within as little as 9 hours using topical steroids and discusses Cushing’s syndrome as a possible result to topical corticosteroid addiction.[xxxii] Addiction typically becomes apparent when during the course of a taper in an effort to wean the patient and avoid the potentially life threatening adverse side effects, it results in an increase in symptoms, particularly either subjective or objective. Prednisone while being the number one medication used to treat vasculitis is also known to cause medication induced vasculitis, and with no other options, the patient is locked into a lifetime course of corticotherapy. Unfortunately, as this is rarely touched on within the literature, doctors do not typically warn patients of this possibility as a standard of care. Other objective symptomology also may increase to the point where it is medically necessary to reverse the course of a steroid taper at least temporarily. The psychoactive effects of corticosteroids are generally hypomania, increased energy and elevated mood, and have been noted in the face of the debilitating effects of chronic illness that supports a reward system necessary for abuse. On some occasions within the literature, corticosteroids have clearly been abused without the underlying medical condition necessary to support treatment as a standard of care.

 

 

Study

Gender

Addiction

Abuse

Visible Cushing's Syndrome

Corticosteroid

1[xxxiii]

M

Yes

 

no physical description given

ACTH

1

F

 

Yes

no physical description given

ACTH

1

F

 

Yes

no physical description given

ACTH

2[xxxiv]

F

Yes

 

no physical description given

Prednisone

2

F

Yes

 

no physical description given

Prednisone

3[xxxv]

M

Yes

 

Yes

ACTH+

4[xxxvi]

F

Yes

 

Yes

Prednisone

5[xxxvii]

F

Yes

 

Yes

Prednisone

5

F

Yes

 

Yes

Prednisone

5

F

 

Yes

Yes

Prednisone

5

M

 

Yes

No

Prednisone

5

F

Yes

 

Yes

Prednisone

6[xxxviii]

M

 

Yes

Yes

Prednisone+

7[xxxix]

F

 

Yes

Yes

Prednisone

7

M

 

Yes

Yes

Prednisone

7

M

Yes

 

no physical description given

Prednisone

8[xl]

F

 

Yes

Yes

Prednisone

9[xli]

M

 

Yes

No

Prednisone

Factitious:

10[xlii]                        F                                              Yes                                 Yes                                    Indeterminate              

11[xliii]                       F                                              Yes                                 Yes                                    Indeterminate              

                                F                                              Yes                                 Yes                                    Indeterminate              

                                F                                              Yes                                 Yes                                    Indeterminate              

                                F                                              Yes                                 Yes                                    Indeterminate              

                                F                                              Yes                                 Yes                                Indeterminate  

                                M                                            Yes                                 Yes                                    Indeterminate              

12[xliv]                       F                                              Yes                                 Yes                                     Prednisone

13[xlv]                        F                                              Yes                                 Yes                                    Indeterminate              

                                F                                              Yes                                 Yes                                    Indeterminate              

                                F                                              Yes                                 Yes                                    Indeterminate              

                                F                                              Yes                                 Yes                                    Indeterminate              

14[xlvi]                       M                                            Yes                                 Yes                                    Hydrocortisone

15[xlvii]                      F                                              Yes                                 Yes                                    Indeterminate              

16[xlviii]                      F                                              Yes                                 Yes                                    Indeterminate              

17[xlix]                       M                                            Yes                                 Yes   hydrocortisone and dexamethasone

                                M                                            Yes                                 Yes                                 betamethasone

18[l]                           F                                              Yes                                 Yes                                 Prednisolone

                                F                                              Yes                                 Yes                                 Prednisone

 

Analysis:

 

9 studies with a total of 18 patients that described either an addictive or abusive situation were identified in the literature according to the definitions above. Dependence was ignored as even short courses of corticosteroids create dependence issues where weaning becomes necessary to restart the functioning of the adrenal glands. Of the 18 patients identified in the studies, those 6 with no physical description that could rule Cushing’s syndrome in or out were discounted. Of the remaining 12 patients, all but two showed either mild or obvious signs of Cushing’s syndrome resulting in an 83% correlation between visibly obvious Cushing’s syndrome and addiction to or abuse of corticosteroids. The two cases where Cushing’s syndrome was not obvious by way of visual examination may have fit the description of subclinical Cushing’s syndrome. The case study by Dixon and Christy where the patient did not visually exhibit signs of Cushing’s syndrome did describe generalized muscle wasting, addiction to narcotics, the typical behaviors of an addict and no estimation of how long the patient had been taking Prednisone, or what the cumulative lifetime dosage might have been. The other case study by Brown that did not reflect an appearance of Cushing’s syndrome did identify him as having taken between 5 and 60 mg/day for 17 years. There was no identification of cumulative lifetime dosage. The patient’s described behavior seems to be consistent with the characteristics of subclinical Cushing’s syndrome as described by Guldiken & Guldiken.[li] Subsequent searches for factitious Cushing’s Syndrome turned up another 19 case studies which by definition showed a 100% correlation between the visible appearance of Cushing’s Syndrome and the current definition of Corticosteroid Use Disorder. It was approximated in a retrospective review of a large cohort study that 6 of 860, or about 0.7% of Cushing’s Syndrome patients are characterized as having surreptitiously taken large amounts of corticosteroids without having an underlying medical basis to do so.[lii] These 19 factitious cases only address the abuse part of the definition of what is now termed Corticosteroid Use Disorder, but it neglects to address what is very likely a far larger incidence of addiction to corticosteroids, possibly for subjective symptoms, or even for objective symptoms.

