Carotid artery constriction in autoimmune hypophysitis: three case reports and literature review

Data collection and inclusion criteria

A total of 2,204 patients with sellar region pathologies underwent transsphenoidal surgery at our department between January 2005 and February 2023. Our surgical series included 15 patients with histopathologically confirmed AiHy. Among these patients, three patients with internal carotid artery constriction or occlusion (ICAc/o) within the cavernous sinus (CS) were identified.

Clinical symptoms, diagnostic findings, treatment, and follow-up data were retrieved from patients’ files.

The study was approved by the ethics committee of the University of Tuebingen (number: 230/2023BO2).

Radiological assessment

Preoperative and postoperative magnetic resonance imaging (MRI) of the sellar region included coronal and sagittal T1-weighted images without and with contrast, coronal T2-weighted images, and axial T2 fluid-attenuated inversion recovery images. The internal carotid arteries (ICAs) and collaterals were assessed using time-of-flight magnetic resonance angiography (TOF MRA) or computed tomography angiography (CTA).

The abbreviation ‘ICAc’ was used if the ICA showed incomplete constriction on imaging studies, and ‘ICAo’ was used if the ICA was completely occluded. ICAc/o addressed both variants.

Endocrinological evaluation

Preoperative, postoperative, and follow-up endocrinological assessments were provided by the referring endocrinologists. In addition, oestradiol, follicle-stimulating hormone, luteinising hormone, free thyroxine, free triiodothyronine, thyroid-stimulating hormone, cortisol, prolactin, growth hormone, and insulin-like growth factor 1 levels were determined the day before surgery and 5 days after surgery during the perioperative hospital stay in our neurosurgical department in a standardised manner.

Transsphenoidal surgery

For transsphenoidal biopsy, all patients were placed under general anaesthesia in the supine position, with the head reclined at 10°. Transsphenoidal surgery was performed under the operating microscope. A direct prenasal approach with the septum-pushover technique was used.

Histopathological analysis

The histopathological analysis included evaluation of CD3+ T cells, CD20+ B cells, CD138+ plasma cells, IgG4+ plasma cells, reticulin, and the pituitary gland’s tissue structure.

Literature research

A PubMed search was performed to identify publications in English or German up to December 2024. The search terms ‘hypophysitis’ combined with ‘carotid artery’ and ‘hypophysitis’ combined with ‘CS’ were used. Full-text articles were reviewed to identify published cases of AiHy and ICAc/o. Citation searches of the reviewed articles were performed to identify additional cases.

Case 1

In 2008, a 35-year-old female patient presented with weight loss and vomiting. She had a history of schizoaffective disorder. An endocrinological evaluation revealed panhypopituitarism, and replacement therapy with hydrocortisone and L-thyroxine was commenced. She was also taking an oral contraceptive. No evidence of arginine vasopressin (AVP) deficiency was found throughout her case history. MRI showed an intrasellar lesion with a slight suprasellar extension and clear thickening of the pituitary stalk, as well as a parasellar T2 dark sign and dural enhancement suggestive of AiHy (Table 1). The clinical, endocrinological, and radiological findings remained unchanged on regular follow-up examinations until 2015.

In 2015, the patient complained of blurry vision and weight gain with food cravings (Table 2). An examination of the cerebrospinal fluid (CSF) revealed slight lymphocytic pleocytosis. The serum and CSF were negative for soluble interleukin-2 receptor and angiotensin-converting enzyme. MRI revealed a significant increase in the pituitary lesion (Fig. 1). TOF MRA and carotid Doppler sonography showed bilateral ICAo (Fig. 1, Table 2). The anterior circulation was supplied by collaterals from the vertebrobasilar circulation via a large left and small right posterior communicating artery (Fig. 1). No signs of brain infarction were detected. Under the presumptive diagnosis of AiHy, treatment with methylprednisolone was started, with prompt improvement of the visual disturbance (Table 3). However, treatment had to be discontinued after 10 days because of the exacerbation of her psychosis.

