Monitoring for potential residual disease activity by serum insulin-like growth factor 1 and soluble Klotho in patients with acromegaly after pituitary surgery: is there an impact of the genomic deletion of exon 3 in the growth hormone receptor (d3-GHR) gene on "safe" GH cut-off values?

BACKGROUND: Acromegaly is an illness usually defined by excessively high growth hormone (GH) and insulin like growth factor 1 (IGF-1) levels, the latter mainly reflecting GH action on the liver. IGF-1, also known as somatomedin C, mediates several actions of GH. The diagnosis and management of acromegaly is relatively straight forward, but long-term follow-up of patients can be difficult, as elevated IGF-1 levels can occur in the presence of apparently normalised GH levels and late recurrence of acromegaly may arise despite previous suppression on oral glucose tolerance testing. Data suggest this applies especially to patients in whom the GH receptor lacks exon 3. In such patients, GH may not always be a useful marker of disease, and traditional GH cut-offs may be misleading. Recent data suggest that soluble Klotho (sKlotho), besides and in addition to IGF-1, may help monitor the activity of GH-producing adenomas (presumably reflecting GH action on the kidneys) and may be a useful supplementary tool. METHODS: GHR genotyping was performed in 112 patients with acromegaly. IGF-1 and sKlotho levels were measured in the sera of patients before and after transsphenoidal surgery, with emphasis on patients judged inconclusively cured by surgery or with small residual tumour masses shortly after surgery. Patients were assessed for recurrence of acromegaly with GH levels (random or nadir during an oGTT). RESULTS: Of the 48 patients who underwent surgery between 2000 and 2009 and who had well-documented longer term follow-up at our institution, 29 had no biochemical evidence of residual disease activity after transsphenoidal surgery (marked reduction in IGF-1 and sKlotho levels, GH suppressible to <1 ng/ml) and were classified as in remission. 2 of these patients developed recurrent symptoms of acromegaly during follow-up with increasing levels of IGF-1 and sKlotho, and both patients were carriers of the d3-GHR genotype. CONCLUSIONS: Acromegalic patients with the d3-GHR polymorphism might be - for a given low postsurgical GH level - at higher risk for recurrence and may require a lower GH nadir during oGTT to be classified as in remission. Soluble Klotho could be useful in the follow-up of acromegalic patients. The question arises whether sKlotho not only reflects the activity of GH-secreting pituitary adenomas but whether Klotho (ectodomain clipping?) could also mediate selected actions of GH.

Antibiotic-impregnated versus silver-bearing external ventricular drainage catheters: preliminary results in a randomized controlled trial.

BACKGROUND: Evaluation of antibiotic-impregnated (AI) and ionized silver particle coated external ventricular drainage catheters (EVD) in patients with subarachnoid (SAH) or intracranial hemorrhage (ICH). METHODS: Between February 2011 and June 2012, 40 patients with acute hydrocephalus due to SAH, ICH or intraventricular hemorrhage were enrolled in a prospective, randomized, mono-center pilot study. Primary endpoints were defined as: number of events of cerebrospinal fluid (CSF) infections. Secondary endpoints were defined as: neurosurgical complications following the placement of the EVD, number of revisions of EVD catheters, and cost effectiveness. RESULTS: Sixty-one EVD placements in 40 patients, 32 antibiotic-coated (Bactiseal(®)), 29 silver-bearing catheters (VentriGuard(®)), have been performed. Confirmed or high suspicion of CSF infections occurred in 11 out of 61 events (confirmed infection: p = 0.71, probable infection: p = 0.90). Revisions of EVD were needed in 13 cases (22 %) due to CSF infection, dysfunction, impaired healing, or malplacement (p = 0.37). CONCLUSION: Regarding CSF infection rate and dysfunction, no statistical significant differences between the two EVD catheters Bactiseal(®) versus VentriGuard(®) were found. The silver-bearing catheter might offer a safe and cost-conscious alternative to the AI catheter.

Excessively high soluble Klotho in patients with acromegaly.

