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Table of Contents    
LETTERS TO EDITOR
Year : 2019  |  Volume : 67  |  Issue : 4  |  Page : 1128-1130

Tuberculous Meningitis in a Patient with Cushing's Disease: Glucocorticoid-mediated Immunosuppression: Case Report, and Review of the Literature


1 Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, Bethesda, Maryland, USA
2 Section on Reproductive Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA
3 Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA

Date of Web Publication10-Sep-2019

Correspondence Address:
Dr. Prashant Chittiboina
Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, 10 Center Drive, Room 3D20, Bethesda, Maryland, 20892-1414
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.266237

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How to cite this article:
Chatain GP, Mehta GU, Nieman LK, Sharma S, Yuditskaya S, Chen RY, Yockey L, Holland SM, Chittiboina P. Tuberculous Meningitis in a Patient with Cushing's Disease: Glucocorticoid-mediated Immunosuppression: Case Report, and Review of the Literature. Neurol India 2019;67:1128-30

How to cite this URL:
Chatain GP, Mehta GU, Nieman LK, Sharma S, Yuditskaya S, Chen RY, Yockey L, Holland SM, Chittiboina P. Tuberculous Meningitis in a Patient with Cushing's Disease: Glucocorticoid-mediated Immunosuppression: Case Report, and Review of the Literature. Neurol India [serial online] 2019 [cited 2019 Sep 23];67:1128-30. Available from: http://www.neurologyindia.com/text.asp?2019/67/4/1128/266237




Sir,

Chronic exposure to excess glucocorticoids leads to Cushing's syndrome (CS), with exogenous administration of supraphysiologic doses being the most common cause.[1] The most frequent endogenous etiology of CS is hypersecretion of adrenocorticotropic hormone (ACTH) from a pituitary adenoma, termed Cushing's disease (CD).[1] Patients suffering from CD have an estimated four-fold excess mortality, underlying the importance of early diagnosis.[2] The clinical presentation of CS varies significantly; some of the signs (e.g., hypertension, weight gain) are common in the general population, which may delay recognition of the syndrome.

Uncontrolled hypercortisolemia in CS induces immunosuppression that leads to infectious complications in up to 42% of untreated patients.[3] The immune system is impaired in a dose-dependent fashion, with increasing risk of serious and opportunistic infections seen with higher plasma cortisol levels.[4] Among reports of opportunistic infection in CD, few have described tuberculosis (TB): only one report of TB reactivation was found [Table 1] - Tsubota 1991]. We present the first case of a young man who developed TB meningitis and was ultimately diagnosed with CD.
Table 1: Review of opportunistic tuberculous infections previously linked to Cushing's Disease

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Our patient had a history of latent TB at age 12, treated with 2 months of isoniazid after which he was lost to follow-up. As a 20-year-old male college student, he presented to an emergency room with severe headaches, nausea and photophobia. After treatment for elevated blood pressure, he was discharged. Twenty-four hours later, he was found obtunded. Computed tomography demonstrated multifocal cerebral edema with mild mass effect. Cerebrospinal fluid (CSF) contained elevated protein (2041 mg/dL), elevated WBC (333 cells/μL), decreased glucose (18% of serum), and was culture positive for Mycobacterium tuberculosis. Appropriate therapy with isoniazid, rifampin, pyrazinamide, and ethambutol was initiated along with high-dose dexamethasone. A right frontal ventriculo-peritoneal shunt was inserted for treatment of hydrocephalus. Further investigation of his TB meningitis revealed basal meningitis and multiple tuberculomas on magnetic resonance imaging (MRI) [Figure 1]. Testing for underlying immunological defects was nondiagnostic. During his admission, despite clearing his CSF of Mycobacterium tuberculosis, cognitive impairment, hearing loss, bitemporal hemianopia, and hypertension were noted. His functional status continued to be poor and was discharged to inpatient rehabilitation, where he made minimal recovery.
Figure 1: MRI images demonstrate basal meningitis and a pituitary adenoma. Preoperative MRI images demonstrate severe basal meningitis (asterisk) in T1W postcontrast image (a), and in FLAIR images (b). Inflammatory mass extends from the midline along the middle cerebral arteries bilaterally. Dedicated pituitary 3D SPGR postcontrast coronal (c) and sagittal (d) images demonstrate a hypoenhancing adenoma (white arrowhead) within the sella. T1W postcontrast (e) and FLAIR (f) images obtained 18 months following surgery demonstrate improving basal meningitis. 3D SPGR – volumetric spoiled gradient, FLAIR – fluid attenuated inversion recovery, MRI – magnetic resonance imaging, T1W – T1 weighted

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Due to ongoing inflammation without much improvement and the progressive sequelae of high-dose dexamethasone, he was started on weekly methotrexate as a steroid-sparing regimen along with folate supplementation. Despite progressive steroid taper, his weight increased from 86 to 128 kg over 8 months with no improvement in his hypertension. On examination, he was obese with moon facies and a prominent dorsocervical fat pad. An ACTH stimulation test, done to determine hypothalamic–pituitary–adrenal (HPA) axis function following taper of long-term high-dose steroids, was unexpectedly robustly normal just a few weeks after completion of the taper. These findings prompted workup for hypercortisolemia.