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Case 1. (A) Sagittal T1-weighted MRI post-contrast at the time of bilateral ICAo diagnosis in 2015 shows intrasellar hypophysitis with suprasellar extension. Strong dural enhancement is found (arrow). (B) Coronal T1-weighted MRI post-contrast shows bilateral CS infiltration and ICA occlusion (arrows). Non-tapering of the pituitary stalk is found (asterisk). (C) T2-weighted MRI demonstrates parasellar T2 dark sign (arrow). (D) 3D TOF MRA confirms bilateral ICA occlusion (asterisk for right side) and supply of the anterior circulation mainly via a large posterior communicating artery on the left side (arrow). Following treatment with GC and short-term azathioprine, sagittal MRI (Fig. 1E) and TOF MRA (Fig. 1F) from October 2019 demonstrated size reduction of hypophysitis but persistent bilateral occlusion of the ICA. Postoperative sagittal (G) and coronal (H) T1-weighted MRI post-contrast from June 2021 demonstrate a reduced size of the pituitary lesion.

Citation: Endocrine Connections 14, 6; 10.1530/EC-25-0120

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In October 2019, the patient experienced another episode, with a severe decline in vision in her left eye and a headache that resolved with 500 mg methylprednisolone over 3 days, which precipitated another psychotic episode. She also received short-term treatment with azathioprine, which had to be terminated because of deteriorated haematopoiesis (Table 3). Following medical treatment, MRI demonstrated reduction of lesion size, and TOF MRA showed persistence of bilateral ICA occlusion (Fig. 1).

In October 2020, the patient presented to our neurosurgical department due to newly developed double vision. Left-sided incomplete abducens nerve palsy was found. MRI showed a slight increase in the pituitary lesion. Because of the severe and recurrent course of her condition, we decided to perform a biopsy for a definite diagnosis (Table 3). During transsphenoidal surgery, greyish and firm intrasellar tissue and atrophic anterior pituitary tissue were found. Histopathological evaluation of the biopsy showed infiltration of the anterior pituitary gland with CD3+ T-lymphocytes and, to a lesser extent, with CD20+ B-lymphocytes, confirming the diagnosis of LyHy. There were only single CD138+ plasma cells and no IgG4+ plasma cells (Fig. 2, Table 3).

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In all three cases, the pituitary gland showed a lymphocytic infiltration with CD3+ T-lymphocytes and variable numbers of CD138+ plasma cells. IgG4+ plasma cells were absent or only rarely found, thus not indicating IgG4-related hypophysitis.

Citation: Endocrine Connections 14, 6; 10.1530/EC-25-0120

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In the postoperative course, the abducens nerve palsy spontaneously regressed (Table 4). Postoperative MRI showed a clear decrease of the space-occupying lesion (Fig. 1). In November 2024, she suffered a recurrence with visual decline, which regressed after 4 days of high-dose prednisolone treatment. Currently, she declines non-steroidal immunosuppressive treatment for fear of side effects.

Case 2

In May 2020, a 48-year-old female patient presented to our neurosurgical department with a 2-week history of severe headache and neck pain followed by double vision and slight nausea a few days later (Table 2). She also reported increasing adynamia. Her menstrual cycle was normal. An endocrinological evaluation showed mild secondary hypothyroidism. Prolactin was mildly elevated. There was no evidence of adrenal insufficiency, growth hormone deficiency, or hypogonadism. Surprisingly, serum cortisol became subnormal 3 days later, and replacement therapy with hydrocortisone was commenced (Table 2). An ophthalmological examination revealed a right-sided incomplete oculomotor nerve palsy and abducens nerve palsy (Table 2). The visual fields were normal. MRI showed a symmetrical intrasellar and suprasellar lesion with homogeneous contrast uptake and a slight elevation of the optic chiasm (Fig. 3). A parasellar T2 dark sign and broadening of the CS were found. MRI and TOF MRA revealed bilateral intracavernous narrowing of the internal carotid artery that was more pronounced on the left side (Fig. 3). Lumbar puncture revealed a count of 12 lymphocytes/μL and was otherwise normal. The suspected diagnosis of LyHy was confirmed by transsphenoidal surgery, which was performed in June 2020 (Fig. 2, Table 3). Immunoglobulin G4 (IgG4)-positive plasma cells were rarely found, excluding a diagnosis of IgG4-related hypophysitis. Postoperatively, the ocular nerve palsies rapidly regressed (Table 4). Therefore, immunosuppressive treatment was withheld. On postoperative TOF MRA, complete regression of ICA narrowing was found (Fig. 3). FDG-PET/MRI showed no evidence of systemic IgG4-related disease. Two months after surgery, a short Synacthen test showed a normalised adrenal axis, and hydrocortisone was discontinued. In August 2024, the patient suffered recurrence of double vision that regressed after treatment with 1,000 mg prednisolone over 5 days. At present, she is feeling well and has a normal ophthalmological status (Table 4).

