Dysregulated Genes and Signaling Pathways in the Formation and Rupture of Intracranial Aneurysm.

Intracranial aneurysm (IA) has the potential to rupture. Despite scientific advances, we are still not in a position to screen patients for IA and identify those at risk of rupture. It is critical to comprehend the molecular basis of disease to facilitate the development of novel diagnostic strategies. We used transcriptomics to identify the dysregulated genes and understand their role in the disease biology. In particular, RNA-Seq was performed in tissue samples of controls, unruptured IA, and ruptured IA. Dysregulated genes (DGs) were identified and analyzed to understand the functional aspects of molecules. Subsequently, candidate genes were validated at both transcript and protein level. There were 314 DGs in patients with unruptured IA when compared to control samples. Out of these, SPARC and OSM were validated as candidate molecules in unruptured IA. PI3K-AKT signaling pathway was found to be an important pathway for the formation of IA. Similarly, 301 DGs were identified in the samples of ruptured IA when compared with unruptured IAs. CTSL was found to be a key candidate molecule which along with Hippo signaling pathway may be involved in the rupture of IA. We conclude that activation of PI3K-AKT signaling pathway by OSM along with up-regulation of SPARC is important for the formation of IA. Further, regulation of Hippo pathway through PI3K-AKT signaling results in the down-regulation of YAP1 gene. This along with up-regulation of CTSL leads to further weakening of aneurysm wall and its subsequent rupture.

Intracranial Germinoma Masquerading as Secondary Granulomatous Hypophysitis: A Case Report and Review of Literature.

Germinomas are highly immunogenic tumors eliciting a strong peri-tumoral immune response that can spillover into the surrounding healthy tissues. This phenomenon can also occur in intracranial germinomas, manifesting as secondary hypophysitis. Herein, we report a case of 12-year-old-girl presenting with polyuria and polydispsia. She had central diabetes insipidus (CDI) and panhypopituitarism. Imaging revealed a sellar-suprasellar mass with infundibular stalk thickening. Transphenoidal biopsy revealed epithelioid granulomas with immunostaining negative for germinomatous cells. Other causes of hypophysitis were ruled out. Accordingly, she was diagnosed as primary granulomatous hypophysitis and treated with high-dose corticosteroids. Three years later she again presented with headache, vomiting and diminution of vision. Imaging showed a heterogeneous, solid-cystic peripheral rim-enhancing lesion at the same location with involvement of hypothalamus, ependyma and pineal gland. Cerebrospinal fluid beta-human chorionic gonadotropin was markedly elevated, confirming the diagnosis of an intracranial germ cell tumor. She was started on chemotherapy; however, she succumbed to febrile neutropenia. We performed a literature search and found 18 anecdotal cases of secondary hypophysitis associated with intracranial germinomas. There was a slight male preponderance (male:female 5:4). Two-thirds of the cases were below 18 years of age. Polyuria was the most common presenting manifestation (83%). CDI and panhypopituitarism were seen in 89 and 78% cases, respectively. Imaging evidence of pituitary stalk thickening was seen in 12 cases (67%), while pituitary enlargement and/or sellar mass were reported in 11 cases (61%). Pineal involvement was extremely rare, being reported in only 1 case, implying the predilection of suprasellar (rather than pineal) germinomas in causing secondary hypophysitis. Histologically, 82% had lymphocytic hypophysitis, while 18% had granulomatous hypophysitis. Initially, the diagnosis of germinoma was missed in 60% of the cases who were wrongly treated with corticosteroids. To conclude, physicians should make it a dictum that all children and adolescents presenting with CDI and pituitary stalk thickening should be rigorously screened for an underlying intracranial germinoma before labeling them as primary hypophysitis.

Glucose-dependent Insulinotropic Polypeptide (GIP) Resistance and ß-cell Dysfunction Contribute to Hyperglycaemia in Acromegaly.

