Nelson Syndrome: Clival Invasion of Corticotroph Pituitary Adenoma Resulting in Alternating Sixth Nerve Palsies

A 44-year-old woman presented with 2 painful and self-limited episodes of binocular horizontal diplopia within 1 year that at the beginning were thought to be secondary to microvascular insult. Her medical history was significant for Cushing syndrome status post transsphenoidal resection with bilateral adrenalectomy 4 years prior, hypertension, and diabetes mellitus. Neuro-ophthalmic evaluation was significant for left abduction deficit and incomitant esotropia consistent with left abducens nerve palsy. Of note, the patient had experienced a similar episode but on the contralateral side a few months prior. Although initially MRI of the brain demonstrated stable residual postoperative finding in the sella, upon review, an heterogenous T-1 hypointense marrow in the clivus was noted. Hypermetabolism of the clivus was also noted on computed tomography positron emission tomography of the skull base. A clival biopsy demonstrated a corticotroph adenoma with elevated proliferation index and scattered mitoses. A corticotroph pituitary adenoma after adrenalectomy, also known as Nelson syndrome, was diagnosed. Radiation therapy was offered to the patient, and resolution of symptoms was gradually observed.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD, PhD Nelson Syndrome: Clival Invasion of Corticotroph Pituitary Adenoma Resulting in Alternating Sixth Nerve Palsies Vivian P. Douglas, MD, DVM, MBA, Konstantinos A. A. Douglas, MD, DVM, MBA, Otto Rapalino, MD, Samantha N. Champion, MD, Bart K. Chwalisz, MD Downloaded from http://journals.lww.com/jneuro-ophthalmology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 05/04/2022 Abstract: A 44-year-old woman presented with 2 painful and self-limited episodes of binocular horizontal diplopia within 1 year that at the beginning were thought to be secondary to microvascular insult. Her medical history was significant for Cushing syndrome status post transsphenoidal resection with bilateral adrenalectomy 4 years prior, hypertension, and diabetes mellitus. Neuroophthalmic evaluation was significant for left abduction deficit and incomitant esotropia consistent with left abducens nerve palsy. Of note, the patient had experienced a similar episode but on the contralateral side a few months prior. Although initially MRI of the brain demonstrated stable residual postoperative finding in the sella, upon review, an heterogenous T-1 hypointense marrow in the clivus was noted. Hypermetabolism of the clivus was also noted on computed tomography positron emission tomography of the skull base. A clival biopsy demonstrated a corticotroph adenoma with elevated proliferation index and scattered mitoses. A corticotroph pituitary adenoma after adrenalectomy, also known as Nelson syndrome, was diagnosed. Radiation therapy was offered to the patient, and resolution of symptoms was gradually observed. Journal of Neuro-Ophthalmology 2021;41:114–118 doi: 10.1097/WNO.0000000000001141 © 2020 by North American Neuro-Ophthalmology Society Division of Neuro-Ophthalmology (VPD, KAAD, BKC), Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts; and Departments of Radiology (OR), Pathology (SNC), and Neurology (BKC), Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts. The authors report no conflicts of interest. Address correspondence to Bart K. Chwalisz, MD, Department of Neurology, Massachusetts General Hospital, 15 Parkman Street, Boston, MA 02114; E-mail: [e-mail] 114 Drs. Douglas VP, Douglas KAA, Chwalisz: A 44-year-old woman presented with 2 episodes of binocular horizontal diplopia within 1 year. She had a history of Cushing disease status post transsphenoidal resection, difficult-to-control hypertension, and secondary diabetes mellitus. Due to failure to normalize cortisol and adrenocorticotropic hormone (ACTH) levels after pituitary surgery, bilateral adrenalectomy was performed 4 years before presentation, which led to resolution of diabetes and improvement in hypertension. Initially, the patient presented to the emergency department (ED) with a complaint of severe right-sided throbbing headache and light sensitivity, and her blood pressure was found to be elevated. A noncontrast head computed tomography (CT) showed no evidence of acute intracranial hemorrhage or large intracranial mass. A lumbar puncture was performed without an opening pressure measurement, showing a normal cerebrospinal fluid analysis. She was prescribed diphenhydramine, hydromorphone, and metoclopramide and reported some improvement. She was discharged but presented to the ED again the day after with headache of similar intensity but now accompanied by binocular horizontal