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Case 2. (A) Sagittal T1-weighted MRI post-contrast at initial presentation shows intrasellar hypophysitis with suprasellar extension. Strong dural enhancement (arrow) and swelling of the sphenoid sinus mucosa are found. (B) Coronal T1-weighted MRI post-contrast shows bilateral CS infiltration with bulging of the CS towards the temporal lobe (black arrow) and narrowing of the left ICA (white arrow). (C) 3D TOF MRA confirms bilateral constriction of the ICA within the CS (arrows). (D) Follow-up 3D TOF MRA shows regression of ICA constriction with normal ICA diameters.

Citation: Endocrine Connections 14, 6; 10.1530/EC-25-0120

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Case 3

A 31-year-old female patient presented to an external endocrinological department in January 2023 with tiredness, muscle pain, secondary amenorrhoea, and headache (Table 2). She reported long-standing arterial hypertension and had lost 7 kg of body weight in the past 18 months. An endocrinological evaluation revealed panhypopituitarism, with a serum cortisol level as low as 0.8 μg/dL (Table 2). Fluid intake and output were within normal limits. The patient was started on 30 mg hydrocortisone and 50 μg L-thyroxine per day. Her neurological status was normal. MRI showed an intrasellar and slightly suprasellar lesion with a central cystic or necrotic appearance, enlargement of the pituitary stalk, and a parasellar T2 dark sign (Fig. 4). A presumptive diagnosis of LyHy was made. MRI demonstrated complete occlusion of the left ICA within the CS, which was confirmed by CTA (Fig. 4). No evidence of cerebral ischaemia was found on MRI. Because of the serious finding of ICAo, we recommended a transsphenoidal biopsy to clearly confirm the diagnosis. Thus, the patient was referred to our neurosurgical department and a biopsy was performed via a transsphenoidal approach in January 2023 (Table 3). The histopathological examination confirmed the diagnosis of LyHy with both B-lymphocytes and T-lymphocytes, with the latter prevailing. Focally, several CD138+ plasma cells were noted, among them only singular IgG4+ plasma cells (Fig. 2, Table 3).

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Case 3. (A) Sagittal T1-weighted MRI post-contrast at initial presentation shows an intrasellar space-occupying lesion. Strong dural enhancement is found (arrow). (B) Coronal T1-weighted MRI post-contrast shows occlusion of the left ICA (white arrow). (C) CT angiography confirms complete occlusion of the left ICA in the cavernous segment (asterisk) and a perfused right ICA with normal calibre (arrow). (D) T2-weighted MRI demonstrates parasellar T2 dark sign (arrow). (E) Sagittal T1-weighted MRI post-contrast shows reduced size of the lesion following surgery and GC therapy. (F) Coronal T1-weighted MRI post-contrast shows persistent occlusion of the left internal carotid artery following surgery and GC therapy (white arrow) and a regular flow signal in the normal-sized right internal carotid artery (black asterisk).

