Progressive improvement of impaired visual acuity during the first year after transsphenoidal surgery for non-functioning pituitary macroadenoma.

OBJECTIVE: Improvement of visual field defects continues even years after the initial surgical treatment. Because this process of continuing improvement has not been documented for visual acuity, we audited our data to explore the pattern of recovery of visual acuity until 1 year after transsphenoidal surgery for non-functioning pituitary macroadenoma. DESIGN: Retrospective follow-up study. PATIENTS: Forty-three patients (mean age 56 +/- 14 years), treated by transsphenoidal surgery for non-functioning pituitary macroadenoma, were included in this analysis. RESULTS: Visual acuity improved significantly within 3 months after transsphenoidal surgery. The mean visual acuity increased from 0.65 +/- 0.37 to 0.75 +/- 0.36 (P < 0.01) (right eye), and from 0.60 +/- 0.32 to 0.82 +/- 0.30 (P < 0.01) (left eye). Visual acuity was improved 1 year after transsphenoidal surgery compared to the 3 months postoperative values. The mean visual acuity increased from 0.75 +/- 0.36 to 0.82 +/- 0.34 (P < 0.05) (right eye), and from 0.82 +/- 0.30 to 0.88 +/- 0.27 (P < 0.05) (left eye). CONCLUSION: Visual acuity improves progressively after surgical treatment for non-functioning pituitary macroadenomas, at least within the first year after transsphenoidal surgery.

Long-term follow-up results of postoperative radiotherapy in 36 patients with acromegaly.

In acromegaly, pituitary irradiation is a slow, but effective, intervention in decreasing GH concentration. Few studies addressing the outcome of radiotherapy have used the currently accepted strict criteria for remission in the analysis of data. These studies report a low percentage of remission after radiotherapy. Doubt has especially been raised as to whether radiotherapy is effective in normalizing serum insulin-like growth factor (IGF)-I concentration. We analyzed the long-term follow-up data of postoperatively administered radiotherapy in 36 patients with postoperative persistent acromegaly, using both the normalization of GH suppression during oral glucose loading (GTT) and the normalization of IGF-I concentration as criteria for remission. Before radiotherapy, mean suppressed GH was 9.8 +/- 1.9 mU/L (n = 31), and mean IGF-I concentration was 44.3 +/- 3.9 nmol/L, equivalent to + 4.76 +/- 0.78 age-related IGF-I SD score (n = 13). The median radiation dose was 40 Gray (range, 25-50 Gray). At 5, 10, and 15 yr follow-up, 18 out of 30 patients (60%), 23 out of 31 patients (74%), and 16 out of 19 patients (84%), respectively, achieved normal serum IGF-I concentration. At the last assessment of all patients, after a mean follow-up period of 139 +/- 12 months, 27 out of 36 (75%) patients had a normal IGF-I concentration without additional medication, whereas 5 patients still required treatment with octreotide. Remission, as judged by normalization of GH suppression during GTT, was documented in 65% of patients from 2-5 yr after radiotherapy (n = 34); in 69% of patients, up to 10 yr after radiotherapy (n = 29); and in 71% of patients, up to 15 yr post irradiation (n = 17). At the latest assessment, a mean of 125 +/- 11 months after radiotherapy, 71% of patients (n = 35) were in remission, as defined by normal suppression of serum GH during GTT. Remission, as judged by normalization of both GTT and IGF-I, was found in 40% of patients 3-5 yr after radiotherapy (n = 30); in 61% of patients, 6-10 yr after radiotherapy (n = 28); in 65%, after 11-15 yr after radiotherapy (n = 17); and in 63% of patients, at the end of the follow-up period (n = 35). Substitution of one or more pituitary hormone deficiencies was required in 11% of patients postoperatively; in 29%, 5 yr after radiotherapy; in 54%, 10 yr after radiotherapy; and in 58%, more than 15 yr after radiotherapy. Our findings support the use of radiotherapy as an effective intervention in the treatment of residual clinical activity of disease after surgery for acromegaly.

Treatment of pituitary-dependent Cushing's syndrome: long-term results of unilateral adrenalectomy followed by external pituitary irradiation compared to transsphenoidal pituitary surgery.

