Vestibular assessment in patients with vestibular schwannomas: what really matters?

Vestibular function is often underdiagnosed in vestibular schwannomas (VS). To evaluate it in a selected group of patients harbouring vestibular schwannomas, 64 patients were included in this study, recruited between March 2008 and June 2011 at our institution. All patients underwent Gd-enhanced MRI and complete neurotological evaluation before gamma knife surgery. Morphological measurements included Koos Classification and quantification of internal acoustic canal filling in length and diameter. Cochlear and vestibular functions were assessed considering pure tone and speech audiometry, bedside examination and caloric test by videonystagmography. A statistical analysis was performed to find possible correlations between morphological and cochleovestibular data. Patients with a higher intracanalicular length (ICL, mean value 8.59 and median 8.8 mm) of the tumour presented a higher value of UW than the subgroup with a lower length (51.9 ± 24.3% and 38.8 ± 18.1% respectively, p = 0.04), while no difference was detected for pure tone audiometry (PTA) values (50.9 ± 22.3 db and 51.1 ± 28.9 db respectively). Patients with a higher ICL also presented a higher rate of positive HIT (88% and 60% respectively, p = 0.006). Patients with a higher value of intracanalicular diameter (ICD, mean value 5.22 and median 5.15 mm) demonstrated higher values of UW (50.2 ± 29.1% and 39.3 ± 21% respectively, p = 0.03), but not different PTA (50.2 ± 29.1 db and 51.9 ± 29.9 db respectively). Finally, patients with a positive head impulse test (HIT) demonstrated significantly higher values of unilateral weakness (UW) (p = 0.001). Vestibular disorders are probably underdiagnosed in patients with VS. ICL and ICD seem to be the main parameters that correlate with vestibular function. Also, in case of small intracanalar T1 VS a slight increase of these variables can result in significant vestibular impairment. The data reported in the present study are not inconsistent with the possibility of proactive treatment of patients with VS.

Review of cerebellopontine angle medulloblastoma.

Cerebellopontine angle (CPA) medulloblastomas (MB) are rare lesions with few cases previously described in the literature. We report two further cases of CPA MB. The patients were a 22-year-old man and a 26-year-old woman with a mass developing in the CPA. The preoperative radiological diagnosis was vestibular schwannoma in the first case and petrosal meningioma in the second case. The patients were operated on through a retrosigmoid approach. The intraoperative findings revealed an intra-axial tumour and the histological diagnosis was classic type of MB in both cases. We review the literature and discuss pathological and radiological features and possible pathogenesis of CPA MB, underlining the necessity to consider MB in the differential diagnosis of CPA lesions.

Painful cervical dystonia triggered by the extension wire of a deep brain stimulator.

Deep brain stimulation (DBS) can be complicated by adverse events, which are generally classified as surgical-hardware or stimulation-related. Here we report the onset of a painful cervical dystonia probably triggered by the extension wire of a subthalamic nucleus (STN)-DBS device in a woman suffering from advanced Parkinson's disease (PD). Two months after implantation of the STN-DBS device, our patient developed a painful cervical dystonia, which was not responsive to neurostimulation or to medication. No sign of infections or fibrosis was detected. A patch test with the components of the device was performed, revealing no hypersensibility. The patient was referred back to surgery to reposition the pulse generator in the contralateral subclavian region. A deeper channeling of the wire extensions produced a complete remission of the painful dystonia.

Changes in brain glucose metabolism in subthalamic nucleus deep brain stimulation for advanced Parkinson's disease.

BACKGROUND: Despite its large clinical application, our understanding about the mechanisms of action of deep brain stimulation of the subthalamic nucleus is still limited. Aim of the present study was to explore cortical and subcortical metabolic modulations measured by Positron Emission Tomography associated with improved motor manifestations after deep brain stimulation in Parkinson disease, comparing the ON and OFF conditions. PATIENTS AND METHODS: Investigations were performed in the stimulator off- and on-conditions in 14 parkinsonian patients and results were compared with a group of matched healthy controls. The results were also used to correlate metabolic changes with the clinical effectiveness of the procedure. RESULTS: The comparisons using Statistical parametric mapping revealed a brain metabolic pattern typical of advanced Parkinson disease. The direct comparison in ON vs OFF condition showed mainly an increased metabolism in subthalamic regions, corresponding to the deep brain stimulation site. A positive correlation exists between neurostimulation clinical effectiveness and metabolic differences in ON and OFF state, including the primary sensorimotor, premotor and parietal cortices, anterior cingulate cortex. CONCLUSION: Deep brain stimulation seems to operate modulating the neuronal network rather than merely exciting or inhibiting basal ganglia nuclei. Correlations with Parkinson Disease cardinal features suggest that the improvement of specific motor signs associated with deep brain stimulation might be explained by the functional modulation, not only in the target region, but also in surrounding and remote connecting areas, resulting in clinically beneficial effects.