Impaired insulin sensitivity (IS) and ß-cell dysfunction result in hyperglycaemia in patients of acromegaly. However, alterations in incretins and their impact on glucose-insulin homeostasis in these patients still remain elusive. Twenty patients of active acromegaly (10 each, with and without diabetes) underwent hyperinsulinemic euglycaemic clamp and mixed meal test, before and after surgery, to measure indices of IS, ß-cell function, GIP, GLP-1 and glucagon response. Immunohistochemistry (IHC) for GIP and GLP-1 was also done on intestinal biopsies of all acromegalics and healthy controls. Patients of acromegaly, irrespective of presence or absence of hyperglycaemia, had similar degree of insulin resistance, however patients with diabetes exhibited hyperglucagonemia, and compromised ß-cell function despite significantly higher GIP levels. After surgery, indices of IS improved, GIP and glucagon levels decreased significantly in both the groups, while there was no significant change in indices of ß-cell function in those with hyperglycaemia. IHC positivity for GIP, but not GLP-1, staining cells in duodenum and colon was significantly lower in acromegalics with diabetes as compared to healthy controls possibly because of high K-cell turnover. Chronic GH excess induces an equipoise insulin resistance in patients of acromegaly irrespective of their glycaemic status. Dysglycaemia in these patients is an outcome of ß-cell dysfunction consequent to GIP resistance and hyperglucagonemia.

Imatinib Inhibits GH Secretion From Somatotropinomas.

Background: Imatinib, a tyrosine kinase inhibitor, causes growth failure in children with chronic myeloid leukemia probably by targeting the growth hormone (GH)/insulin like growth factor-1 (IGF-1) axis. We aim to explore the imatinib targets expression in pituitary adenomas and study the effect of imatinib on GH secretion in somatotropinoma cells and GH3 cell line. Materials and Methods: The expression pattern of imatinib's targets (c-kit, VEGF, and PDGFR-α/ß) was studied using immunohistochemistry and immunoblotting 157 giant (≥4 cm) pituitary adenomas (121 non-functioning pituitary adenomas, 32 somatotropinomas, and four prolactinomas) and compared to normal pituitary (n = 4) obtained at autopsy. The effect imatinib on GH secretion, cell viability, immunohistochemistry, electron microscopy, and apoptosis was studied in primary culture of human somatotropinomas (n = 20) and in rat somato-mammotroph GH3 cell-line. A receptor tyrosine kinase array was applied to human samples to identify altered pathways. Results: Somatotropinomas showed significantly higher immunopositivity for c-kit and platelet-derived growth factor receptor-ß (PDGFR-ß; P < 0.009 and P < 0.001, respectively), while staining for platelet-derived growth factor receptor-α (PDGFR-α) and vascular endothelial growth factor (VEGF) revealed a weaker expression (P < 0.001) compared to normal pituitary. Imatinib inhibited GH secretion from both primary culture (P < 0.01) and GH3 cells (P < 0.001), while it did not affect cell viability and apoptosis. The receptor tyrosine kinase array showed that imatinib inhibits GH signaling via PDGFR-ß pathway. Conclusion: Imatinib inhibits GH secretion in somatotropinoma cells without affecting cell viability and may be used as an adjunct therapy for treating GH secreting pituitary adenomas.

Impact of transsphenoidal surgery on asymptomatic cardiomyopathy in patients with acromegaly. A single-blinded study.

BACKGROUND: Patients with acromegaly have 2-3 times the expected mortality rates primarily due to cardiovascular risks. Echocardiographic studies showing improvement of cardiac function following transsphenoidal surgery (TSS) are limited. MATERIALS AND METHODS: All patients with acromegaly underwent preoperative echocardiography and tissue Doppler (Philips i33, 3D ECHO) for assessment of cardiac indices. In the prospective group of patients, echocardiography was repeated after 6 months of surgery. In the retrospective group of patients, echocardiography was performed for left ventricular diastolic dysfunction and ejection fraction. Biochemical cure was confirmed at least after 6 months by glucose-suppressed plasma growth hormone (GH) concentrations (GH-OGTT) of less than 0.4 ng/ml, random GH of less than 1 ng/ml, and normal age-corrected insulin-like growth factor (IGF-1) values. RESULTS: In the prospective group (38 patients), there was a significant decrease in the left ventricular mass (LVM) and LVM index (LVMI) in patients who were cured as well as in patients with postoperative growth hormone (GH) 1-5 ng/ml. In the prospective group, LVMI completely normalized in 2 and a new-onset deterioration was detected in 1 patient (who was not cured) and improved in 8 others. Left ventricular systolic function was abnormal at baseline in 18 (47.3%) patients, which normalized in 11 (61.1%) patients postoperatively, and in 7 patients, it improved significantly although it did not normalize completely. There was also a significant improvement in the left ventricular ejection fraction (P = 0.01). Post TSS, in patients with GH-OGTT >5 ng/ml, there was no significant decrease in the LVM, LVMI and ejection fraction (EF). In the retrospective group, 62 patients were analyzed for a change in the EF with a mean follow-up of 20.3 months. There was a significant improvement in the left ventricular EF in patients who were cured (P < 0.001). CONCLUSION: Reduction in growth hormone levels and insulin-like growth factor type 1 can decrease the LVM and LVMI, which directly or indirectly contributes to the improvement in diastolic as well as systolic function and probably mortality.