BACKGROUND: The preferred treatment of Cushing's disease (CD) nowadays is transsphenoidal pituitary surgery (TPS). Prior to TPS, patients at the Leiden University Medical Centre were treated by unilateral adrenalectomy followed by external pituitary irradiation (UAPI). We report on long-term results of both UAPI and TPS and compare remission, relapse rates, and complications. PATIENTS AND METHODS: A retrospective study was carried out on 130 patients with CD. Patients with pituitary macroadenoma were excluded. Eighty-six and 44 patients underwent UAPI and TPS, respectively. Of these patients, 85 and 41 were evaluable for long-term results. RESULTS: Remission following UAPI and TPS was identical at 64% (54/85 and 27/41). Cumulative relapse was also comparable - 17% (9/54) and 22% (6/27), respectively, - for UAPI and TPS, although the mean follow-up periods were different - 21.4 years and 8.5 years, respectively. Cumulative disease-free survival curves after UAPI and TPS are identical until 5 years of follow-up, but diverge thereafter indicating more sustained remissions following UAPI (P = 0.17, Wilcoxon statistic). Pituitary dysfunction following UAPI (36%) and pituitary surgery (55%) likewise did not differ significantly. However, pituitary dysfunction was an immediate event after TPS, whereas it developed after a mean interval of 17.8 years following UAPI.Low-dose dexamethasone testing during follow-up had no value in predicting therapeutic outcome. CONCLUSIONS: The results of unilateral adrenalectomy followed by external pituitary irradiation do not justify that this therapy is totally abandoned in favour of transsphenoidal pituitary surgery. Unilateral adrenalectomy followed by external pituitary irradiation is a valid therapeutic modality for the treatment of Cushing's disease, and could be considered as alternative to bilateral adrenalectomy and under some circumstances to transsphenoidal pituitary surgery.

Ten-year follow-up results of transsphenoidal microsurgery in acromegaly.

Fifty-nine acromegalic patients, transsphenoidally operated by a single neurosurgeon (H.v.D.) were followed for at least 10 yr to assess the late outcome of surgery. Mean follow-up was 16 +/- 0.4 yr (range, 10-22). Criteria for remission were a serum GH concentration below 2.5 microg/L, a normal glucose-suppressed GH (oral glucose tolerance test), and a normal serum insulin-like growth factor I (IGF-I) concentration. Mean serum GH concentration decreased from 59 +/- 8.7 microg/L to 5.6 +/- 1.4 microg/L after surgery. Early postoperative remission rates were 61% (GH, <2.5 microg/L), 67% (suppressed GH), and 60% (both GH <2.5 microg/L and suppressed GH). Early postoperative remission was significantly related to preoperative serum GH concentration (P: = 0.023), but not to tumor size. Of 36 patients with postoperative remission (GH, <2.5 microg/L), 9 patients received (prophylactic) radiotherapy for persistent paradoxical reaction to TRH or probable invasive tumor growth. All nine patients are in remission at the end of follow-up. Of the other 27 patients with postoperative remission, 5 (19%) developed recurrence, becoming evident within 5 yr in 4 patients and after 10 yr in 1 patient. Of these 27 patients, surgical remission rates at the end of follow-up are 78% (random GH, <2.5 microg/L), 73% (normal glucose-suppressed GH), 74% (normal IGF-I), and 65% (normal IGF-I and GH suppression). Of the patients with postoperative persistent disease, 18 patients were irradiated and 5 patients were followed without further treatment. Two of five nontreated patients had spontaneous normalization of GH concentration at the 6 months visit and remained in remission by surgery only. The long-term efficacy of multimodality treatment was evaluated after exclusion of the prophylactically irradiated patients. At the end of follow-up, 48% of patients had not required adjuvant therapy and the rest received radiotherapy (34%), octreotide (10%), or both (8%). Remission rates of multimodality therapy were 96% (serum GH, <2.5 microg/L) and 94% (normal serum IGF-I concentration). Remission rates of transsphenoidal surgery alone were 46% (serum GH, <2.5 microg/L), 44% (normal IGF-I concentration), 41% (suppressed serum GH), and 37% (normal serum IGF-I and suppressed GH). In this first report on separate 10 or more years results of transsphenoidal surgery for acromegaly, using strict criteria for remission, 19% of patients with postoperative remission developed recurrence. Nevertheless, about 40% of patients remain in remission after only surgical intervention, even after a mean follow-up of 16 yr.

Direct postoperative and follow-up results of transsphenoidal surgery in 19 acromegalic patients pretreated with octreotide compared to those in untreated matched controls.