Combined treatment of non-small cell lung cancer with synchronous brain metastases: a single center experience.

AIM: The aim of this study was to analyze our experience with combined treatment of non-small cell lung cancer with synchronous brain metastases. METHODS: Between 1992 and 2008, 31 patients were treated by performing neurosurgery (or stereotactic radiosurgery) and lung surgery. Patients were divided into two groups according to their preoperative mediastinal work-up: group A (CT scan) and group B (FDG-PET scan). RESULTS: Twenty-six patients had one brain metastasis and five had two. Neurosurgery was performed in 10 patients, stereotactic radiosurgery in 20 and both approaches in 1. Seven patients underwent chemotherapy after cerebral procedure. Pulmonary resection was complete in 27 cases and incomplete in 4. Histological findings showed: adenocarcinoma in 19 cases, squamous cell carcinoma in 8 and large cell carcinoma in 4. All patients underwent adjuvant chemotherapy. Overall 1, 2 and 5-year survival rates were 83%, 47% and 21%, respectively. The median survival was 22 months. Univariate analysis showed a better prognosis for complete resection (P=0.008), adenocarcinomas (P=0.015), N0 disease (P=0.038), and Group B (P=0.045). Multivariate analysis showed that only the radicality of the resection (P=0.027) and Group B (P=0.047) were independent prognostic factors. CONCLUSION: Our experience confirms that selected patients with non-small cell lung cancer and synchronous brain metastases may be effectively treated by combined therapy. Complete resection, adenocarcinoma histology and N0 disease were prognostic factors. The incorporation of FDG-PET scan into the preoperative work-up may translate into a survival benefit.

The role of radiation therapy in the management of non-functioning pituitary adenomas.

Surgical removal of non-functioning pituitary adenoma (NFPA) is the first-choice therapeutic option, but radical removal of the tumor cannot be accomplished in all patients. The best strategy to prevent regrowth of NFPA is still a matter of debate. Adjuvant radiotherapy is very effective in reducing recurrence rate after incomplete removal of NFPA, but concerns still exist about long-term toxicity of radiation. Different modalities have been developed to irradiate the pituitary region. One major distinction is between radiation techniques that deliver the total dose in multiple sessions using 3 fixed radiation beams and radiosurgical equipment that delivers the total dose to the target volume in a single treatment session. Progression-free survival of patients with NFPA treated by adjuvant radiotherapy is well above 90% at 5 yr in most studies and diminishes only slightly at 10 yr. Very few studies have a more prolonged follow-up. In comparison, the 5- and 10-yr estimated recurrence rate without adjuvant radiotherapy ranged from 15% to 51% and from 44% to 78%, respectively. Complications of radiation include rare but severe side-effects, such as secondary brain neoplasm, optic neuropathy, cerebrovascular accidents, and more frequent but less severe complications, such as pituitary deficiency. Optimal management of patients with residual or recurring NFPA after surgical debulking can be achieved through the judicious use of different treatment options, necessitating close cooperation between neurosurgeons, endocrinologists, and radiation oncologists.

Surgical excision of clival tumors via the enlarged transcochlear approach. Indications and results.

