Acromegaly complicated with fulminant pituitary apoplexy: clinical characteristic analysis and review of literature

Characterization of the study population

A total of 1850 acromegaly patients were admitted to our hospital from February 2013 to September 2021, of which 10 patients were diagnosed with fulminant pituitary apoplexy, with an incidence of 0.54%. The ratio of male to female was 1:1 and the mean age at apoplexy was 37.1 ± 13.4 years old. The average course from acromegaly to apoplexy was 6.8 ± 5.8 years. Eight patients visited a hospital within 2 weeks from the onset of apoplexy, one in 2 months after severe headache, and 1 in 9 months after acute vision loss in one eye. Six patients had multiple comorbidities, including five cases of diabetes mellitus, three cases of hypertension, one case of hyperlipidemia, and one case of coronary heart disease.

Clinical manifestations of pituitary apoplexy

Among the ten patients, nine cases had sudden severe headache, including eight cases with vomiting, four cases with vision loss, and two cases with diplopia. One patient only presented as acute loss of vision. In addition, two patients developed drowsiness during the apoplexy, and one had fever with a maximum temperature of 38.5 °C and neck resistance. After treatment, the above symptoms were all relieved except one patient who was admitted to hospital 9 months after apoplexy failed to recover her vision.

Changes in hormone levels before and after pituitary apoplexyChanges in GH/IGF-1 levels

The median random GH after pituitary apoplexy in ten patients was 25.5 (12.63, 46.33) ng/ml. The average GH nadir and IGF-1×ULN were 14.84 ± 9.87 ng/ml and 1.84 ± 1.13. GH/IGF-1 levels were recorded in four patients before and after apoplexy (Table 1), with average decreases of 85.3% and 43.1% in random GH and absolute IGF-1 values after the onset. One patient reached biochemical remission at 2 months after apoplexy. The variation trends of GH/IGF-1 were recorded in three patients within 3 weeks after apoplexy. Random GH, OGTT-GH nadir, and IGF-1 levels decreased gradually with time, but none of them fell back to normal value.

Table 1 Changes in GH/IGF-1 levels before and after pituitary apoplexy in four patientsChanges in other pituitary functions

There were seven patients with secondary hypothyroidism, five with hypogonadotropic hypogonadism, five with secondary hypoadrenocorticism, and one with central diabetes insipidus. Among four patients with documented pre-apoplexy hormone levels, menstruation history, and medication, two developed new hypopituitarism after stroke. One case only developed secondary hypothyroidism, the other presented secondary hypothyroidism, secondary hypoadrenocorticism, and central diabetes insipidus simultaneously.

Pituitary magnetic resonance imaging (MRI) features

All ten patients had macroadenomas, with a median maximum diameter of 30.8 (24.6–41.0) mm from 15.8 mm to 60.0 mm, of which three were giant adenomas [6]. MRI of the pituitary gland was available in nine patients, including two, one, two, and four cases with Knosp grading of 1–4, respectively, and six of them presented invasiveness of cavernous sinus (Knsop ≥ 3). Two cases showed a slightly low signal on T1, and the others showed isointensity to hyperintensity on T1 and T2. After gadolinium injection, all cases showed uneven or rim enhancement and signs of hemorrhage or necrosis. (Fig. 1) Compression and elevation of optic chiasma were presented in four patients with visual impairment, and short T1 signal of posterior pituitary disappeared in one patient with central diabetes insipidus.

Fig. 1figure 1

Typical pituitary MRI characteristics of acromegaly complicated with fulminant pituitary apoplexy (a) (d) (g) 7 days before apoplexy: macroadenoma about 26 × 19 × 20 mm showed isointensity on both T1 and T2 and mild enhancement; (b) (e) (h) 9 days after apoplexy: macroadenoma about 31 × 21 × 21 mm showed hyperintensity on both T1 and T2 and uneven enhancement, indicating subacute hemorrhage; (c) (f) (i) 3 months after surgery: postoperative changes in the pituitary gland, with isointensity to hyperintensity on T1, hypointensity to isointensity on T2, and mild enhancement

Coagulation measurements

Blood coagulation was measured in nine patients after apoplexy. The reference ranges of prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen (FBG) in PUMCH are 10.4–12.6 s, 28.9–32.5 s, and 1.8–3.5 g/L, respectively. Except for one patient who was using warfarin, the average PT and APTT were 12.61 ± 0.91 s and 33.48 ± 6.55 s respectively, and median FBG was 2.72 (2.35, 4.85) g/L. Further analysis showed a significant positive correlation between PT and IGF-1 × ULN (Fig. 2, Pearson correlation coefficient = 0.766, p = 0.027).