OBJECTIVES: Klotho-deficient mice develop a syndrome resembling accelerated ageing, and genetic variants of Klotho have been associated with human ageing. In humans, serum levels of soluble Klotho decrease with age and with chronic renal failure. The aim of our study was to examine the relationship between excess growth hormone (GH) and serum levels of Klotho in patients with acromegaly, a disease usually caused by a pituitary adenoma, which is associated with high phosphate levels and reduced life expectancy. PATIENTS AND DESIGN: We determined the levels of soluble Klotho, GH and insulin-like growth factor 1 (IGF-1) in serum samples from 24 consecutive patients with acromegaly (nine women/15 men, age 28-76 years) before and after transsphenoidal surgery. RESULTS: Soluble Klotho levels were excessively high at baseline (mean ± SEM, 4.2 ± 0.7 ng mL(-1) ) and correlated with GH (r = 0.64), IGF-1 (r = 0.57) and tumour size (r = 0.5). In multiple regression analysis, soluble Klotho was associated with GH after correction for age, gender and levels of creatinine and phosphate (P = 0.029). After surgery, GH and IGF-1 levels decreased in all patients (from 26.3 ± 5.2 to 2.6 ± 0.6 µg L(-1) , P <0.0001, and from 588 ± 35 to 193 ± 12 µg L(-1) , P < 0.001, 0.0001, respectively). Creatinine increased from 71 ± 3 to 80 ± 3 µmol L(-1) (P < 0.001), and phosphate decreased from 1.37 ± 0.04 to 1.06 ± 0.02 mmol L(-1) (P < 0.001). The markedly increased preoperative levels of soluble Klotho returned towards normal after surgery (0.7 ± 0.1 ng mL(-1) , P < 0.0001). CONCLUSIONS: This is the first study to show dramatically increased soluble Klotho levels in an acquired disease in humans. Reversal following tumour removal suggests a causal relation between the GH-producing adenoma and high serum Klotho concentration in acromegaly.

Intraoperative high frequency ultrasound in intracerebral high-grade tumors.

PURPOSE: To demonstrate the utility of a new concept of intraoperative use of high frequency ultrasound (hfioUS) in maximizing the extent of resection (EOR) of intracerebral high-grade tumors. MATERIALS AND METHODS: 22 Patients harboring an intracerebral high-grade tumor were retrospectively included in this study (14 primary tumors, 8 metastasis). 14 of them had a perilesional edema equal or greater to lesion volume, 3 had previously received radiotherapy. Following macroscopic tumor debulking, the small (11 × 31 mm) L15 - 7io (Philips, Bothell, USA) high-frequency probe (7 - 15 MHz) was introduced into the resection cavity and its walls were meticulously scanned to search for tumor remnants. Postoperative MR scan was evaluated by a board-certified independent neuroradiologist, who assessed the EOR. RESULTS: Gross total resection was achieved in 21 patients (95.5 %). One patient had a small tumor remnant (6 × 4 × 3 mm) of a very large (80 × 60 × 74 mm) anaplastic astrocytoma, detected in the postoperative MR scan. A permanent postoperative hemiparesis was diagnosed in one patient with a metastasis in the motor area, while the other patients recovered without permanent neurological deficits from the surgery. CONCLUSION: The hfioUS probe allowed in this study a precise detection of the tumor and a detailed discrimination between normal, pathological and edematous tissue in all 22 cases.

The transnasal transclival approach for clivus chordoma.

BACKGROUND: We present our experience using a standardized transnasal transclival approach (TTA) for endoscopic removal of chordomas of the clivus. PATIENTS: 13 patients with clival chordoma (CC) underwent tumor resection. Patients were operated by a surgical team consisting of a rhinosurgeon and a neurosurgeon. All patients underwent postoperative proton radiotherapy. Residual tumor was left in situations where radical removal would have entailed an increased risk of neurological deficits. RESULTS: Radical or near total removal of CC was accomplished in 12/13 patients. Intraoperative MRI (IMRI) was used in 4/13 CC patients. A watertight dural seal presented as the main challenge specifically for tumor extensions resulting in large dural defects. CONCLUSION: The TTA provides an elegant alternative to classical approaches to clival lesions especially for midline tumor locations. For large tumors iMRI is of significant help. Dural reconstruction of large defects emerged as the greatest challenge of this technique even for experienced endoscopic surgeons.

Insulin-like growth factor-I mRNA and peptide in the human anterior pituitary.

