General Hospital Psychiatry xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

General Hospital Psychiatry journal homepage: http://www.ghpjournal.com

Case Report

Psychiatric symptoms in a patient with isolated adrenocorticotropin deficiency: case report and literature review Yoko Morigaki ⁎, Jun-ichi Iga, M.D., Naomi Kameoka, M.D., Satsuki Sumitani, M.D., Tetsuro Ohmori, M.D. Department of Psychiatry, The University of Tokushima School of Medicine, Tokushima 770–8503, Japan

a r t i c l e

i n f o

Article history: Received 18 August 2013 Revised 10 February 2014 Accepted 11 February 2014 Available online xxxx Keywords: ACTH deficiency Isolated Depression Psychotic disorders Organic mental disorders Neuroleptic malignant syndrome

a b s t r a c t We report a 59-year-old man with isolated adrenocorticotropin (ACTH) deficiency. The patient presented with sudden onset of delusions and hallucinations at the age of 54, which resolved gradually without treatment. Subsequently, the patient manifested stereotypy, wandering, hypobulia, and autistic symptoms, and was treated with antipsychotics for 1 year without any improvement. He suffered from neuroleptic malignant syndrome-like symptoms at the age of 59. A thorough endocrine assessment revealed isolated ACTH deficiency. After hydrocortisone supplementation, the physical and psychiatric symptoms improved dramatically. Clinicians should consider this rare disease when diagnosing patients with refractory psychiatric symptoms and unique physical symptoms of isolated ACTH deficiency. © 2014 Elsevier Inc. All rights reserved.

1. Introduction

2.2. History of the present illness

Isolated adrenocorticotropin deficiency (IAD) is a rare pituitary disorder characterized by decreased secretion of adrenocorticotropin (ACTH), which causes secondary adrenal insufficiency [1]. Although dysfunction of ACTH cells due to autoimmune mechanisms has been suspected, the precise cause of this disease is still unknown [1]. According to epidemiology investigations in Japan, the incidence of IAD is 0.09 per 100,000 persons per year and the prevalence of IAD is 1.91 per 100,000 persons [2]. To our knowledge, there is no literature concerning the epidemiology of IAD in other countries, including European countries and the United States of America. General fatigue, loss of appetite and hypoglycemia are frequent as physical symptoms, while psychiatric symptoms related to ACTH deficiency are rare. Here, we report a patient with IAD who experienced various psychiatric symptoms. The literature is also briefly reviewed.

At the age of 54, he developed a stereotypic movement of the fingers, as though rubber was being pulled and stretched out. At the age of 55, he experienced delusions and visual hallucinations. He said he was attached to a transmitter and there was something shiny above his head. At this time there was social withdrawal and he began to lead an idle life. At the age of 58, he was admitted to another hospital, where the negative symptoms of schizophrenia were considered to be present. He was diagnosed with schizophrenia. Blood laboratory examination was normal. A dose of 10 mg/day olanzapine did not relieve the hypobulia or autistic symptoms.

2. Case report

2.4. Investigations

2.1. Presenting symptoms

On admission to our hospital, blood laboratory examination revealed hyponatremia (125 mEq/l) and increased creatine kinase (3988 U/l). He had a high-grade fever, muscle rigidity and disorientation, suggesting drug-induced SIADH (syndrome of inappropriate secretion of antidiuretic hormone) and the neuroleptic malignant syndrome (NMS). There were no stereotypic movements, delusions or visual hallucinations. Fever, rigidity and disorientation improved after discontinuation of the antipsychotic drug, but the hypobulia and autistic symptoms did not resolve. Brain magnetic resonance images did not reveal any abnormality.

A 59-year-old man was transferred to the University Hospital of Tokushima for spinal surgery. On presentation, he had difficulty walking due to ossification of the cervical posterior longitudinal ligament. Hypobulia and autistic symptoms were also noted. He spoke only one or two words while bowing his head, and said repeatedly, “I’m fed up.” ⁎ Corresponding author. Tel.: +81 88 633 7130; +81 88 633 7131. E-mail address: [email protected] (Y. Morigaki).