In this study 19 patients were preoperatively treated with octreotide for 1-17 months (mean, 5 months), with doses from 150-1500 microg daily, and those patients were matched to 19 untreated patients with comparable tumor classification and preoperative serum GH concentrations. Octreotide was started at 300 microg daily by s.c. injections or continuous sc infusion using a pump in increasing doses, depending on the responses of the serum GH and insulin-like growth factor I (IGF-I) concentrations. During pretreatment, seven patients achieved a serum GH concentration below 5 mU/L, whereas six patients normalized their serum IGF-I. Postoperatively, a serum GH concentration below 5 mU/L was achieved in 15 pretreated and 14 untreated patients, a normal serum IGF-I level (<2 SD) was achieved in 10 pretreated and 15 untreated patients, and normal serum GH suppression during GTT was reached in 12 treated and 14 control patients. No differences were found in complication rate or incidence of hypopituitarism caused by surgery. Adjuvant therapy was required in 7 treated and 5 untreated patients. At follow-up examination, 5.7 and 4 yr postoperatively, 10 pretreated and 12 control patients could be considered cured by surgery only, according to our criteria for remission (serum GH, <5 mU/L; normal GH suppression and normal serum IGF-I). In summary, we found no difference in direct postoperative and follow-up results of transsphenoidal surgery between pretreated patients and untreated patients. This finding is in discordance with other studies, which have claimed a beneficial effect of octreotide pretreatment.

Can intra-operative GH measurement in acromegalic subjects predict completeness of surgery?

OBJECTIVE: Results of trans-sphenoidal pituitary surgery, in terms of long-term cure, vary considerably between centres. Additional techniques, which can assist the neurosurgeon in deciding whether surgery is complete or not, might therefore be important. One such potential tool is the intra-operative measurement of GH and calculating the plasma half-life from the plasma samples obtained after the presumed complete resection of the adenoma. METHODS: GH half-life was calculated from 5-10 min plasma samples after adenomectomy in 20 patients. GH was measured with a sensitive and rapid IFMA, and the results could be reported within 30 min, but were not used in this study for per-operative decisions. Cure was defined by a glucose suppressed plasma GH concentration below 1 mU/l (0.38 microgram/l) during follow-up studies and a normal plasma IGFI concentration. RESULTS: In 13 cured patients the plasma half-life was 22.2 +/- 1.9 min (range 14-40.6). In three non-cured patients the plasma half-life could not be calculated, and in four other patients the plasma half-life was 35.8 +/- 5.9 min (range 25.8-51 min). By applying 25 min as the upper normal limit for the GH plasma half-life, the sensitivity was 77%, specificity 100%, and positive predictive value 100%. CONCLUSION: Per-operative plasma GH monitoring is a potentially useful tool for determining the completeness of trans-sphenoidal surgery in acromegaly.

Pituitary apoplexy in acromegaly, a long-term follow-up study in two patients.

Pituitary apoplexy is a serious complication in about 3% of patients with a pituitary adenoma. Very often, the diagnosis of a functioning or non-functioning adenoma is made in retrospect. In this report, we describe two patients in whom the diagnosis of acromegaly was made before the apoplexy. In one patient, surgical intervention was necessary because of remaining clinical and biochemical activity; in the other patient conservative follow-up was pursued. Seven and nine years after apoplexy, respectively, the patients were clinically and biochemically in remission. During the follow-up, three and five years after apoplexy, respectively, the patients underwent a 10-min venous sampling procedure for 24 hours, and the GH secretory profile was investigated with multiparameter deconvolution analysis and by approximate entropy (ApEn), a scale- and model-independent regularity measure. The deconvolution analysis revealed an increased basal (nonpulsatile) GH secretion rate, while the total 24 h secretion rate was normal compared with 13 healthy male control subjects. ApEn was much larger for each patient than for any control subject value, indicating markedly more irregular GH secretion. We hypothesize that these subtle abnormalities are caused by non-specific damage as a result of vascular insult, leading to abnormal vascular supply, or abnormal autocrine and paracrine GH regulation within the remaining gland.

Does intervention improve the natural course of glomus tumors? A series of 108 patients seen in a 32-year period.