diplopia. Diagnoses of right sixth nerve palsy and migraine were made. Two days later, the patient was evaluated by a neurologist and was admitted to the hospital for further work up. Brain MRI with and without gadolinium showed stable postoperative findings, whereas MRA and magnetic resonance venogram studies were normal. She was treated symptomatically with magnesium oxide and sumatriptan. Gradual improvement of diplopia was noted over the next several months. Nine months after the initial ED presentation, she again presented emergently as she developed left-sided headache and neck pain. She was given a migraine cocktail, which included diphenhydramine, ketorolac, and metoclopramide, leading to temporary improvement in her headache. Nevertheless, 2 days Douglas et al: J Neuro-Ophthalmol 2021; 41: 114-118 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study later, the headache recurred, and binocular horizontal diplopia again developed, this time worse on left gaze. She returned to the ED again and was diagnosed with migraine and new left sixth nerve palsy. She was referred for neuro-ophthalmic examination, which showed good afferent visual function with normal visual acuity, color vision, visual fields, pupillary function, and fundi. An isolated left abduction deficit with incomitant left esotropia was noted. No additional ocular signs of myasthenia gravis or thyroid eye disease were observed. Neurologic examination was normal. In addition, facial hirsutism was noted, and the patient had experienced skin tanning, which she attributed to sun exposure as she was working outdoors for many hours each day. Dr. Rapalino: A brain MRI obtained approximately 3 months after the second ED visit (Fig. 1) showed postoperative findings in the sella, a slight increase of abnormal hypoenhancing soft tissue within the left aspect of the sella, mild rightward deviation of the infundibular stalk, confluent heterogeneously T1-hypointense and enhancing marrow abnormalities in the body of the clivus with diffusion restriction, and a smooth abnormal soft tissue contour centrally along the dorsal aspect of the clivus. This abnormal soft tissue along the dorsal aspect of the clivus had progressively increased compared with prior MRI studies (Fig. 2). A CT-positron emission tomography (PET) of the skull base showed abnormal enhancing and hypermetabolic soft tissue within the sella (with abnormal nodular thickening of the stalk) and adjacent sphenoid bone extending into the dorsum sellae and epidural surface of the clivus, as well as the progression of bony sclerosis within the clivus, compared with prior head CT scan (Fig. 3). CT-PET of the body showed no evidence of malignancy. A follow-up MRI obtained 3 months later demonstrated progression of the changes in the sella and clivus. Lumbar puncture yielded normal cerebrospinal fluid. A transsphenoidal biopsy of the clivus was performed. FIG. 1. Brain MRI with and without contrast obtained after the second ED presentation. T1-weighted sagittal without contrast (A), axial 3D T2-weighted Fast Imaging Employing Steady-state Acquisition, axial diffusion (b value = 1,000), and postcontrast T1-weighted axial fat suppressed spin echo (D) sequences. Panels A and D show an abnormal epidural soft tissue along the dorsal aspect of the clivus extending from the dorsum sellae down to the basiocciput (yellow arrows). Axial FIESTA image (B) shows the cisternal segments of the abducens nerves bilaterally (black arrowheads). An abnormal hyperintense signal is seen on the axial diffusion image (C) confluent with the epidural soft tissue abnormality shown in the panels A and D. ED, emergency department. corticotroph adenoma with elevated proliferation index and scattered mitoses. Final Diagnosis Nelson syndrome (adenoma growth after adrenalectomy) causing sequential bilateral sixth nerve palsies. Dr. Champion: The specimen showed pituitary adenoma composed of monomorphous cells with nuclear-to-cytoplasmic ratios, prominent nucleoli, and a minimal to moderate amount of eosinophilic cytoplasm (Fig. 4A). Mitotic figures were scattered (Fig. 4B). The tumor had significant intervening fibrosis (Fig. 4C) and involved bone, soft tissue, and sinonasal mucosa (Fig. 4D–4F, respectively). Immunohistochemistry stains showed that the tumor cells were positive for ACTH (Fig. 4G) and negative for prolactin, human growth hormone, beta-thyroid stimulating hormone, beta-luteinizing hormone, beta-follicle-stimulating hormone, and alpha subunit. The tumor the Ki-67 proliferation index was high, at 4.8% (Fig. 4H). These findings are diagnostic of a Douglas et al: J Neuro-Ophthalmol 2021; 41: 114-118 FIG. 2. Comparison of precontrast T1-weighted sagittal images: Baseline study (A), first ED presentation (B), 1 year after first ED presentation, and shortly after second ED visit (C), MRI before the second surgery (15 months after initial ED presentation) (D). These sagittal T1-weighted images demonstrate the progressive development of abnormal soft tissue along the dorsal aspect of the clivus (white arrows) with involvement of the expected locations of the Dorello canals. ED, emergency department. 