2.3. Past medical history The patient did not report any significant past medical history.

http://dx.doi.org/10.1016/j.genhosppsych.2014.02.012 0163-8343/© 2014 Elsevier Inc. All rights reserved.

Please cite this article as: Morigaki Y., et al, Psychiatric symptoms in a patient with isolated adrenocorticotropin deficiency: case report and literature review, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.02.012

2

Y. Morigaki et al. / General Hospital Psychiatry xxx (2014) xxx–xxx

2.6. Differential diagnosis

Table 1 Results of the combined pituitary function test.

GH ng/ml PRL ng/ml TSH μU/ml LH mIU/ml FSH mIU/ml ACTH pg/ml Cortisol μg/dl

0 min (normal range)

30 min

60 min

90 min

120 min

0.50 (0.0–6.4) 15.5 (1.5–9.7) 7.30 (0.38–3.64) 3.9 (1.7–8.6) 6.2 (1.5–12.4) 6.6 (7–56) 2.0 (4.3–23.3)

5.88 63.1 38.77 54.7 14.7 6.1 1.7

6.51 48.1 34.46 52.5 15.6 6.0 1.6

4.44 32.6 26.79 42.7 15.6 6.1 1.6

1.66 25.5 19.89 35.7 15.0 5.6 1.5

GH: growth hormone, PRL: proractine, LH: luteinising hormone, FSH: follicle stimulating hormone.

Endocrine tests were carried out to investigate the cause of hyponatremia, which revealed that he had low cortisol (0.9 μg/dl) and ACTH (4.7 pg/ml) levels. The combined pituitary function test was performed to assess the anterior pituitary reserve for production of anterior pituitary hormones (Table 1). Four exogenous hypothalamic hormones were administered and corresponding pituitary hormones were assessed every 30 minutes for the next two hours. Secretions of growth hormone, luteinizing hormone and thyrotropin were maintained within normal limits, whereas those of ACTH and cortisol were diminished. Thus, the patient was diagnosed with IAD.

2.5. Treatment Hormonal substitution with hydrocortisone resulted in dramatic improvement of both the hyponatremia and psychiatric symptoms. Hydrocortisone replacement therapy was started with drip infusion of 100 mg/day hydrocortisone, which was gradually tapered off and discontinued on Day 8. Oral hydrocortisone (30 mg/day) was started on Day 9. The patient’s speech increased gradually and he regained motivation for rehabilitation 14 days after the beginning of the hydrocortisone replacement therapy. He could tell jokes on Day 17. He received spinal surgery on Day 28. He recovered enough to talk about future plans regarding housing and employment on Day 40. His psychiatric symptoms did not relapse during a 20-month followup period.

Steroid responsive encephalopathy associated with thyroditis (SREAT) also presents with various psychiatric symptoms in association with elevated titers of anti-thyroid antibodies and is responsive to steroid treatment [3]. In this case, the serum level of thyroid stimulating hormone (TSH; 12.64 μU/ml) was elevated and triiodothyronine (T3; 2.6 pg/ml) and thyroxine (T4; 0.82 ng/ml) levels were low. TSH, T3 and T4 levels did not change after hydrocortisone replacement therapy was begun. After discharge, levothyroxine sodium hydrate was started, and the thyroid hormone levels were normalized. Anti-thyroid peroxidase (10 IU/ml) and thyroid autoimmunity marker (b10 IU/ml) levels were normal. Therefore, SREAT could be ruled out, and this patient had IAD with concomitant primary hypothyroidism. 3. Discussion We admitted a patient with IAD that manifested with psychiatric symptoms. Hydrocortisone replacement therapy dramatically improved these symptoms. A search of the PubMed database and the Japanese literature revealed only 17 previously reported cases of IAD with psychiatric symptoms [4–19]. More than 80% of those patients were middle-aged, consistent with the typical age of onset of IAD. Unresponsiveness to psychotropic medications was the most frequently reported reason for making the correct diagnosis. Hypoglycemia, hyponatremia, disturbance of consciousness and abnormal electroencephalogram findings were often reported, and these might be useful as diagnostic aids (Table 2). Although NMS-like symptoms have often been reported in IAD without psychiatric symptoms, to our knowledge, the current report is the first of a case manifesting both NMS-like symptoms and psychiatric symptoms [20]. Definitive diagnosis should be made by endocrinological loading tests [1]. The exact mechanisms underlying NMS-like syndrome also remain largely unknown. However, a decrease in cortisol levels can play an important role in the development of NMS-like symptoms [20]. It has been suggested that glucocorticoid regulates levels of adrenal phenyl ethanolamine N-methyltransferase (PNMT), which is an enzyme that converts

