Idiopathic Intracranial Hypertension After Surgical Treatment of Cushing Disease: Case Report and Review of Management Strategies

Accepted Manuscript Idiopathic intracranial hypertension following surgical treatment of Cushing disease: case report and review of management strategies Jeffrey Wagner, BA/BS, Cara M. Fleseriu, Aly Ibrahim, MD, Justin S. Cetas, MD, PhD PII:

S1878-8750(16)30821-X

DOI:

10.1016/j.wneu.2016.09.008

Reference:

WNEU 4548

To appear in:

World Neurosurgery

Received Date: 7 July 2016 Revised Date:

30 August 2016

Accepted Date: 1 September 2016

Please cite this article as: Wagner J, Fleseriu CM, Ibrahim A, Cetas JS, Idiopathic intracranial hypertension following surgical treatment of Cushing disease: case report and review of management strategies, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.09.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Idiopathic intracranial hypertension following surgical treatment of Cushing disease

Idiopathic intracranial hypertension following surgical treatment of Cushing disease: case report and review of management strategies

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Jeffrey Wagner, BA/BS, Cara M. Fleseriu, Aly Ibrahim, MD, and Justin S. Cetas, MD, PhD

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Department of Neurological Surgery and Northwest Pituitary Center, Oregon Health & Science University, Portland Oregon

CORRESPONDING AUTHOR CONTACT INFORMATION:

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Justin S. Cetas, MD, PhD Department of Neurological Surgery (CH8N) Oregon Health & Science University 3303 SW Bond Ave. Portland, Oregon 97239 [email protected] 503-494-4314

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ACCEPTED MANUSCRIPT Idiopathic intracranial hypertension following surgical treatment of Cushing disease

ABSTRACT BACKGROUND: Idiopathic intracranial hypertension (IIH) in Cushing’s disease (CD) patients, following treatment, is rarely described, in adults. Etiology is thought to be multifactorial,

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potentially related to a relative decrease in cortisol following surgical resection or medical

treatment of a corticotroph pituitary adenoma. We investigated our center’s CD database (140 surgically and 60 medically (primary or adjunct) treated patients) for cases of IIH, describe our

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center’s experience with symptomatic IIH, and review treatment strategies in adults with CD after transphenoidal resection.

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CASE DESCRIPTION: We present the case of a 22-year-old female who presented with worsening headache, nausea, vomiting, blurry vision, diplopia, visual loss and facial numbness 14 weeks after surgical resection of adrenocorticotropic hormone-positive pituitary adenoma. Her CD had been in remission since surgery with subsequent adrenal insufficiency (AI), which

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was initially treated with supraphysiologic glucocorticoid (GC) replacement, tapered down to physiologic doses at the time the IIH symptoms developed. CONCLUSION: Symptomatic IIH is very rare in adult patients, but can be severe and result in

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permanent vision loss. A high index of suspicion should be maintained and a fundus exam is necessary to exclude papilledema, whenever there are suggestive symptoms that initially may

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overlap with AI. It is possible that some cases of mild IIH are misdiagnosed as GC withdrawal and/or AI, however further studies are needed. Treatment consists of re-initiation of higher steroid doses together with acetazolamide with or without cerebrospinal fluid diversion and the priority is to preserve vision and reverse any visual loss.

KEYWORDS: Idiopathic intracranial hypertension, pseudotumor cerebri, Cushing disease, transsphenoidal resection

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INTRODUCTION Cushing disease (CD), caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma, often presents a clinical challenge for both diagnosis and treatment.

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Transphenoidal surgery (TSS) remains first line therapy; if remission is achieved

postoperatively, patients will most likely have adrenal insufficiency (AI) requiring

glucocorticoid (GC) replacement. Medical treatment is also used as primary or adjuvant

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treatment in CD and can decrease cortisol production and/or its effects.1,2 In cases where

complete disease remission is achieved, either through medication, surgery or both, the rapid fall

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of circulating cortisol may give rise to a relatively rare complication: idiopathic intracranial hypertension (IIH), otherwise known as pseudotumor cerebri (PTC) or benign intracranial hypertension (ICH). Idiopathic intracranial hypertension is a disorder of unknown etiology characterized by signs and symptoms of increased intracranial pressure (ICP) such as headache,

on evaluation.3-6

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abducens nerve palsy, visual abnormalities, and tinnitus where a mass or abnormality is absent

Idiopathic intracranial hypertension has been reported frequently in the pediatric Cushing

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population,7 however, very few cases have been reported in adults.8 We retrospectively reviewed our center’s prospectively maintained CD database (140

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surgically and 60 medically (primary or adjunct) treated patients; data collected over the course of 18 years) for cases of IIH. This revealed one patient with symptomatic IIH, which developed three-and-a-half months (14 weeks) post-endoscopic TSS of a pituitary adenoma. Clinical, laboratory, and radiographic findings for this patient were reviewed, retrospectively (patient provided authorized use and disclosure of protected health information).