The pituitary is the central organ regulating virtually all endocrine processes, and pathologies of the pituitary cause manifold adverse effects. Because insulin-like growth factor (IGF)-I appears to be involved in tumour pathogenesis, progression, and persistence, and only few data exist on the cellular synthesis sites of IGF-I, the present study aims to create a basis for further research on pituitary adenomas by investigating the presence of IGF-I in the human pituitary using reverse transcriptase-polymerase chain reaction, in situ hybridisation, immunohistochemistry and immunocytochemistry. IGF-I was expressed in the pituitary, and gene sequence analysis revealed a sequence identical to that found in human liver. The distribution pattern of IGF-I mRNA found by in situ hybridisation corresponded to that of IGF-I peptide in immunohistochemistry. In all pituitary samples investigated, IGF-I-immunoreactivity occurred in almost all adrenocorticotrophic hormone (ACTH)-immunoreactive cells. Occasionally, an interindividually varying number of growth hormone (GH) and, infrequently, follicle-stimulating hormone and luteinising hormone cells contained IGF-I-immunoreactivity but none was detected in supporting cells. At the ultrastructural level, IGF-I-immunoreactivity was confined to secretory granules in coexistence with ACTH- or GH-immunoreactivity, respectively, indicating a concomitant release of the hormones. Thus, in humans, IGF-I appears to be a constituent in ACTH cells whereas its production in GH-producing and gonadotrophic cells may depend on the physiological status (e.g. serum IGF-I level, age or reproductive phase). It is assumed that locally produced IGF-I plays a crucial role in the regulation of endocrine cells by autocrine/paracrine mechanisms in addition to the endocrine route.

Afferents to the rat red nucleus studied by means of D-[3H]aspartate, [3H]choline and non-selective tracers.

Following injection of horseradish peroxidase-labeled wheat germ agglutinin or of rhodamine-labeled microspheres as non-selective tracers into the rat red nucleus, the origins of the corticorubral and cerebellorubral pathways, as well as a considerable number of other brain structures including dorsal raphé nucleus, zona incerta and several hypothalamic nuclei showed retrogradely labeled perikarya. Labeling patterns obtained with horseradish peroxidase-labeled wheat germ agglutinin compared well with those observed following application of rhodamine-labeled microspheres which produced injection sites restricted to the small nucleus. In these latter cases, counterstaining with phosphine allowed a better definition of anatomical structures. After D-[3H]aspartate application, retrogradely labeled perikarya were observed in cerebral cortex (layer V), zona incerta, dorsal raphé nucleus and in several other structures also labeled by non-selective tracers. Following application of [3H]choline and using an improved autoradiographic method, perikaryal labeling was massive within nucleus interpositus, while it was absent in dorsal raphé nucleus, cerebral cortex and zona incerta. Retrograde tracing experiments with D-[3H]aspartate and [3H]choline revealed that these transmitter related compounds are selective markers for two subsets of afferents to the red nucleus. The transmitter specificity of the selective labeling with [3H]choline in the cerebellorubral pathway is supported only in part by the results obtained with other methods. The selective labeling with D-[3H]aspartate in the corticorubral pathway, on the other hand, is consistent with its transmitter specificity.

A new artifact-free device for frameless, magnetic resonance imaging-guided stereotactic procedures.

OBJECTIVE: A new, artifact-free, nonobstructive device was required for planning, guiding, and performing stereotactic procedures in an open magnetic resonance imaging (MRI) system (Signa SP; General Electric, Milwaukee, WI). DESCRIPTION OF INSTRUMENTATION: We devised an MRI-compatible instrument set that was adapted to an optical triangulation system (FlashPoint System; Image Guided Technologies, Boulder, CO) and consisted of a Pathfinder for planning burr holes and trajectories and a Snapper-Stereoguide for guiding minimally invasive instruments such as biopsy cannulae, endoscopes, and laser fibers. The instruments were composed of biocompatible plastic (polyacetal). During evaluation, special attention was paid to safety, accuracy, operation times, and susceptibility artifacts of the system. RESULTS: The first 20 stereotactic procedures performed in the open MRI scanner included 15 biopsies, 1 cyst and 3 abscess evacuations, and 1 endoscopic procedure for treatment of multiseptate hydrocephalus. There were no adverse outcomes, and all biopsies were diagnostic. The frameless stereotactic system in combination with the FlashPoint System proved to be accurate, with a mean error of 1.5 mm. The biopsy devices did not cause any susceptibility artifacts. Highly vascularized structures were clearly visible and were included in the trajectory planning. With experience, the procedure time was reduced to less than 1 hour. CONCLUSION: This device was found to be quite helpful for planning and guiding stereotactic procedures in the open MRI scanner. Nearly real-time planning and monitoring of stereotactic procedures and the positional accuracy of the system make the open MRI system a definite improvement, compared with conventional stereotactic systems.