BACKGROUND: The results of the surgical resection of 9 clival tumors using the enlarged transcochlear approach (ETCA) are evaluated. The literature is reviewed to compare the ETCA with other approaches to the clival and petroclival region; the surgical indications are discussed. METHODS: Between June 1996 and June 1997, 9 patients were operated on through the ETCA either alone or combined with other approaches. Only meningiomas and chordomas with a significant involvement of the clivus and huge extension into the posterior fossa were included into this study. RESULTS: Gross total tumor removal was achieved in 5 cases and in 4 cases a residual meningioma was left in place inside the cavernous sinus and treated by radiosurgery. No postoperative mortality or major neurological morbidity were recorded. The postoperative facial nerve function was good in 75% of cases. No tumor recurrence was recorded (mean follow-up = 45.9 months). CONCLUSIONS: The indications to the ETCA should be as strict as possible. The ETCA is an effective procedure in the treatment of large clivopetrous tumors. Tumor characteristics like consistency, vascularity, encasements of vertebro-basilar vessels, bone erosion and previous surgery are also indicative. The transient postoperative facial nerve palsy and deafness should be considered as major disadvantages related to this approach.

Desmopressin stimulation test before and after pituitary surgery in patients with Cushing's disease.

OBJECTIVE: The desmopressin test has been proposed as a useful tool for the differential diagnosis of Cushing's disease. The aim of our study was to investigate, in a large series of patients with Cushing's disease, the incidence of a positive ACTH and cortisol response to desmopressin. Moreover, we repeated the test soon after surgery to verify its usefulness in the assessment of early and late surgical results. PATIENTS AND METHODS: One hundred and seven consecutive patients with Cushing's disease, 89 female and 18 male patients, with a mean age of 37.2 +/- 1.3 years, were studied. All patients, except three, repeated the test 5-6 days after surgery. Desmopressin (10 microg) was injected i.v. and blood samples were drawn 15, 30, 45 and 60 minutes thereafter. Plasma ACTH and serum cortisol were measured in duplicate by commercially available immunoassays. A positive response to desmopressin was considered to be a plasma ACTH and serum cortisol increment of at least 30% and 20% above baseline, respectively. RESULTS: Mean basal plasma ACTH level was 17.3 +/- 1.7 pmol/l and rose to a peak level of 42.7 +/- 4.9 pmol/l at 15 minutes Mean basal serum cortisol level was 574 +/- 19 nmol/l and rose to a peak level of 814 +/- 28 nmol/l at 45 minutes. ACTH and cortisol incremental changes were inversely correlated with their respective basal levels. Ninety patients (84.1%) had an ACTH and 84 patients (78.5%) had a cortisol response to desmopressin. Several clinical and demographic characteristics were not significantly different among desmopressin responders and non responders, except that basal ACTH and cortisol levels were significantly higher in desmopressin non responders (27.2 +/- 8.3 pmol/l, 781 +/- 86 nmol/l) than in desmopressin responders (15.4 +/- 1.2 pmol/l, 535 +/- 14 nmol/l). Disappearance of the ACTH and cortisol response to desmopressin after surgery occurred in 50 of 87 (57%) ACTH responders and in 57 of 81 (70.4%) cortisol responders, respectively. However, concordance between the desmopressin test and surgical outcome was not complete. Indeed, 18 patients considered in remission still showed an ACTH increase after desmopressin and, on the contrary, four patients with disappearance of the ACTH response had persistence of hypercortisolism. During follow-up monitoring, three patients, who had persistence of the ACTH response to desmopressin, relapsed 24, 38 and 54 months after surgery. CONCLUSIONS: Desmopressin administration elicits a significant rise in ACTH and cortisol levels in the majority but not all patients with Cushing's disease. There is a good, but not complete, concordance between the response to the desmopressin test and the surgical outcome. Our preliminary data show that persistence of the ACTH response to desmopressin in the early postoperative period might be associated with a higher risk of late relapse.

Endocrine inactive and gonadotroph adenomas: diagnosis and management.

Endocrine inactive pituitary adenomas represent about one quarter of all pituitary tumors. By immunocytochemistry, most of these tumors are positive for intact gonadotropins and/or their subunits. Clinical presentation is usually secondary to mass effect symptoms, such as visual disturbances, headache, and hypopituitarism. Differential diagnosis is usually accomplished by neuroradiologic studies, even though in selected cases positron emission tomography and/or single photon emission tomography may aid to distinguish pituitary adenomas from other endocrine inactive lesions, such as meningiomas and craniopharyngiomas. Surgical management is usually considered the first choice treatment for patients with endocrine inactive pituitary adenomas because it is very effective in ameliorating symptoms of chiasmal compression and headache. Radical removal of the tumor, however, is difficult to obtain because of the frequent invasiveness into the cavernous sinus. Radiation therapy diminishes the likelihood of tumor recurrence, especially in patients with demonstrable tumor remnants after surgery. Medical therapy with dopaminergic drugs, somatostatin analogs, or gonadotropin-releasing hormone agonists or antagonists causes mild reduction of tumor size in few patients and, therefore, seems to be of limited value in the therapeutic management of patients with endocrine inactive pituitary adenomas.