Corticotropin releasing hormone (CRH) stimulation was consistent with a pituitary source of ACTH secretion. Pituitary MRI demonstrated a left-sided 5 × 4 mm pituitary adenoma on high-resolution three-dimensional (3D) spoiled gradient sequences [Figure 2]. High-dose dexamethasone suppression test (HDDST) failed to adequately suppress serum cortisol and was confounded by low dexamethasone level, likely due to concomitant rifampin treatment.[5] Therefore, confirmatory inferior petrosal sinus sampling (IPSS) with CRH stimulation was performed showing lateralization. These results confirmed a pituitary adenoma as the source of ACTH-dependent hypercortisolemia.
Figure 2: Histopathological examination confirmed an ACTH positive pituitary adenoma. Hematoxylin and eosin staining (A) revealed a distinct pituitary adenoma (a) with monomorphic basophilic cells separate from the normal gland (n) that demonstrated a more polymorphic appearance with acinar architecture. Loss or normal acinar architecture (n) in the adenoma (a) is also highlighted in reticulin stained specimen (B). The adenoma (a) was also uniformly avid to ACTH stain (C), confirming an ACTH positive pituitary adenoma. Scale bar = 100 μm. ACTH – adrenocorticotropic hormone, H and E – hematoxylin and eosin

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The patient underwent transsphenoidal exploration of the pituitary gland. A 5 × 5 × 5 mm left-sided lesion was completely resected using a pseudocapsular technique. Histological assessment confirmed ACTH-secreting pituitary adenoma.

At 18-month post-transsphenoidal follow-up, MRI brain revealed improvement in basilar meningitis. ACTH stimulation testing showed progressive HPA axis recovery. Cognitive ability and fatigue continued to improve slowly.

The predisposition to opportunistic infections in states of hypercortisolemia results from effects of glucocorticoids on cellular and humoral immunity. The transcription factor nuclear factor-κB (NF-κB) plays a central role in immune and inflammatory responses and is inhibited by glucocorticoids.[6] Other transcription factors may be affected as well.[7],[8] Glucocorticoid exposure leads to reversible lymphopenia and monocytopenia by decreasing the number of circulating mononuclear leukocytes.[9]

Approximately 10–12% of pituitary adenomas arise from ACTH-secreting corticotropes. In his original report, Harvey Cushing indicated that “the malady appears to leave the patients with a definite susceptibility to infections.”[10] The extent of immunological compromise and risk of opportunistic infections demonstrate a direct relationship with the degree of hypercortisolism.[4] Most frequently such infections in CS occur with ectopic ACTH secretion rather than in CD, as serum cortisol levels are typically much greater.[1] Among reports of infection associated with CD, three reports have described TB infection with only one report of possible reactivation [Table 1] - Tsubota 1991]. In that report, an elderly gentleman diagnosed with CD developed tuberculous peritonitis. He had a past medical history of pulmonary TB and later died of pituitary apoplexy resulting in intraventricular hemorrhage, a rare complication of CD. Two previous cases of TB were also linked to CD; however, the patients had no known prior contact with TB [Table 1] - Hill 1998, Kwon 2006]. To the best of authors' knowledge, this is the first case of TB meningitis reported in CD.

This case demonstrates the management challenge of CD and concurrent opportunistic infections. In this patient, effective treatment of presenting TB meningitis included high-dose corticosteroid treatment and may have led to a delay in diagnosis and treatment of CD. HDDST results were also confusing due to concomitant rifampin therapy [5] leading to further delay and the need for IPSS in this patient.

Although tuberculous meningitis has not been previously described in the setting of CD and that it may be a possible coincidental finding with an ACTH-secreting adenoma, our report suggests that hypercortisolemia causes immunosuppression that may lead to reactivation of latent TB and dissemination. We emphasize the need to consider hypercortisolemia in a patient presenting with unexplained immunological compromise and symptoms consistent with cortisol excess.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgement

This research was supported by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke and the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, et al. Diagnosis and complications of Cushing's syndrome: A consensus statement. J Clin Endocrinol Metab2003;88:5593-602.  Back to cited text no. 1
    
2.
Etxabe J, Vazquez JA. Morbidity and mortality in Cushing's disease: An epidemiological approach. Clin Endocrinol (Oxf)1994;40:479-84.  Back to cited text no. 2
    
3.
da Mota F, Murray C, Ezzat S. Overt immune dysfunction after Cushing's syndrome remission: A consecutive case series and review of the literature. J Clin Endocrinol Metab2011;96:E1670-4.  Back to cited text no. 3
    
4.
Sarlis NJ, Chanock SJ, Nieman LK. Cortisolemic indices predict severe infections in Cushing syndrome due to ectopic production of adrenocorticotropin. J Clin Endocrinol Metab 2000;85:42-7.  Back to cited text no. 4
    
5.
Yamada S, Iwai K. Letter: Induction of hepatic cortisol-6-hydroxylase by rifampicin. Lancet 1976;2:366-67.  Back to cited text no. 5
    
6.
Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections. Lancet 2003;362:1828-38.  Back to cited text no. 6
    
7.
Ray KP, Farrow S, Daly M, Talabot F, Searle N. Induction of the E-selectin promoter by interleukin 1 and tumour necrosis factor alpha, and inhibition by glucocorticoids. Biochem J 1997;328:707-15.  Back to cited text no. 7
    
8.
Ohtsuka T, Kubota A, Hirano T, Watanabe K, Yoshida H, Tsurufuji M, et al. Glucocorticoid-mediated gene suppression of rat cytokine-induced neutrophil chemoattractant CINC/gro, a member of the interleukin-8 family, through impairment of NF-kappa B activation. J Biol Chem 1996;271:1651-9.  Back to cited text no. 8
    
9.
Balow JE, Hurley DL, Fauci AS. Immunosuppressive effects of glucocorticosteroids: Differential effects of acute vs chronic administration on cell-mediated immunity. J Immunol 1975;114:1072-6.  Back to cited text no. 9
    
10.
Cushing H. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). 1932. Obes Res 1994;2:486-508.  Back to cited text no. 10
    


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