Near-real-time guidance using intraoperative magnetic resonance imaging for radical evacuation of hypertensive hematomas in the basal ganglia.

OBJECTIVE: To report our preliminary clinical experience in treating patients with hypertensive hemorrhage in the basal ganglia using a minimally invasive approach facilitated by intraoperative real-time imaging of an open magnetic resonance imaging (MRI) system and a newly designed cutting suction device. METHODS: We developed an artifact-free device for use during intraoperative MRI consisting of a guiding base that locks into a burr hole, a side-cutting composite-based cannula connected to a standard aspirator, and a handpiece that allows aspiration strength to be regulated by the surgeon. Thirteen patients with hypertensive bleeding in the basal ganglia were included in the study. Outcome was evaluated by mortality, Glasgow Outcome Scale score, activities of daily living score, and Rankin score at 2 weeks and at a median of 4.2 months after the hemorrhage. RESULTS: In this group of 13 patients, complete evacuation was achieved in 8 patients (62%) and subtotal evacuation of 75 to 90% of the initial volume in 4 patients (31%); the evacuation was partial in 1 patient (8%). Vascular malformations were preoperatively excluded angiographically. There was no rebleeding during surgery or postoperatively, as demonstrated by immediate postoperative MRI and computed tomography on the 1st postoperative day. Hematomas were evacuated on median Day 4 after the hemorrhage, varying between Day 1 and Day 8; evacuation was performed on Day 21 after the hemorrhage in one patient. Twelve of the 13 patients survived during a median follow-up time of 4.2 months. Neurological function improved in 11 of the 12 patients eligible for assessment. One patient with an additional head injury died 15 days after surgery from pulmonary embolism. CONCLUSION: This study shows an excellent outcome with regard to mortality and a positive trend regarding neurological outcome for the specific group of patients with hypertensive hematomas in the basal ganglia. This minimally invasive approach is feasible in the open intraoperative MRI in combination with the cutting suction device developed in our institution. Online imaging is extremely helpful for planning, guiding, and real-time monitoring of the procedure.

Interactive magnetic resonance imaging-guided management of intracranial cystic lesions by using an open magnetic resonance imaging system.

OBJECT: The authors present their experience with neurosurgical procedures requiring real-time imaging feedback such as aspiration of a cystic structure or abscess cavity, decompression of hydrocephalic ventricles, management of arachnoid cysts, and installation of permanent or temporary drainage conduits, in which interactive magnetic resonance (MR) imaging guidance was used to monitor structural alterations associated with the procedure. METHODS: Drainage of eight intraparenchymal brain abscesses in seven patients, decompression of space-occupying cystic or necrotic brain tumors in four patients, and endoscopic management of hydrocephalus associated with arachnoid cysts in three patients were performed using MR imaging-guided frameless stereotaxy in an open-configuration 0.5-tesla superconducting MR imaging system. Intraoperative MR imaging guidance provided accurate information on the course of the surgical procedure and associated intraoperative changes in tissue position, such as the degree of cyst aspiration, the presence or absence of hemorrhage or induced swelling, and changes associated with decompression of adjacent brain parenchyma and the ventricular system. No clinically significant complications were encountered in any patient. There were no targeting errors, and procedural objectives were accomplished in all cases. CONCLUSIONS: Drainage of brain abscesses, punctures of cystic or necrotic intracranial lesions with subsequent aspiration, and management of hydrocephalus can be performed safely and accurately by monitoring the procedure using real-time MR imaging to obtain immediate feedback on associated dynamic tissue changes.

Clinical assessment of a novel antiadhesion barrier gel: prospective, randomized, multicenter, clinical trial of ADCON-L to inhibit postoperative peridural fibrosis and related symptoms after lumbar discectomy.

