Departments of Neuroradiology and Endocrinology University Hospitals of Grenoble (V.L., M.M., A.V., P.B., I.B., O.C.) and Bordeaux, (B.G., A.T., J.B.) France
Simultaneous and bilateral inferior petrosal sinuses sampling (BIPSS) for ACTH measurement before and after corticotropin-releasing hormone (CRH) injection is the gold standard for the etiological diagnosis of ACTH-dependent Cushings syndrome (1, 2). We read with great interest the recent paper of G. Kaltsas et al. (3), which confirms the very high sensitivity and specificity of this procedure. However, whether or not the invasiveness of BIPSS is detrimental remains controversial. Major neurological complications (4, 5, 6, 7) and pulmonary embolism (2, 8) have been reported, but only few reports about the true incidence of these complications among large series are available (4). Kaltsas et al. (3) report no major complications in 128 patients, even though Newell-Price et al. (2) have recently reported the occurrence, in the same institution, of one nonfatal pulmonary embolism in more than 120 patients.
To assess the safety of BIPSS, we retrospectively studied the frequency of complications recorded in all procedures performed between 1985 and 1998 in two institutions (University Hospitals of Grenoble and Bordeaux, France) that share similar indications and protocols. One hundred sixty-six BIPSS were performed in 158 patients (131 women and 27 men; mean age, 44.5 yr, (range, 677 yr)). BIPSS was performed essentially as described previously (9, 10). In 139 procedures, inferior petrosal sinus (IPS) were directly catheterized with 4-French catheters. In the 27 procedures performed in Grenoble after 1995, 6-French catheters were placed bilaterally in the jugular bulb, and Tracker-25 infusion catheters (Target Therapeutic, Boston, MA) were advanced into the IPS. An intravenous bolus of 3000 IU heparin was administered only when the procedure was technically difficult and/or when clotting occurred. The patients were continuously monitored with a pulse oximeter, an electrocardiographic monitor, and an automatic blood pressure cuff. Contrast material (iopamidol) was injected softly to assess the precise localization of the catheter tips. Bilateral central (petrosal and/or jugular) and peripheral blood samples were simultaneously collected. An average of 3 sets of basal venous samples were obtained at 3-min intervals. An intravenous bolus of 100 µg of synthetic ovine CRH was then administered, and subsequent poststimulation sets of samples were obtained at 1, 3, 5, and 10 min.
Of the 158 patients, 133 (84%) were diagnosed as having Cushings disease on the basis of a petrosal to peripheral ACTH ratio (IPS:P) of more than 2 in basal samples and a peak IPS:P ratio of 3 or over after CRH administration. In 83 of these patients (62%), a pituitary corticotropic adenoma was identified immunohistologically. In 26 patients (19.7%), no adenomatous tissue was identified, but clinical and biochemical remission were achieved postoperatively, suggesting that a minute pituitary adenoma had been removed. Thirteen patients were not cured by surgery and underwent either medical therapy or adrenalectomy, with or without pituitary radiotherapy. Eight patients were not operated, and 3 failed to keep in contact. In 25 of the 158 patients (16%), an ectopic ACTH syndrome was diagnosed: 11 bronchial carcinoid tumors, 2 thymic carcinoid tumors, 1 pancreatic carcinoid tumor, 1 medullary thyroid carcinoma, and 1 metastatic ACTH secreting tumor of unknown origin were identified. The source of ACTH secretion remained occult in 9 patients.
Apart from minor groin hematomas and vasovagal reactions, one mild left femoral arteriovenous fistula that spontaneously resolved was noted in a 49-yr-old woman. No case of pulmonary thromboembolism occurred.
One transient neurological complication occurred in this series (0.6%). In a 52-yr-old woman, IPSS could only be performed on the right side because the left internal jugular vein was occluded, as confirmed later by a cervical venous doppler. She experienced severe headache during the catheterism, and a right diplopia due to isolated sixth nerve palsy occurred at the end of the procedure. Computed tomography scanning of the brain revealed no hemorrhage, and anticoagulation with heparin was therefore administrated. The cervical venous doppler also showed that the right internal jugular vein remained patent after the procedure. The sixth nerve palsy completely recovered within 2 months.
The mechanism responsible for the neurological complication reported here is uncertain. Isolated sixth nerve palsies have only rarely been related to small brain stem injuries, which have to involve the intrapontine abducens nerve fascicle but spare the surrounding tissue (11). They are most frequently caused by focal lesions of the nerve in the cavernous sinus, superior orbital fissure, or subarachnoid space. Before reaching the cavernous sinus, the sixth nerve penetrates the IPS through the Dorellos canal (12). The sixth nerve palsy might therefore be related to the thrombosis of the IPS at the end of the procedure. Localized venous hypertension could also have played a role. Due to pre-existing left internal jugular vein occlusion, an unusually increased venous pressure might have occurred in the right internal jugular vein during the procedure, thus creating transient intracranial hypertension. However, three patients with unexplained occlusion of one internal jugular vein showed no complications after BIPSS (13). Severe headache has also been reported during placement of the catheters, as well as during contrast injection, but was not associated with neurological complication (13).
Major neurological complications of BIPSS have all been ascribed to brainstem vascular damage, except for one case with subarachnoid hemorrhage probably due to venous perforation (7). Three cases of brain stem injury have been reported: 2 originate from small series (5, 6), and a third case was reported by Miller et al. (4). In the largest series reported so far, only one major neurological complication (brain stem injury) was reported in 508 procedures (0.2%), while such lesion was presumably avoided in two other patientsbrain stem vascular damage may be preventable if the procedure is halted at the first sign of any unexplained event (4). Subsequently, these investigators performed over 700 BIPSS and encountered no problems (14).
In conclusion, our report confirms that the prevalence of neurological complications secondary to BIPSS in trained hands is low (less than 1%) but definite, although their mechanism is uncertain. Preexisting unilateral occlusion of an internal jugular vein might possibly increase the risk of neurological complications. We believe that BIPSS should be restricted to patients with ACTH-dependent Cushings syndrome, in whom the source of ACTH secretion is not clearly established after magnetic resonance imaging and biochemical testing. As described for the success rate of catheterization (3), one may hypothesize that the safety of the procedure is operator-dependent. Therefore, BIPSS should be performed by experienced teams to reduce the morbidity of the procedure without hampering its unrivaled diagnostic characteristics.
Footnotes
Address correspondence to: Olivier Chabre, Service dEndocrinologie, Centre Hospitalier Universitaire, BP 217X 38043 Grenoble, France.
Received May 11, 1999.
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