Acromegaly with hypophosphataemia: McCune-Albright syndrome.

A 38-year-old man presented with excessive height gain and progressive enlargement of the extremities since childhood. This was compounded by lower limb deformities over the past 5 years. On examination, his height was 196 cm, he had macroglossia, acral enlargement, seborrhoea, hyperhidrosis-suggesting acrogigantism. He had facial asymmetry, wind-swept deformity of lower limbs and a café-au-lait macule over his trunk. Investigations revealed normal-sized pituitary gland with dysplastic cranial bones. Isotope bone scintigraphy was suggestive of polyostotic fibrous dysplasia. A diagnosis of McCune-Albright syndrome was made and trans-sphenoidal hypophysectomy was undertaken. He had persistent hypophosphataemia. Tubular reabsorption of phosphate adjusted for glomerular filtration rate was low and serum FGF-23 level was high. Ga-DOTATATE scintigraphy showed somatostatin-receptor expression in all the dysplastic lesions. FGF-23 produced by the bony lesions could counteract the phosphate-retaining effect of GH excess resulting in hypophosphataemia, which further worsened following hypophysectomy.

Primary Intracranial Extraskeletal Mesenchymal Chondrosarcoma: Clinical Mimicry as Glomus Jugulare.

BACKGROUND: Extraskeletal mesenchymal chondrosarcoma (ESMCS) is an unusual pathologic variant of chondrosarcoma. There are no specific clinicoradiographic parameters to distinguish it from other intracranial pathologies. The diagnosis can be established only on the basis of histopathology, which may pose significant challenges in certain unusual locations. PURPOSE: In this case, we discuss the pitfalls in diagnosis, management, and major characteristics of ESMCS with a review of current literature. METHODS AND RESULTS: A 47-year-old female patient presented with a jugular foramen tumor which was misdiagnosed as glomus jugulare tumor for which she received primary gamma knife radiosurgery at 2 instances. But unfortunately, the patient died because of the increase in size of the lesion associated with necrosis. Autopsy analysis revealed a highly cellular tumor, rich in sarcomatous cells, and well-differentiated cartilages consistent with ESMCS. CONCLUSION: A definite preoperative diagnosis of ESMCS is crucial though difficult especially when located at complex sites like jugular foramen and clinicoradiological mimicry. The most crucial step in the management of ESMCS is accurate diagnosis with critical evaluation of clinical, radiological, and histopathological parameters and realization of highly variable clinical course of the disease.

Dose fractionated gamma knife radiosurgery for large arteriovenous malformations on daily or alternate day schedule outside the linear quadratic model: Proof of concept and early results. A substitute to volume fractionation.

BACKGROUND: To evaluate the feasibility, safety and efficacy of dose fractionated gamma knife radiosurgery (DFGKRS) on a daily schedule beyond the linear quadratic (LQ) model, for large volume arteriovenous malformations (AVMs). MATERIAL AND METHODS: Between 2012-16, 14 patients of large AVMs (median volume 26.5 cc) unsuitable for surgery or embolization were treated in 2-3 of DFGKRS sessions. The Leksell G frame was kept in situ during the whole procedure. 86% (n = 12) patients had radiologic evidence of bleed, and 43% (n = 6) had presented with a history of seizures. 57% (n = 8) patients received a daily treatment for 3 days and 43% (n = 6) were on an alternate day (2 fractions) regimen. The marginal dose was split into 2 or 3 fractions of the ideal prescription dose of a single fraction of 23-25 Gy. RESULTS: The median follow up period was 35.6 months (8-57 months). In the three-fraction scheme, the marginal dose ranged from 8.9-11.5 Gy, while in the two-fraction scheme, the marginal dose ranged from 11.3-15 Gy at 50% per fraction. Headache (43%, n = 6) was the most common early postoperative complication, which was controlled with short course steroids. Follow up evaluation of at least three years was achieved in seven patients, who have shown complete nidus obliteration in 43% patients while the obliteration has been in the range of 50-99% in rest of the patients. Overall, there was a 67.8% reduction in the AVM volume at 3 years. Nidus obliteration at 3 years showed a significant rank order correlation with the cumulative prescription dose (p 0.95, P value 0.01), with attainment of near-total (more than 95%) obliteration rates beyond 29 Gy of the cumulative prescription dose. No patient receiving a cumulative prescription dose of less than 31 Gy had any severe adverse reaction. In co-variate adjusted ordinal regression, only the cumulative prescription dose had a significant correlation with common terminology criteria for adverse events (CTCAE) severity (P value 0.04), independent of age, AVM volume, number of fractions and volume of brain receiving atleast 8 Gy of radiation. CONCLUSION: DFGKRS is feasible for large AVMs with a fair nidus obliteration rate and acceptable toxicity. Cumulative prescription dose seems to be the most significant independent predictor for outcome following DFGKRS with 29-30 Gy resulting in a fair nidus obliteration with least adverse events.