Table 2 Nine previously reported cases of isolated adrenocorticotropin deficiency mimicking depressive disorder [4–11]. Author/year

Age/sex

Psychiatric symptoms

Other

Treatment/effect

Prognosis

Iwata et al./2012

19/M

School refusal

56/M

Paroxetine/not effect Hydrocortisone/completely ameliorate Glucocorticoid/improved

Not mentioned

Miyasaka et al./2011 Tatsuzawa et al./2011

62/M

Sertraline/not effect Hydrocortisone/dramatically resolved

Not mentioned

Matsuishi et al./1996

60s/M

Anhedonia Apathy Disturbed consciousness, Stupor Depressive mood, Suicidal behavior, Loss of pleasure, Psychomotor retardation Psychomotor retardation, Willingness decline

Amoxapine/improved appetite temporarily Hydrocortisone/improved

Remission

Matsuishi et al./1996

50s/M

Sulpiride/not effect Hydrocortisone/remission

Remission

Choy et al./1991

55/F

Not mentioned

Sato et al./2008

54/M

Methylpredonisolone/lethargy and weakness remitted Hydrocortisone/improved Hydrocortisone/remission

Parenti et al./2007

43/F

Glucocorticoid/remission

Not mentioned

Hirao et al./2007

76/M

Fluvoxamine/not effect Hydrocortisone/remission

Not mentioned

Psychomotor retardation, Willingness decline, Depressive mood

Willingness decline, Visual hallucination

Withdrawal, general fatigue, Hyponatremia, Hypoglycemia General fatigue, Appetite loss, Anemia, Hyponatremia, Hypothyroidism, Insomnia Appetite loss, Insomnia, Nausea, Vomiting, General fatigue, Hyponatremia, Hypercalcemia, Renal dysfunction Appetite loss, Insomnia, Nausia, Vomiting, General fatigue, Anemia, Renal dysfunction Painful stiff joints, Frozen shoulders, Tiredness, Lethargy, Nausia, Vomitting, Weight loss Severe appetite loss, General malaise, Hypotension, Hypogonadism Nausea, Hyporexia, Muscle weakness, Insomnia, Weight loss, Amenorrhea, Hypoglycemia, Hyponatremia Nausea, Vomitting, General fatigue, Hyponatremia, Hyperosmia, Disorientation

Not mentioned

Not mentioned

Please cite this article as: Morigaki Y., et al, Psychiatric symptoms in a patient with isolated adrenocorticotropin deficiency: case report and literature review, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.02.012

Y. Morigaki et al. / General Hospital Psychiatry xxx (2014) xxx–xxx

3

Table 3 Five previously reported cases of isolated adrenocorticotropin deficiency mimicking psychotic disorder [12,17–19]. Author/year