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We conducted a literature review to identify further cases, focusing on clinical presentation and management of IHH in CD patients.

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CASE REPORT

A 22-year-old female presented at our center with symptoms of hypertension, central weight gain, amenorrhea, and purple striae with bruising for further investigation for

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hypercortisolemia. A CD diagnosis was confirmed by elevated urinary free cortisol (UFC) of 633 µg/dL/24 hours (14 times the upper limit of normal; ULN) and ACTH of 64 pg/mL (1.5 times

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ULN). Brain magnetic resonance imaging (MRI) with contrast revealed a small pituitary microadenoma. Subsequently, inferior petrosal sinus sampling (IPSS) revealed ACTH at plus three minutes of 1,830 pg/mL on the right and 10,990 mg/dL on the left, while peripheral ACTH was 65 pg/mL. These findings confirmed a central source of ACTH overproduction, leading to a

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final diagnosis of CD. She underwent endoscopic TSS, with intraoperative gross total resection. Immunohistochemistry revealed ACTH-positive expression of tumor cells, which were TP53-negative, and Ki67-positive at 1%. Cortisol levels postoperatively achieved a nadir less

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than 2mcg/dL and she was started on hydrocortisone at 30 mg (3 times daily, orally). Her postoperative course was complicated by hyponatremia (130 mg/dL) alleviated with fluid

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restriction and sinus tachycardia of unknown etiology. She was discharged home on 20 mg twice daily of hydrocortisone to be lowered by 5-10 mg every 2 weeks as tolerated up to 20 mg once daily. Over the subsequent 3 months, the patient’s symptoms improved including return of menses, loss of facial plethora, resolution of supraclavicular fat pads, weight loss of 13.32 kg, and diminishing purple striae.

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At 3.5 months postoperatively, the patient presented to the emergency department (ED) of our institution with 2 weeks of headache, intermittent nausea and vomiting, with 1 week of diplopia, and blurriness, and acute onset of left facial numbness and weakness, and left arm

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numbness and tingling. In the 2 weeks prior, she started to have symptoms of nausea and

vomiting and blurriness, and had called our center; we recommended she be evaluated by the closest emergent care facility. We also recommended she increase her hydrocortisone dose from

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20 mg once daily to three times daily as it was not clear if her symptoms were related to GC withdrawal or mild AI due to glucocorticoid taper (hydrocortisone had been decreased from 20

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mg twice a day to once a day, the previous month). Despite increase in hydrocortisone dose, she continued to have nausea (without vomiting) and progressed to new onset of diplopia, and facial numbness and weakness. Prior to visiting our ED the patient visited a local ophthalmologist who prescribed Diamox at 250 mg three times daily, however, she continued to decline. On physical

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examination in the ED, blood pressure was 122/73 mmHg, pulse 83 beats/min, respiratory rate 20/min, and temperature 36.8 °C. She was alert and oriented and was confirmed to have bilateral abducens nerve palsies, papilledema, and left facial nerve palsy. A lumbar drain was placed,

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revealing opening pressure of 55 cm H2O with normal cerebrospinal fluid; CSF-analysis (clear fluid, white blood cells 1, red blood cells 7, glucose 48 mg/dL, protein 29mg/dL).

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She was started on high dose dexamethasone (4 mg twice daily, orally). A computed

tomography (CT) venogram was negative, demonstrating no residual adenoma or other identifiable pathology. Following admission to the hospital, patient underwent a lumbar drain, which demonstrated high opening pressure (55 cm H2O). The decision was made to place a right frontal ventriculoperitoneal shunt due to high opening pressure and progressive course, which resulted in complete resolution of her symptoms. She was discharged from the hospital with

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acetazolamide 250 mg three times daily and hydrocortisone 20 mg twice daily, orally; acetazolamide was stopped 2 weeks after discharge and hydrocortisone was slowly tapered to 20

adrenal (HPA) axis with no complications or recurrence to date.

DISCUSSION

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mg daily for 2 months and then discontinued after normalization of hypothalamic–pituitary–

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A rare complication of achieving complete biochemical remission in CD patients is development of IHH.9 This complication is not specific to CD, but has been described with other conditions in

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which supraphysiologic levels of circulating GC fall rapidly.