A prospective, multicenter, randomized, double-blind, controlled study of ADCON-L Anti-Adhesion Barrier Gel (a medical device by Gliatech Inc, Cleveland, OH) was conducted in 298 patients undergoing first-time lumbar discectomy to evaluate the safety and effectiveness of ADCON-L in preventing postoperative peridural fibrosis and in improving patient clinical outcome. After lumbar discectomy, patients were randomized to receive either ADCON-L gel or nothing (control group) at the conclusion of the surgical procedure. Six months after surgery, peridural scar was evaluated by magnetic resonance imaging, and postoperative pain and straight-leg-raise angle were assessed. No statistically significant differences between the ADCON-L and control groups were observed in terms of adverse events or wound healing characteristics. ADCON-L gel was shown to be safe and to significantly inhibit peridural scar compared with the control group (P = 0.002). That peridural scarring was reduced with ADCON-L gel was further supported by direct visualization of scar tissue at reoperation in both groups. ADCON-L-treated patients had better clinical outcomes than did control patients. The incidence of activity-related pain was significantly reduced (P = 0.013), straight-leg-raise examination scores were significantly improved (P = 0.024 on the operative side and P = 0.015 on the nonoperative side), and ADCON-L reduced low back pain when it was most severe (P = 0.047) and at the end of the day (P = 0.044).

Intrasellar malignant peripheral nerve sheath tumor (MPNST).

Intracranial malignant peripheral nerve sheath tumors (MPNST) and intrasellar schwannomas are rare tumors. We describe a case of an intrasellar schwannoma with progression to a MPNST, a finding that, although very rare, extends the differential diagnosis of intrasellar lesions.

Dynamic changes during evacuation of a left temporal abscess in open MRI: technical case report.

We demonstrate the usefulness of "near real-time" neuro-navigation by open MRI systems for guidance of stereotactic evacuation of intracranial abscesses. A 70-year-old patient was referred to our institution with an intracranial left temporal abscess. He presented with headache, senso-motor aphasia and mild right hemiparesis. The abscess (35 x 25 mm) was stereotactically evacuated under MRI guidance, and a recurrence of a daughter abscess was again evacuated on the 9th postoperative day. "Near real-time" imaging showed an indentation of the abscess wall of 11 mm along the trajectory. A thermosensitive MRI protocol demonstrated a higher temperature around the abscess capsule than in the brain tissue more distant to the capsule, demonstrating the inflammatory process. The patient had 6 weeks of antibiotic therapy for gram-negative bacteria and was discharged with improved clinical symptoms 5 weeks after admission. Follow-up CT 2 months postoperatively showed a complete resolution of the abscess. Open MRI-guided interventions with "near real-time" imaging demonstrate the anatomical changes during an ongoing procedure and can be accommodated for enhancing the overall precision of stereotactic procedures. Thermosensitive MRI protocols are capable of revealing temperature gradients around inflammatory processes.

Extensive spherical amyloid deposition presenting as a pituitary tumor.

A 71-yr-old man was admitted for further evaluation and trans-sphenoidal surgery of a pituitary tumor. He complained of impotence and decreased libido over a period of about 40 yr. Thirty-eight yr ago he was treated for bilateral gynecomastia with galactorrhea. Endocrinological investigation at presentation revealed only mild hyperprolactinemia and hypogonadotropic hypogonadism. Pituitary magnetic resonance imaging (MRI) showed a tumor up to 2.5 cm in diameter with infiltration of the sphenoid sinus and right cavernous sinus. The tumor exhibited a heterogeneous hyperintense signal on T1-weighted images and hypointense signal on T2-weighted images. Standard trans-sphenoidal surgery was performed and a brownish mass was found inside the sella, which was removed. Histological examination of the mass revealed extensive spherical amyloid deposits with strongly positive immunohistochemical staining for prolactin. Therefore, a prolactinoma with extensive spherical amyloid deposition was diagnosed. Extensive spherical amyloid deposition is a rare finding in prolactin-secreting pituitary adenomas. So far, characteristic radiological findings by MRI have been described only twice. Due to characteristic MRI findings, the diagnosis of extensive intrasellar amyloid deposition can be entertained pre-operatively. Trans-sphenoidal surgical resection is essential to confirm the diagnosis histologically and because of the potential lack of tumor shrinkage under dopaminagonist therapy in this type of prolactinoma.