Fig. 2figure 2

The correlation between PT and IGF-1×ULN in acromegaly patients complicated with pituitary apoplexy

TreatmentTreatment methods

Among the ten patients, one patient went to our hospital for radiotherapy after going through surgery, radiotherapy, and medication since his onset of pituitary apoplexy 17 years ago; another patient achieved biochemical remission simultaneously 2 months after pituitary apoplexy and therefore did not receive further treatment. The other eight apoplexy cases were treated for the first time, of which seven cases received operation, and one case underwent intramuscular injection of 20 mg octreotide acetate microspheres due to high operation risk caused by dilated cardiomyopathy. Dark old blood or bean dregs-like necrosis could be seen during those seven operations. Postoperative histopathological analysis were obtained in five cases, three of which had Ki-67 ≥ 3%. Patients with hypopituitarism received physiological hormone replacement.

GH/IGF-1 changes after treatment

These eight patients had a significant decrease in random GH, OGTT-GH nadir and IGF-1 × ULN after treatment [Table 2, 24.05 ± 26.35 ng/ml vs. 1.65 (0.70, 5.03) ng/ml, p = 0.017; 13.93 ± 9.50 ng/ml vs. 2.00 (0.30, 5.33) ng/ml, p = 0.043; 1.65 ± 0.63 vs. 0.95 ± 0.40, p = 0.029]. Two patients treated with surgery and one patient treated with long-acting somatostatin analog achieved biochemical remission after treatment immediately; the other five patients who did not achieve biochemical remission experienced 54% [34.12 ± 29.12 ng/ml vs. 3.60 (1.50, 16.65) ng/ml] and 15% (1.53 ± 0.62 vs. 1.20 ± 0.24) decrease in average in random GH and IGF-1 × ULN, respectively after surgery.

Table 2 GH/IGF-1 changes in eight patients who were first treated in our hospitalFollow-up and prognosis

The overall remission rate at the last follow-up was 50% in ten patients. Tumor recurrence was confirmed by MRI in one case 5 years after operation, and the GH/IGF-1 hormone levels of other four cases showed a descending trend but did not reach biochemical remission up to the last follow-up. The remission rate was significantly higher in patients with Knosp grade <3 at the time of apoplexy than those with Knosp grade ≥ 3 (100% vs. 16.7%, p = 0.048). Also, patients who achieved remission during the follow-up had significantly smaller maximum diameter of the adenoma [20.1 (20.1, 28.0) mm vs. 44.0 (44.0, 60.0) mm, p = 0.016]. In addition, only one of the five patients with visual impairment at the onset achieved remission. Hypopituitarism that developed after apoplexy did not recover after the operation and during follow-up.

Comparison with previous literature

In 1986, our department summarized the clinical characteristics of eight cases of acromegaly complicated with fulminant pituitary apoplexy admitted in 1979–1984 in PUMCH [7]. We also performed a review of literature, searching on PubMed and CNKI using the keywords “pituitary apoplexy”, “pituitary infarction”, “acromegaly”, and “growth hormone adenoma”. We retrieved 109 articles related, including 75 cases of acromegaly complicated with fulminant pituitary apoplexy. In Table 3, we summarized all the cases above and compared with case series in PUMCH. The gender and age compositions were similar between three groups. In addition to typical headache and visual impairment, some patients also manifested other neurological symptoms such as fever, meningeal irritation, and consciousness disorders. Most of the patients presented a decreasing trend of GH/IGF-1 hormone after apoplexy. Imaging features showed that almost all the pituitary GH adenomas complicated with apoplexy were macroadenomas. MRI was the best way to diagnose pituitary lesions, while CT had satisfying performance in determining hemorrhage in emergency. Compared with the previous 8 patients in PUMCH, the incidence of pituitary apoplexy in acromegaly patients in this series was lower than before (0.54% vs. 2.4%, p = 0.003), and the time from onset to medical consultation was significantly shorter [0.50 (0.50, 0.88) months vs.1.50 (1.00, 11.25) months, p = 0.007].

Table 3 Clinical characteristics of 10 patients in this study compared with previous literature

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