Citation: Endocrine Connections 14, 6; 10.1530/EC-25-0120

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Having confirmed the diagnosis, prednisolone pulse therapy was commenced in February 2023 with a starting dose of 50 mg daily (Table 3). In November 2023, Doppler sonography and CTA showed persistent ICAo and normal perfusion of the right ICA, as well as normal cerebral perfusion. Under prednisolone treatment, the patient’s general well-being was much improved. As rapid tapering of prednisolone was not tolerated, the dose was slowly reduced and reached a replacement dose in October 2024. Postoperative endocrinological follow-up examinations showed unchanged panhypopituitarism. MRI from December 2024 showed regression of the pituitary lesion, but the persistence of left-sided ICAo (Table 4; Fig. 4).

Clinical presentation

In the literature, 16 cases of AiHy with ICAc or ICAo were reported between 1990 and 2024 (1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17). The present study adds three cases (Tables 2, 3, 4). The average age at initial presentation with AiHy was 46 years, and the average age at the time of ICAc/o diagnosis was 48 years. Interestingly, an association with pregnancy was not found in any of the cases.

Of 19 patients, eight patients presented with cranial nerve (CN) palsy as a clinical sign of CS involvement (Table 2). The CNs III and VI were affected, with a predominance of CN IV (abducens nerve). Four patients (cases 1, 2, 9, 17) presented with chiasmal syndrome.

All patients suffered from some degree of hypopituitarism, with seven suffering from panhypopituitarism. Interestingly, only five patients suffered clear AVP deficiency (Table 2).

Bilateral ICAo was observed in seven cases (36.8%); see Table 2. Four of them suffered ischaemic stroke with neurological deficits (Table 2). Of note, three patients with bilateral ICAo remained free of cerebral infarction and were neurologically intact. None of the patients with incomplete ICAc or unilateral pathology suffered infarction or neurological deficits.

Eleven of 19 patients (57.9%) had a recurrent course of hypophysitis (Table 3). In eight patients, ICAc/o was detected during a recurrent episode of hypophysitis.

Treatment

The subtype of hypophysitis was confirmed in 17 cases by transsphenoidal biopsy. Biopsy was undertaken in 12 patients at the time when ICAc/o was detected, in three patients at an earlier stage (cases 4, 14, 16), and in one patient at a later stage (case 17). The time of surgery was not available for one patient. Among the 17 cases with biopsy, 13 cases suffered from LyHy, two had GrHy, and two had IgG4-related hypophysitis (Table 3). In our own cases, the histopathological findings were not different from typical findings in AiLy without ICAc/o. In particular, no evidence of severe destructive inflammation indicating aggressiveness was found (Fig. 2).

Thirteen of 15 patients with sufficient treatment information were treated with glucocorticoids (GC), some with several GC pulses (Table 3). From 2016 onward, seven patients were treated with non-steroidal immunosuppressive medication (Table 3). In one patient with a difficult clinical course, stereotactic radiosurgery with Gamma Knife was successfully performed.

In six cases, clear evidence exists that ICAc/o influenced the management (bypass surgery in one case and more aggressive treatment with GC and/or non-steroidal immunosuppression in five cases). In five additional cases, ICAc/o has likely influenced the management with more extensive immunosuppressive treatment. In two of these cases, incomplete ICAc was reversible under intensified treatment.

In one patient, reduced cerebral perfusion was treated with a bilateral cerebral bypass surgery (Table 3). Anticoagulant or antiplatelet treatment was reported in four patients.

Outcome

The mean follow-up period after diagnosis of ICAc/o was 32.2 months (range 0–115 months; median 12 months).

ICAo was irreversible in all affected patients. In contrast, incomplete ICAc regressed in three patients (Table 4). One out of four patients with cerebral stroke had an adverse neurological outcome. The outcome of CN palsies was favourable (Table 4). A decrease in the pituitary lesion during follow-up was reported in seven patients, unchanged size in five patients, and no information on final lesion size in seven patients. The overall outcome was reported to be favourable in 12 patients and not reported in six patients, while one patient remained disabled following an ischaemic stroke.

Posterior pituitary function remained unchanged during follow-up in all cases (Table 4). Anterior pituitary function was restored in only one patient (case 11).