Proliferation index of nonfunctioning pituitary adenomas: correlations with clinical characteristics and long-term follow-up results.

OBJECTIVE: The recurrence of nonfunctioning pituitary adenomas (NFPAs) after surgical removal is common. The aim of our study was to investigate and correlate the growth fraction of NFPAs with clinical characteristics and long-term follow-up results. METHODS: Tumor specimens were obtained from 101 consecutive patients with NFPAs (48 female patients and 53 male patients; mean age, 52.0 +/- 1.5 yr). Specimens were immediately fixed in 10% buffered formalin and then embedded in paraffin. The Ki-67 antigen was assessed by immunocytochemical analysis using the monoclonal antibody MIB-1. The Ki-67 antigen labeling index (LI) was determined by counting a total of at least 1,000 neoplastic nuclei. RESULTS: The mean Ki-67 LI for the 101 patients was 2.4 +/- 0.3% (range, 0-23.0%). Only age at surgery was inversely correlated with the Ki-67 LI; sex, maximal tumor diameter, and invasiveness into the cavernous sinuses did not significantly affect the Ki-67 LI. The mean follow-up period was 39.7 +/- 2.1 months. During follow-up monitoring, 23 patients experienced tumor recurrence, after a mean period of 28.6 +/- 4.8 months. Invasiveness of the tumor on preoperative magnetic resonance imaging scans was the strongest predictor of late tumor recurrence, followed by previous pituitary surgery, younger age, and lack of postoperative radiotherapy. The Ki-67 LI had no independent prognostic value. CONCLUSION: Our study suggests that the clinical characteristics of patients with NFPAs, except for age at surgery, are not correlated with the Ki-67 LI. Moreover, the Ki-67 LI does not seem to provide independent information to identify patients at high risk for tumor recurrence.

Non-random trisomies of chromosomes 5, 8 and 12 in the prolactinoma sub-type of pituitary adenomas: conventional cytogenetics and interphase FISH study.

Specimens from 53 pituitary adenomas (PAs), including 17 NFPA, 16 PRL-, 9 ACTH-, 9 GH- and 2 TSH-secreting tumors, underwent cytogenetic analysis by the direct and short-term culture methods. Only 8 tumors (15%) appeared to have an abnormal karyotype. To increase the resolution of cytogenetic analysis, direct preparations from 31 PAs were investigated by interphase FISH with probes specific for chromosomes 5, 8, 12 and X, for which gain in pituitary tumors has been reported. Of these 31 PAs, 17 (54.8%) had an abnormal dosage of one or more of the 4 chromosomes tested. Separate or combined trisomies of chromosomes 5, 8 and 12 were found in 10/10 prolactinomas and in 4/9 NFPA, whereas the combined loss of chromosomes 5 and 8 was observed in 1/6 ACTH- and 1/6 GH-secreting PAs. Present and earlier data on 23 PAs showed that tumors with the highest frequency of abnormal karyotypes revealed by cytogenetics and/or interphase FISH were PRL (78%), followed by NFPA (26%) and GH (18%). Recurrent structural rearrangements affecting chromosomes 1, 3 and 12 were also identified in prolactinomas, which therefore appear to be the only pituitary adenoma sub-type with a defined trend of tumor-specific chromosomal changes. Cytogenetic and FISH analyses of different pituitary tumor sub-types indicate that they may harbour genetically distinct lesions.

Determination of the proliferation and apoptotic index in adrenocorticotropin-secreting pituitary tumors : comparison between micro- and macroadenomas.