115 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 3. Skull base PET CT obtained 1 month before the second transsphenoidal surgery. Axial and sagittal reformatted images of the contrast-enhanced CT (A and C) and PET (B and D) data sets. The PET images show abnormally increased fluorodeoxyglucose uptake in the sphenoid bone, sellar region, and along the dorsal aspect of the clivus (black arrows). The CT images demonstrate abnormal enhancing soft tissue in the sellar region (with nodular thickening of the infundibular stalk) contiguous with abnormal soft tissue along the dorsal aspect of the clivus. CT, computed tomography; PET, positron emission tomography. Drs. Douglas VP, Douglas KAA, Chwalisz: Nelson’s syndrome it is a rare condition that was first described in 1958 by Don Nelson (1). In that case report, a young woman with Cushing’s disease who had undergone total bilateral adrenalectomy (TBA) 3 years prior presented with visual field defects, skin hyperpigmentation and increased plasma ACTH levels. On imaging (X-ray), a sellar mass was found, which was identified as a pituitary corticotrophinoma. Symptoms gradually resolved after surgical removal of the mass. Nelson syndrome is a potentially life-threatening complication of TBA with mortality rate as high as 12% if not timely diagnosed and treated (2). Overall, this is a rare clinical entity that is more commonly encountered in younger people after TBA. More specifically, in patients after bilateral adrenalectomies, its incidence has been estimated to be 8%–38% in adult population, whereas in pediatric population, it can range from 25% to 66% and represents approximately up to 12% of all pituitary adenomas (3–5). It occurs predominantly in women with a female-to-male ratio of 8:1, and a peak incidence in the third to fourth decades of life (6). Clinically, Nelson syndrome tends to present with advanced clinical findings as a result of the compressive effects of the ACTH-secreting pituitary adenoma, most commonly visual field defects (such as bitemporal hemianopsia), and hyperpigmentation of skin and mucous membranes due to elevations of proopiomelanocortin-related peptides, such as the melanocyte-stimulating hormone, as also observed in this patient (7). Headaches are another common clinical finding (8). Furthermore, diabetes insipidus, panhypopituitarism, and pituitary apoplexy have been also described. With regard to efferent neuro-ophthalmic manifestations, oculomotor nerve palsy has been also reported in the literature, and there is a case report of abducens nerve palsy secondary to pituitary apoplexy and subarachnoid hemorrhage (9,10). To our knowledge, this is the first case of Nelson syndrome presenting with abducens nerve palsy due to tumor growth within the clivus resulting from corticotroph pituitary adenoma invasion into the adjacent skull base. Marked elevation of ACTH plasma levels after adrenalectomy is considered a reliable laboratory finding. The cutoff for plasma values is yet to be defined, but because normal ACTH values range from 0 to 80 pg/mL, it has been suggested that values above 200 pg/mL can be generally considered diagnostic for Nelson syndrome (6). In our case, plasma ACTH levels had never completely normalized in intervening years but had increased dramatically from 664 to 4,800 pg/mL over the 12 months before presentation. Dr. Rapalino: Advances in neuroimaging, particularly the development of high-resolution MR imaging (11), have improved the diagnosis of recurrent pituitary adenomas. MRI of the brain with and without contrast has become the most frequently used imaging modality for evaluating pituitary adenomas, FIG. 4. A. Bone with scattered nests of atypical cells in fibrotic stroma (·20). (B) Atypical cells have round-to-oval nuclei and eosinophilic cytoplasm (·20). (C) Strongly ACTH-positive staining (·40). (D) Ki-67 stain showing high proliferation index (·40). 