Idiopathic intracranial hypertension was first reported in 1893 by Heinrich Quincke, and described as a case of “meningitis serosa”, which he theorized was a result of increased ICP due to inadequate CSF absorption.10 Though the etiology remains unclear, IIH has strong predilection

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for young overweight females. Risk factors associated have been identified including medications (amiodarone, tetracycline, all-trans-retinoic acid), past medical history of systemic lupus erythematous (SLE), and steroid use or taper from steroids.4,11-13 It has been suggested that

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in those genetically predisposed, female sex hormones along with endocrinologically active adipose tissue directly result in IIH. Aldosterone has been also proposed as important in IIH

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occurrence.7,14

Current literature reports of IIH after treatment of CD have been largely documented in

children, with very few adult cases being recorded.8 Though etiology remains unknown, the prevalence of pediatric cases affect both male and females equally, contrary to reports of adult cases that occur predominantly in women. In adults, the delay time from CD remission to IIH can be pretty wide and ranges from 2 weeks to 10 month.8 Idiopathic intracranial hypertension

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can develop also after medical therapy for CD. Ketoconazole, which blocks adrenal steroidogenesis and lowers cortisol levels, has also been reported to cause IIH.15 As initial symptoms can also be confused with AI in both children or adults,9 the exact prevalence of mild

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IHH in patients treated with adrenal steroidogenesis inhibitors is not known. Retinoic acid,

which has the potential to decrease ACTH and cortisol in some patients, has also been described to induce IIH in patients with chronic lymphocytic leukemia (CLL).16,17 However, this

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association has not been established in CD patients treated with retinoic acid.

Clinical presentation appears to be highly variable. In the case we present the patient

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experienced headaches, nausea, and vomiting that had been occurring for 2 weeks. In other cases, patients have presented with similar symptoms which could easily thought to be due to AI or GC withdrawal.7 The relative low incidence of IIH might be due to under diagnosis, mild IIH symptoms can be confused with AI and treated with increasing doses of GC replacement, which

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would presumably also treat IIH. Additional symptoms with disease progression in the case we present included diplopia that had been occurring for 1 week, double vision and blurriness, and an acute (hours) onset of left sided facial numbness and facial weakness. Though most likely a

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continuum, symptoms started approximately 3.5 months after surgery. Diagnosis is further confirmed with the presence of papilledema and a high opening CSF pressure on lumbar

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puncture (LP). Vision loss is common and if the delay in diagnosis is longer than 6 months it can be permanent.18

A literature review resulted in identification of 16 cases of IHH after treatment of CD8;

12 in children7,19 and four in adults.8,20,21 CD treatment included TSS, medications and adrenalectomy.

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An early description of IIH was in 1980;19 an 18-year-old male patient developed severe IIH following metyrapone and aminoglutethimide treatment of CD. Interestingly, in this case, the patient had already some manifestations of IIH found incidentally on initial assessment

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(papilledema and abnormal opening pressure on LP). However, it was only after starting

effective pharmacological treatment that the patient developed severe IHH symptoms that

responded only to CSF shunting. In a large series22 of 941 patients with CD (723 adults), seven

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patients (all children) developed IIH following surgery. An early report by Martin et al.,21

describes a 29-year-old woman who developed IIH approximately 1 month after successful TSS

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while the patient was taking 30 mg hydrocortisone daily. Another case, a 44-year-old woman who developed IIH following bilateral adrenalectomy after two unsuccessful TSS for CD; the manifestations of IIH began 2 weeks after surgery while still being on supraphysioogic GC (60 mg hydrocortisone (HC) daily).20 Another report9 described the case of a 33-year-old female

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patient who underwent a repeat TSS for CD followed by complete biochemical remission. Eleven months later, about 1 month after tapering her hydrocortisone dose to 15 mg per day, she developed signs and symptoms of IIH.

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In most cases, the development of hallmark headache and blurring vision started approximately 2-4 weeks after tapering of the replacement hydrocortisone dose. Most patients

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developed IIH while still being on a dose ranging from 30 to 60 mg hydrocortisone daily, a dose still considered supraphysiologic. This points to a possible effect of chronic high level of steroids (either endogenous or exogenous) that could not be maintained by a lower, yet relatively supraphysiologic dose. The fact that most of these patients improved on re-introduction of higher doses of corticosteroids plus acetazolamide with an even slower taper, indicates that this presumed effect is not permanent, but may need a much slower taper to be avoided.