Bevacizumab for Radiation Induced Optic Neuritis Among Aggressive Residual/Recurrent Suprasellar Tumors: More Than a Mere Antineoplastic Effect.

BACKGROUND: Angiogenesis and vascular endothelial growth factor (VEGF) have recently been implicated in animal and clinical models of radiation-induced optic nerve, retinal, and brain necrosis. Although there are isolated case reports of anti-VEGF therapy with bevacizumab for management of radiation-induced brain necrosis, there are little data defining its role in radiation-induced optic nerve damage. PATIENTS AND METHODS: This study included patients with a sellar-suprasellar tumor who underwent intensity-modulated or Gamma Knife radiotherapy and developed radiation-induced optic neuritis (RION) refractory to 3 weeks of glucocorticoid therapy who received bevacizumab 5 mg/kg intravenously as initial dose, followed by subsequent doses of 10 mg/kg. RESULTS: Here we report 3 patients with sellar-suprasellar lesions undergoing conventional radiation therapy (2 cases) or Gamma Knife surgery (1 case) who had benefitted from anti-VEGF therapy following radiation-induced optic nerve damage. CONCLUSIONS: Early bevacizumab therapy in steroid-refractory RION shows gratifying results.

Two Cases of Esophageal Injury Following Anterior Cervical Discectomy and Fusion: One Overt and One Covert.

Esophageal perforation is a dreaded complication of anterior cervical spinal surgery. A 52-year-old diabetic man had undergone a surgery for a C6-C7 disc prolapse and developed spiking fever with chills and rigor on the 7th postoperative day. No cause could be found out but a CT scan of thorax done in the course of investigations revealed pneumomediastimum. The patient succumbed on the 10th day after surgery. Autopsy revealed the cause of death to be mediastinitis following iatrogenic esophageal perforation. A second patient, 53 years of age, following surgery for C5-C6 disc prolapse and developed intractable dysphagia. Later, fever and purulent discharge from the wound prompted an MRI showing prevertebral collection extending to the superior mediastinum. Presuming only wound infection, debridement and implant removal was done. However persistent serous discharge from the wound revealed an esophageal injury. Late diagnosis precluded primary repair. With conservative treatment, the fistula finally closed after 42 days. Postoperative dysphagia, a common complaint following surgery, may not always be present in cases of esophageal injury. A high index of suspicion is required for diagnosing and initiating treatment for esophageal perforation before complications set in.

Visual outcome in 2000 eyes following microscopic transsphenoidal surgery for pituitary adenomas: Protracted blindness should not be a deterrent.

OBJECTIVE: To study the visual outcome after surgery for pituitary adenomas with visual deficits. MATERIALS AND METHODS: All patients with pituitary adenoma, who presented from 2003-2014 in a tertiary care institute, were included in the study. Surgical outcome was measured in terms of difference in visual acuity, visual fields and optic fundus parameters documented before surgery, immediate post-operatively and at the third, and twelfth months following surgery. RESULTS: At the initial presentation, visual involvement was seen in 87.2% patients. One year after surgery, 93.2% patients having abnormal vision had improvement in visual acuity and visual fields; whereas visual parameters were static in 5.2%. Visual deterioration occurred only in 1.3% patients. Moreover, five-percent of those who did not even have perception of light at presentation experienced significant improvement in vision after surgery. The shorter the duration of visual symptoms, the more was the percentage of patients having faster recovery in the early postoperative period. CONCLUSION: Post-operative visual outcome was directly proportional to the pre-operative visual acuity. Though the visual outcome was good in the long run irrespective of the duration of symptoms, the speed of recovery was proportional to the duration of visual deficits. However, presence of long-standing visual symptoms should not deter us to subject the patient to surgery. Even patients who are completely visually impaired for years should be subjected to surgery as early as feasible.

Unusual cause of profound weight loss in a young woman.