116 Douglas et al: J Neuro-Ophthalmol 2021; 41: 114-118 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study and it is considered a relatively sensitive imaging modality. However, its sensitivity is lower for the detection of ACTHproducing adenomas (12) than for other types of pituitary adenomas. The presence of postoperative changes also may affect the interpretation because recurrent tumor is often difficult to differentiate from postoperative change. Clival invasion is often seen at the initial presentation of patients with large macroadenomas (approximately 8% at the time of the initial surgery) (13). However, the prevalence of clival invasion in patients with recurrent adenomas has not been extensively characterized. Skull base involvement by any recurrent pituitary adenoma is often a challenging diagnosis, sometimes requiring the combination of different imaging modalities to confirm the diagnosis (14). The clival marrow replacement seen over several scans was initially a subtle finding highlighted by the presence of restricted diffusion within the clivus (15). The abnormal epidural soft tissue was easier to identify compared with prior MRI studies (Fig. 2). Subtle imaging findings such as these are essential to explore in patients after resections of pituitary adenomas presenting with unexplained cranial nerve palsies or focal findings localized to the central skull base. PET imaging has an increasingly recognized role in identifying recurrent pituitary tumors, improving the imaging-based diagnostic accuracy, and complementing the information provided by structural imaging with CT and MRI. The tracers more commonly used in the assessment of recurrent pituitary tumors include 18Ffluorodeoxyglucose (16–18) and 11C-methionine (19,20). Dr. Champion: Corticotroph adenomas are most commonly diagnosed as microadenomas (less than 1.0 cm in size) because the majority are clinically functioning and patients present with Cushing syndrome. However, approximately 20% are clinically silent and thus discovered as macroadenomas (21). A corticotroph adenoma can also present after adrenalectomy (Nelson syndrome), frequently growing undetected and at a rapid rate due to the lack of glucocorticoid negative feedback (22). Histologically, adenomas in Nelson syndrome have similar morphologic features to typical Cushing syndrome– associated adenomas. Mitotic activity is variable, and the Ki67 proliferation index may be increased (23). Somatic mutations in the glucocorticoid receptor have been documented in Nelson syndrome adenomas (22). Notably, although pituitary carcinoma is a rare event, approximately half of carcinomas associated with ACTH-producing Cushing disease occur in the setting of Nelson syndrome (24). Drs. Douglas VP, Douglas KAA, Chwalisz: A multidisciplinary team approach is required for the management of patients diagnosed with Nelson syndrome. Douglas et al: J Neuro-Ophthalmol 2021; 41: 114-118 Pituitary surgery is thought to be an effective treatment option and usually is the preferred one. Currently, the most common surgical approach is transsphenoidal, but in cases of extrasellar extension of the tumor, a transcranial approach can be also performed (25). The mortality rate associated with surgery is as high as 5%, with much higher morbidity rates (26). Adjuvant radiotherapy may be required in cases of incomplete removal of the tumor or progression (27). Other promising treatment options that are supported only by small case series, or single case reports are gamma knife surgery, selective somatostatin analogues, dopamine agonists, peroxisome proliferator-activated receptor g agonists, and temozolomide (28–32). Review of the operative note from the original transsphenoidal resection showed that the surgeon had not found a pituitary adenoma but had remarked on an unusual appearance of the floor of the sella turcica, which in retrospect may have already been infiltrated by corticotroph adenoma. Our patient underwent radiation therapy to the sella/ clivus area of 5040cGY dose of radiation in 28 fractions (180cGY/fraction). Treatment was well tolerated, and only mild fatigue and weakness were noted without other complications. Overall, clinically she is doing well, diplopia has resolved, and she suffers from only occasional headaches. REFERENCES 1. Nelson DH, Meakin JW, Dealy JB, Matson DD, Emerson K, Thorn GW. ACTH-producing tumor of the pituitary gland. N Engl J Med. 1958;259:161–164. 2. Sprague RG. Cushing’s syndrome with special reference to bilateral adrenalectomy. Proc R Soc Med. 1953;46:1069– 1077. 3. Hopwood NJ, Kenny FM. Incidence of Nelson’s syndrome after adrenalectomy for Cushing’s disease in children: results of a nationwide survey. Am J Dis Child. 1977;131:1353–1356. 4. Thomas CG Jr, Smith AT, Benson M, Griffith J. Nelson’s syndrome after Cushing’s disease in childhood: a continuing problem. Surgery. 1984;96:1067–1077. 5. Mindermann T, Wilson CB. 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Treatment of Nelson’s syndrome with temozolomide. Eur J Endocrinol. 2009;160:115–119. Douglas et al: J Neuro-Ophthalmol 2021; 41: 114-118 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.