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The first empirical evidence of the effect of acute steroid withdrawal on CSF dynamic dates back to 1975 when Johnston et al.,22 demonstrated that acute GC withdrawal following chronic therapy leads to an increase in the resistance to CSF absorption at the level of the

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arachnoid villi in canines. It is still not understood why GC withdrawal would lead to decreased CSF absorption, however, GC have historically been used in the treatment of IIH as they have been shown to also significantly reduce CSF production.1,19,23

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Many theories have been proposed to explain the pathogenesis of IIH with an emphasis on the pituitary-adrenal axis. Two main targets of these theories are mineralocorticoid receptors

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and the enzyme 1β-hydroxysteroid dehydrogenase (11β-HSD).24,25 Mineralocorticoid receptors have been identified in the choroid plexus (CP) epithelium and they function in a way similar to their role in the kidney, through activation of Na/K ATPase, altering the composition of CSF, while high GC levels are known to activate mineralocorticoid receptors. The enzyme 1β-

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hydroxysteroid dehydrogenase (11β-HSD) is also expressed in CP epithelium and its normal function is to activate cortisol from cortisone (11β-HSD1) or vice versa (11β-HSD2). Another potential mechanism suggested is activation of aquaporin-1 that is expressed on the apical

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membrane of CP epithelium and regulates water entry into the ventricles.9 There are no clear guidelines for managing IIH26 after treatment of CD due to the scarcity

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of cases, but management strategies have been to initially try to avoid shunting through LP, which is both diagnostic and therapeutic, together with re-introduction of higher GC doses and acetazolamide. Optic nerve sheath fenestration is often a response to visual deterioration after failure of medical therapy; however, in this case we chose to implant a ventriculoperitoneal shunt due to high opening pressure associated with high failure rate of fenestration27 and rapid progression of symptoms. Placement of shunt with programmable valve would allow more

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specific adjustments as course of disease evolved. While etiology unknown there is an association with rapid decrease in steroids. Response is measured through improvement of symptoms, decreased CSF pressure on repeat LP, and an improving, or at least not deteriorating,

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visual exam. Like the general treatment guidelines in IIH, the priority is preserving vision. In the case we present, the high CSF pressure together with deteriorating vision prompted CSF

diversion through ventriculoperitoneal shunt placement. This decision stemmed from the

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likelihood of permanent visual loss. Following initial stabilization, a slower GC should be

initiated, preferably with continued acetazolamide treatment. Not all case reports in the literature

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reported the overall duration of maintenance therapy, nor the incidence of successful complete weaning. Some patients were later successfully weaned and some recurred and required CSF diversion.

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CONCLUSION

Idiopathic intracranial hypertension is a rare finding in adult patients with CD, however a high index of suspicion should be maintained and a fundus exam is necessary to exclude

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papilledema whenever there are suggestive symptoms. Idiopathic intracranial hypertension may arise following either surgical, or medical treatment of CD. Initial symptoms of headache and

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lethargy could be confused with those of hypocortisolemia. If papilledema is present, an immediate LP should be performed. Treatment priority is to preserve vision and reverse any visual loss. Treatment consists of re-initiation of higher GC doses together with acetazolamide with or without CSF diversion. Maintenance of higher GC doses is usually recommended after initial stabilization and tapering should proceed slowly. Treatment needs to be individualized,

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including medical therapy and/or surgical intervention. Further studies are needed to better quantify the risk of IIH for patients with CD and optimal treatment.

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ACKNOWLEDGEMENTS

The authors thank Maria Fleseriu, M.D., for clinical advice, and Shirley McCartney, Ph.D., for

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editorial assistance.

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Highlights

Idiopathic intracranial hypertension; a very rare complication in Cushing disease

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Occurs mostly post-surgery, but can occur post medical therapy

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In our center 1 of 140 patients reviewed had idiopathic intracranial hypertension

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Accurate diagnosis is important to restore any vision loss and prevent further loss

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Treatment with medical therapy and ventriculoperitoneal shunt is recommended

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Abbreviations

Idiopathic intracranial hypertension (IIH) Cushing’s disease (CD)

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adrenal insufficiency (AI) glucocorticoid (GC) adrenocorticotropic hormone (ACTH) transphenoidal surgery (TSS)

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pseudotumor cerebri (PTC) intracranial hypertension (ICH)

urinary free cortisol (UFC) upper limit of normal (ULN) magnetic resonance imaging (MRI) inferior petrosal sinus sampling (IPSS)

cerebrospinal fluid (CSF)

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emergency department (ED)

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increased intracranial pressure (ICP)

computed tomography (CT)

hypothalamic–pituitary–adrenal (HPA)

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systemic lupus erythematous (SLE)

chronic lymphocytic leukemia (CLL)

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lumbar puncture (LP) hydrocortisone (HC)

1β-hydroxysteroid dehydrogenase (11β-HSD) choroid plexus (CP)