Age/sex

Psychotic symptoms

Other

Treatment/effect

Prognosis

Waseda et al./1978

41/M

EEG abnormalities

Methylperidol + Hydrocortisone/hallucination and delusion resolved

Not mentioned

Yokoyama et al./1989

52/F

Empty sella

Cortisone/not effective

Not mentioned

Sakaguchi et al./1996

52/M

Empty sella EEG abnormalities

Hydrocortisone/remission

Remission

Kishi et al./1996

44/M

Empty sella EEG abnormalities

Cortisone/partially improved Hydrocortisone/partially improved

Not mentioned

Present case/2012

59/M

Hallucination Delusion Aggressive behavior Emotion and will attenuation Hallucination Delusion Abnormal behavior Emotional incontinence Aggressive behavior Disorientation Pareidolia Delusion Euphoria Childish behavior Abnormal behavior Hallucination Delusion Stereotypy Autistic symptoms Hypobulia

Neuroleptic Malignant Syndrome-like symptoms

Olanzapine/partially improved Hydrocortisone/remission

Remission

noradrenaline to adrenaline. Reduced PNMT, activity might induce changes in catecholamine metabolism in the brain or muscle. Therefore, an insufficient cortisol level could induce psychiatric- as well as NMS-like symptoms (see Table 3). Various psychiatric symptoms have been reported in patients with IAD. Depressive symptoms are the most prevalent, while hallucinations and delusions are rare (Table 2). These symptoms are dramatically improved by steroid replacement therapy, and antidepressant or antipsychotic agents are usually less effective. There have been 4 reported cases with psychosis-like symptoms including hallucinations and delusions. In 3 of those 4 cases, including the current case, psychiatric symptoms were dramatically improved by hydrocortisone replacement therapy (Table 2). The hypobulia and autistic symptoms in the current case were also dramatically improved by steroid replacement therapy, in parallel with improvement of the physical symptoms. These improvements suggested that the psychiatric symptoms were associated with IAD. Although the hallucinations and the delusional state that was temporarily seen in this patient at the initial disease onset did not recur after discontinuation of the antipsychotic drugs, these symptoms have been also reportedly been improved by steroid replacement therapy and are presumed to be associated with IAD [17,19]. The precise mechanisms involved in the manifestation of psychiatric symptoms in patients with IAD are unknown. Hypercortisolemia or synthetic glucocorticoid treatments are known to induce psychiatric symptoms [21,22], but the association between psychiatric symptoms and hypocortisolemia has not been discussed extensively. Psychosis in patients with Sheehan’s syndrome, another disease that includes hypocortisolemia, has been reported [22–24]. In summary, we reviewed reports of 17 patients with hypocortisolemia and psychiatric symptoms associated with IAD. Most of these patients were initially treated with psychotropic drugs, and the symptoms were refractory to treatment, a fact that was instrumental in obtaining a correct diagnosis. Clinicians should consider this rare disease when treating a patient with refractory psychiatric symptoms and unique physical symptoms of IAD.

References [1] Tanaka K. Anterior pituitary diseases: points and cautionary notes of the diagnosis and treatment isolated ACTH deficiency. Nippon Naika Gakkai Zasshi 1994;83:2087–91 [Japanese]. [2] Katakami H, Ishikawa E, Hidaka K, et al. Clinical feature, incidence, and prevalence of isolated ACTH deficiency (IAD). ACTH related Peptides 2007;18:123–5 [Japanese].