To acquire more insight into the results of treatment versus the "natural" course of glomus tumors, we studied the clinical data of 108 patients, in 58 of whom the disease was hereditary. During a period of 32 years (1956 to 1988), 175 tumors were diagnosed: 52 glomus jugulotympanic tumors, 32 vagal body tumors, and 91 carotid body tumors. The results of radical surgical treatment were disappointing for tumors located at the skull base, ie, nonradical in 59% (n = 23) of the cases, but very good for the carotid body tumors, for which 96% (n = 68) radical excision was achieved. Moreover, surgery at the level of the skull base dramatically increased morbidity, since it frequently induced cranial nerve palsy. During the follow-up period (maximal observation time 32 years, mean 13.5 years) none of the patients died of residual or recurrent tumor or developed distant metastases, irrespective of the mode and outcome of treatment. When these results are combined with the results of pedigree analysis, a realistic approximation of the "natural" course of the disease for both hereditary and nonfamilial tumors can be made. The results raise the question of whether this natural behavior is really improved by intervention. We conclude that removal of carotid body tumors and solitary vagal body tumors should be considered in order to prevent future morbidity. However, for skull base and bilateral glomus tumors a more conservative monitored "wait and see" policy can be sensible and should be considered in any proposal for treatment of head and neck paragangliomas.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical, bacteriological and cost-saving effects of antibiotic prophylaxis in craniotomy]. / Klinische, bacteriologische en kostenbesparende effecten van antibiotische profylaxe bij craniotomie.

Objective of the study. To investigate the effect of antibiotic prophylaxis on the incidence of infections, on the bacterial flora of wounds and on the health-care costs. A retrospective study disclosed an incidence of infection of 8.1% in patients who underwent craniotomy. Methods. Double-blind, placebo-controlled study of the effects of cloxacillin (4 x 1 gr intravenously during 24 h, perioperatively) in 310 patients who had to undergo a craniotomy. Results. In the cloxacillin group significantly fewer infections occurred than in the placebo group, 6 infections in 156 and 20 infections in 154, respectively. In the cloxacillin group significantly fewer samples contained micro-organisms than in the placebo group. Cloxacillin prophylaxis reduces the cost of patient care by about 20%. Conclusion. Cloxacillin prophylaxis in craniotomy cases reduces the percentage of infections, the percentage of positive cultures of the wound, and the costs of patient care.

Efficacy of cloxacillin prophylaxis in craniotomy: a one year follow-up study.

A previous prospective double-blind placebo-controlled study showed that cloxacillin prophylaxis significantly reduces the rate of infection after craniotomy. The purpose of the present follow-up study was to find out whether the data on routine cloxacillin prophylaxis would confirm the decreased infection rate after craniotomy. During this 1-year study, 8 infections occurred after 201 operations (4.0%) in 175 patients. No prophylaxis was given during 17 operations in 15 patients; 4 infections occurred in this group. The most frequently isolated microorganisms were Staphylococcus aureus, S. epidermidis, and Propionibacterium acnes, all of which were sensitive to cloxacillin. We conclude that cloxacillin is beneficial as prophylaxis in patients undergoing craniotomy.

Effect of cloxacillin prophylaxis on the bacterial flora of craniotomy wounds.

During a double-blind placebo-controlled study, the effect of cloxacillin prophylaxis in craniotomies on samples taken for culture from 334 operation wounds in 279 patients was assessed. Patients and operations were equally divided over the cloxacillin and placebo groups. In the cloxacillin group significantly fewer samples contained microorganisms than was the case in the placebo group both just after the incision was made (p less than 0.05) and just before closure of the wound (p less than 0.001). The contaminating bacteria found most frequently were Propionibacterium acnes and Staphylococcus epidermidis. For material collected immediately after the incision, the percentage of cultures positive for S. epidermidis was significantly (p = 0.001) lower in the cloxacillin group than in the placebo group; the percentage of cultures with P. acnes did not differ between the two groups. For samples taken just before the wound was closed, the percentage of cultures with P. acnes or S. epidermidis was significantly (p = 0.008 and 0.003, respectively) lower in the cloxacillin than in the placebo group. In the placebo group neurosurgical infections occurred with P. acnes and/or S. epidermidis as causative microorganisms; in almost all cases those bacteria could be cultured from the edge of the wound. In none of the patients with an infection caused by S. aureus was the bacteria found in the operation area. In 2/6 infections in the cloxacillin group the infecting microorganisms could be cultured from the operation area. These findings support a significant reduction in the infection rate after craniotomy under cloxacillin prophylaxis compared with placebo.

Large pituitary adenomas with extension into the nasopharynx. Report of three cases with a review of the literature.