 

Varney[liii] did not identify whether any of the non-endogenous cases were Cushingoid in appearance, nor was testing reported to indicate any hypercortisolism, but since many of the courses of corticosteroid usage for those patients was of a relatively short nature and that taking supraphysiologicial doses effectively raises glucocorticoid levels, that some form of subclinical Cushing’s Syndrome was likely developing. Since neither of the other two case studies that do not report a visible appearance of Cushing’s syndrome also do not report testing for hypercortisolism, it would be expected that if the patients continued on their current course of supraphysiological dosages, that they would eventually develop Cushing’s syndrome. Even in cases of advanced endogenous Cushing’s syndrome, neurocognitive issues are reported in the literature. While visible Cushing’s syndrome of a patient on chronic corticosteroid therapy does not meet the definition of addiction by itself, it would certainly be an indicator that for those unable to wean from chronic corticosteroid therapy that it is a question of not if, but when neurocognitive impairment occurs, that it will meet that definition. Untreated Cushing’s syndrome is known to be fatal.[liv]

 

 

The persistence of the neurocognitive impairment is clearly shown within the literature. The capability for corticosteroids to produce neurocognitive impairments has been documented in the literature extending back into the middle of the last century. The timing of the effects with respect to the course is well documented within Dr. Wolfowitz’s works, as well as Nils Varney and many others. Criteria E requires close examination on an individual basis, and also requires further study as to the long term effects of corticosteroid therapy on the vascular system, specifically with respect to vasculitis, coagulopathy, ischemia, micro infarcts, stroke, vascular dementia, and the resulting neurocognitive impairment. Further study on the possibility of steroid dementia as a mixed dementia consisting of the classic reversible steroid dementia syndrome and irreversible vascular dementia is indicated, but does not detract from criteria E being met on an individual basis.

 

Weaknesses:

 

There are several weaknesses that can be addressed in further study. The first is small sample sizes, and as a retrospective review of the literature, this is necessarily limited to case studies rather that a large cohort with controls, formal testing for Cushing’s syndrome, and consideration of the cumulative lifetime dosage of exogenous corticosteroids consumed. One third of the case studies within the literature did not present a physical description. The relationship between the adverse vascular side effects of corticosteroids and neurocognitive impairment associated with steroid dementia is not yet fully understood but should be more completely considered.

 

Future:

 

Corticosteroids should be recognized as causing a high rate of dependence, and patients need to be warned of this and that sudden discontinuation of corticosteroids may induce adrenal failure and death. Patients ought to be warned that a medically induced corticosteroid substance disorder as well as Medication (Corticosteroid) Induced Neurocognitive Disorder is a possible outcome so that they might have the opportunity to make an informed consent. Prescribers of corticosteroids ought to offer substance disorder treatment to both the patient and to their families as a standard of care in the event that the treatment crosses into the threshold of either corticosteroid use disorder or Medication (Corticosteroid) Induced Neurocognitive Disorder. Further research on the vascular dementia component of steroid dementia is warranted.

 

Conclusion:

 

While it is not necessary to have exogenous Cushing’s syndrome to be classified as having either a Corticosteroid Use Disorder or a Corticosteroid Induced Neurocognitive Disorder, the literature supports that visibly obvious exogenous Cushing’s syndrome is highly associated with corticosteroid use disorder and Medication (Corticosteroid) Induced Neurocognitive Disorder. A patient being under a doctor’s care who prescribes corticosteroids in no way detracts from these definitions. Corticosteroids appear to be lifesaving medications with a high rate of dependency, and a significant possibility for causing a medically induced use disorder, and that while prolonging the life of the patient, also prolongs and compounds their suffering as well as their loved ones who suffer from the secondary effects of their corticosteroid use disorder. Educating patients regarding this possibility, and providing support for both them and their families in facing this medically induced substance use disorder to a medication of requirement in the same way that would be done for a drug of choice is necessary in order to provide the patient with the maximum support.

 

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