We investigated the growth fraction and cell loss fraction in a large group of patients with Cushing's disease subdivided according to tumor size. Fifty-one patients, 8 males and 43 females, aged 12 through 61 years (mean age 34.6 +/- 1.5 years), were studied. Thirty-six patients had a microadenoma and the remaining 15 a macroadenoma. Immunohistochemical analysis was performed on paraffin-embedded material using a monoclonal antibody (MIB-1) directed against a proliferation-associated nuclear antigen, Ki-67, to measure the growth fraction. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method, using a monoclonal antibody recognizing areas of DNA fragmentation. Ki-67 labeling index and apoptosis were counted on separate slides in at least 1000 evaluable cells. Patients with a macroadenoma had a significantly higher value of Ki-67 index (9.3 +/- 2.7%) than patients with microadenoma (2.8 +/- 0.5%; P < 0.002), whereas the apoptotic index was not significantly different in the two groups (1.7 +/- 0.8% in macroadenomas versus 0.8 +/- 0.3% in microadenomas). Our study shows that ACTH-secreting macroadenomas are characterized by a higher cell growth fraction than microadenomas, whereas the cell loss fraction is not different. A high proliferation rate seems to play a major role in determining the progression from small to large pituitary tumors in Cushing's disease.

Surgical management of thyrotropin-secreting pituitary adenomas.

The reported cases of hyperthyroidism due to a TSH-secreting pituitary adenoma have steadily increased in previous years; however, information about the results and long term outcome after pituitary surgery is scanty. Twenty-four patients with a TSH-secreting adenoma underwent pituitary surgery at our department in the last 15 years. Hypersecretion of other pituitary hormones was diagnosed in 7 patients. Three patients were euthyroid at the time of surgery because of previous ablative thyroid therapies. The success rate of surgery strictly depends on the criteria used. Normalization of elevated FT3 and FT4 levels occurred in 17 of the 21 patients with preoperative hyperthyroidism: however, only those with early postoperative undetectable TSH level (12 cases) had no recurrence of disease during follow-up and no residual tumor tissue on postoperative MRI, whereas recurrence of hyperthyroidism occurred in 3 of the 5 patients without postoperative TSH inhibition. All 3 euthyroid patients had a subtotal removal of the tumor, as judged by postoperative MRI. Surgical removal is the therapy of choice of TSH-secreting adenomas, whereas radiotherapy and medical treatment with somatostatin analogues are usually reserved to patients with incomplete tumor removal. A thorough postoperative evaluation is necessary to discriminate between complete and partial remission of disease.

Usefulness of markers of cell proliferation in the management of pituitary adenomas.

1. Pituitary adenomas are benign and slow-growing tumours whose clinical manifestations depend mainly on the secretory activity of the adenomatous cells. Except for prolactinomas, surgical removal of the tumour is the therapy of choice. 2. Despite extensive research on their clinical and pathophysiological aspects, few studies have explored the oncological characteristics of these rare lesions. Among these, the growth fraction of pituitary adenomas has been determined by different methods, of which the most useful are those performed in archival material. 3. The results reported in the literature show that adrenocorticotropic hormone-secreting tumours seem to be characterized by a higher proliferation index than the other types of pituitary adenomas, despite their usually small tumour size. 4. In small series of patients radiotherapy and medical treatment with dopaminergic drugs and octreotide were associated with a lower proliferation index than untreated tumours. Tumour size was not correlated with the growth fraction of the pituitary tumours, whereas invasiveness was correlated in most studies. 5. From a clinical point of view, however, the more promising utilization of the proliferation index seems to be in predicting the potential of recurrence of the tumour, thus allowing a more rational approach to follow-up and further treatment of patients with pituitary adenomas.

[Study of aspecific bronchial reactivity in subjects with allergic diseases and in bronchial asthma patients]. / Studio sulla reattività bronchiale aspecifica in soggetti allergopatici ed in pazienti affetti da asma bronchiale.

A study has been carried out on the effect of inhalatory metacholine in a series of 29 subjects, 10 of whom were normal, 11 asthmatic and 8 non-asthmatic allergopathics. Respiratory alterations were studied using 8 functional parameters designed to highlight the behaviour of the major and minor airways respectively. Metacholine at very high doses was studied in normal subjects, demonstrating its lack of effect at respiratory level. The functional behaviour of the allergopathics proved to differ from that of the asthmatics and was characterized essentially by a diminution in low expiratory flows unassociated with clinical signs or functional involvement of the main airways. The meaning of the results and their possible clinical importance are discussed.