Three cases of pituitary adenoma with extension into the nasopharynx and nasal cavity are reported. The occurrence of this rare tumor underscores the need to consider a pituitary tumor whenever a patient presents with rhinologic complaints and destruction of the sellar floor. Epistaxis, although exceptional, may be the first manifestation of a pituitary tumor. Immunohistochemical analysis combined with staining for the pituitary hormones proved to be essential for reaching a definite diagnosis. Magnetic resonance imaging seems to be the modality of choice for differentiation between tumorous and nontumorous sinus obstruction.

Plasma growth hormone half-life after selective removal of adenoma in acromegalics determines the outcome of surgery.

We measured plasma GH levels during transsphenoidal surgery in eight patients with acromegaly. After removal of the adenoma GH levels fell monoexponentially in six subjects while they were still under general anaesthesia, but no decrease was noted for two other subjects. Normal postoperative GH and Somatomedin-C levels were found for those patients who exhibited a reduction in GH during surgery. During follow-up studies one patient with a normal GH level exhibited a paradoxical reaction to TRH, attributed to tumour remnants. The plasma half-life found for five patients was 18-33 min; for another cured subject it was longer, i.e. 58 min. The major fraction of the circulating GH, as determined by gel-chromatography, was mol. wt 22,000; this applied for six subjects, while the patient with the long plasma half-life appeared to have a mol. wt 33,000 variant. From this study we conclude that a clear drop in the plasma GH level after removal of the adenoma predicts a favourable outcome of surgery; however, if some tumour remnants are left behind, paradoxical reactions may occur despite normal basal GH levels.

Antibiotic prophylaxis in craniotomy: a prospective double-blind placebo-controlled study.

A prospective double-blind placebo-controlled study was performed to evaluate the efficacy of cloxacillin for the prevention of infections after craniotomy. 310 patients were admitted to the study. 39 died within 90 days after craniotomy without an infection, 20 and 19 of them belonging to the cloxacillin and placebo groups, respectively. In the cloxacillin group 6 neurosurgical infections occurred after 183 operations (3.3%) in 156 patients (3.9%), and in the placebo group 20 after 195 operations (10.3%) in 154 patients (13%). These differences between the 2 groups are statistically significant (p less than 0.01 and p less than 0.05 for patients and operations, respectively). For a craniotomy subgroup, there was no significant difference in infection rate between the cloxacillin and placebo groups. We conclude that cloxacillin significantly reduces the rate of infection after craniotomy, and recommend administration of this antibiotic for prophylaxis in patients undergoing this operation.

Somatomedin-C levels in treated and untreated patients with acromegaly.

With the aid of a recently developed commercially available radioimmunoassay for Somatomedin-C (Sm-C) we measured the Sm-C levels in 38 controls, 24 untreated acromegalics, 45 inactive acromegalics and five pituitary dwarfs. With the exception of the dwarfs, the age and sex distributions for the various groups were similar. In inactive acromegalics the basal GH level (calculated as the mean of four blood samples taken during the day) was less than 5 mU/l; it was depressed to, or less than, 2.5 mU/l during the 100 g oral glucose tolerance test. The mean Sm-C level found for control subjects was 20.4 +/- 5.1 nmol/l and for untreated patients 85.6 +/- 25.7 nmol/l (mean +/- SD, P less than 0.001). The mean Sm-C level for inactive patients who had undergone surgery and invariably showed a normalized paradoxical reaction to TRH was 18.2 +/- 7.1 nmol/l (NS) vs 16.1 +/- 8.2 nmol/l (NS) for those who underwent surgery plus postoperative pituitary radiation therapy. Only one out of 45 inactive acromegalics exhibited an increased Sm-C level. The Sm-C levels correlated significantly not only with the log GH levels (r = 0.82) but also with the fasting insulin/glucose ratio the integrated incremental insulin levels, the maximal insulin increase and the integrated glucose levels during the oral glucose tolerance test as well as the 24-h urinary excretion of calcium and hydroxyproline.(ABSTRACT TRUNCATED AT 250 WORDS)

Infections after craniotomy: a retrospective study.

A retrospective study was performed to evaluate the rate of infection directly related to craniotomy. Of 246 craniotomies performed in 1981, 234 could be evaluated. The overall incidence of infection was 8.1% (19 infections in 18 patients). The infection rate was 15.2% after insertion of a ventricular shunt (seven infections after 45 ventriculostomies). Staphylococcus aureus, Staphylococcus epidermidis and Propionibacterium acnes were the most frequent isolated micro-organisms. We recommended a double-blind prospective study to evaluate the possible benefit of antibiotic prophylaxis in craniotomies.