[3] Carlone C, Todini L, Marini I, et al. Acute psychiatric presentation of steroidresponsive encephalopathy: the underrecognized side of autoimmune thyroiditis. Riv Psichiatr 2013;48:169–73. [4] Iwata M, Hazama GI, Nakagome K. Depressive state due to isolated adrenocorticotropic hormone deficiency underlies school refusal. Psychiatry Clin Neurosci 2012;66:243–4. [5] Miyasaka M, Kojima K, Yasuda M, et al. Patient with isolated adrenocorticotropic hormone (ACTH) deficiency who was depressive before glucocorticoid replacement, and exhibited stupor during continuous ACTH test. Psychiatry Clin Neurosci 2011;65:535. [6] Tatsuzawa Y, Ono Y, Takahashi T, Yoshino A, Nomura S. Case of isolated adrenocorticotropic hormone deficiency mimicking major depressive disorder. Psychiatry Clin Neurosci 2011;65:302. [7] Matsuishi K, Imai H, Ito A, et al. Two cases of isolated ACTH deficiency suspected as depression with severe appetite loss. Seishin Shinkeigaku Zasshi 2010;112: 1073–81 [Japanese]. [8] Choy EH, Corkill MM, Gibson T, Hicks BH. Isolated ACTH deficiency presenting with bilateral frozen shoulder. Br J Rheumatol 1991;30:226–7. [9] Sato Y, Tanda H, Kato S, et al. Isolated ACTH deficiency in a late onset case of hypogonadism (LOH) not diagnosed by examination in an internal medicine clinic. Hinyokika Kiyo 2008;54:573–5 [Japanese]. [10] Parenti G, Ricca V, Zogheri A, et al. A case of hyponatremia caused by central hypocortisolism. Nat Clin Pract Endocrinol Metab 2007;3:369–75. [11] Hirao K, Kikawada M, Otoguro M, et al. Elderly case of isolated ACTH deficiency presenting with depression and digestive symptoms. Nihon Ronen Igakkai Zasshi 2007;44:117–21 [Japanese]. [12] Yokoyama T, Komurasaki Y, Uemoto M, Ogura J, Maeda K. Three patients with hypopituitarism accompanied by primary empty sella presenting mental symptoms. Rinsho Shinkeigaku 1989;29:1023–7 [Japanese]. [13] Nishitani H, Yuji S. Case of isolated ACTH deficiency associated with neurologic symptoms. Nihon Rinsho 1978;36:3016–21 [Japanese]. [14] Kuo YH, Chang Y, Chen HC, Liao SC. Sertraline alleviated osmophobia caused by partial hypopituitarism with Isolated ACTH deficiency. Gen Hosp Psychiatry 2013;35:574.e9–574.e10. [15] Nagai Y, Shimizu H, Sato N, Mori M. A case of isolated ACTH deficiency with dementia. Nihon Naibunpi Gakkai Zasshi 1994;70:989–94 [Japanese]. [16] Kajantie E, Otonkoski T, Kivirikko S, Somer M. A syndrome with multiple malformations, mental retardation, and ACTH deficiency. Am J Med Genet A 2004;126A:313–8. [17] Waseda Y, Tomonari H. On a case of isolated ACTH deficiency with marked mental symptoms and electroencephalographical abnormalities. Seishin Igagu 1978;20:399–406 [Japanese]. [18] Sakaguchi H, Inoue D, Maekawa T, Koshiyama H. A case of Isolated ACTH deficiency with various mental symptoms. Naika gakkai zasshi 1996;77:989–91 [Japanese]. [19] Kishi T, Kitani M, Naganuma R. A case of Isolated ACTH deficiency with mental symptoms and electroencephalographical abnormalities. Seishin Igagu 1996;38:187–94 [Japanese]. [20] Sekijima Y, Hoshi KI, Kasai H, et al. Three patients with isolated adrenocorticotropin deficiency presenting with neuroleptic malignant syndrome-like symptoms. Intern Med 2001;40:510–4. [21] Fietta P, Fietta P, Delsante G. Central nervous system effects of natural and synthetic glucocorticoids. Psychiatry Clin Neurosci 2009;63:613–22. [22] Brown ES. Effects of glucocorticoids on mood, memory, and the hippocampus. Treatment and preventive therapy. Ann N Y Acad Sci 2009;1179:41–55. [23] Shoib S, Dar MM, Arif T, et al. Sheehan's syndrome presenting as psychosis: a rare clinical presentation. Med J Islam Repub Iran 2013;27:35–7. [24] Kale K, Nihalani N, Karnik N, Shah N. Postpartum psychosis in a case of Sheehan's syndrome. Indian J Psychiatry 1999;41:70–2.

Please cite this article as: Morigaki Y., et al, Psychiatric symptoms in a patient with isolated adrenocorticotropin deficiency: case report and literature review, Gen Hosp Psychiatry (2014), http://dx.doi.org/10.1016/j.genhosppsych.2014.02.012