A 27-year-old woman presented with anorexia, weight loss and psychiatric symptoms for the past 4 years. She did not have history of headache, visual disturbances or symptoms of raised intracranial pressure. She was sarcopenic with body mass index of 10.16 kg/m2Her systemic examination was normal except for temporal hemianopia suggesting a sellar/suprasellar lesion. Hormonal evaluation revealed pan-hypopituitarism with central diabetes insipidus. Subsequent neuroimaging revealed sellar-suprasellar mass lesion with intense contrast enhancement and leptomeningeal metastases. Cerebrospinal fluid analysis showed elevated ß human chorionic gonadotropin and the presence of syncytiotrophoblast germ cells. Histopathology from the mass lesion confirmed the diagnosis of germinoma. Immunohistochemistry of the tumour tissue was positive for c-kit and placental alkaline phosphatise. She received a combination of chemotherapy with craniospinal irradiation. Significant weight loss in a young woman may not always be an eating disorder like anorexia nervosa albeit more common than germ cell tumour.

Pushing the limits of the Leksell stereotactic frame for spinal lesions up to C3: fixation at the maxilla.

BACKGROUND: Spinal radiosurgery is not considered in the domain of traditional Gamma Knife radiosurgery (GKRS) setup. The major obstacles in GKRS for upper cervical spine lesions remain in difficulty of frame fixation, avoiding collision and maintaining the integrity of the relative position of the lesion from image acquisition to treatment. METHODOLOGY: The supraorbital margin remains the standard lowest fixation point for Leksell stereotactic frame. We describe fixation at the maxilla to target and treat upper cervical spine lesions (up to C3 vertebra) with measures to ensure cervical immobilisation and precision of the GKRS treatment. RESULTS: We have treated two patients at the upper cervical spine up to C3 vertebra by fixing anterior pillars of the Leksell stereotactic frame at the maxilla. To ensure cervical immobilisation and precision of treatment, the neck was immobilised with a Philadelphia collar. The relative position between the head and sternum with the couch from image acquisition to the radiation delivery was kept constant. Docking angle was kept neutral (90 degrees) throughout the treatment (from image acquisition to actual treatment). CONCLUSIONS: The maxilla is a potential alternative for stereotactic frame fixation. Measures to ensure cervical immobilisation with lower-down frame position permits treatment of lesions as low as C3 vertebra.

Can immediate postoperative random growth hormone levels predict long-term cure in patients with acromegaly?

BACKGROUND: Growth hormone (GH) levels following oral glucose tolerance test (OGTT) at 12 weeks or later after surgery have been accepted as the most reliable parameter for defining remission and/or cure in patients with acromegaly. However, the role of random GH in predicting remission in the immediate postoperative period using modern criteria is not known. This study was undertaken to evaluate the role of random GH levels in first 5 postoperative days as an early predictive tool for long-term remission of patients with acromegaly following transsphenoidal pituitary surgery (TSS). PATIENTS AND METHODS: Seventy-five consecutive acromegaly patients with at least three postoperative OGTT values at 3, 6, and 12 months of follow-up were included in the study. GH levels were measured just before surgery, in the immediate postoperative period, at 6 h and on day 1 to day 5 after surgery. Remission was defined as normal age-specific insulin-like growth factor-1 and either basal fasting GH <1 ng/ml or a nadir GH following OGTT <0 .4 ng/ml at 3 months of surgery. RESULTS: Of the 75 patients with acromegaly who underwent TSS, long-term remission was achieved in 42 (56%) patients. GH values ≤1.55 ng/ml at 6 h of surgery showed the highest predictive power for long-term remission, with a sensitivity of 81.2% and a specificity of 83.3%. The duration of disease and tumor volume had no effect on the 6 h GH value-related prediction of cure. CONCLUSION: Early postoperative GH values may be used to predict long-term cure. A value of ≤1.5 ng/ml at 6 h following surgery may predict long-term cure in two-thirds of the patients with acromegaly who undergo TSS.

Clinical profile and outcome of patients with acromegaly according to the 2014 consensus guidelines: Impact of a multi-disciplinary team.

AIM: The diagnosis and treatment of acromegaly, a rare and possibly curable disease, has undergone a paradigm shift in the past few decades. Our aim was to study the changing trends in clinical presentation, management and outcome of the disease in the last fifteen years. METHODOLOGY: 271 consecutive patients with acromegaly treated at the Departments of Endocrinology and Neurosurgery, PGIMER, Chandigarh, between 2000 and 2014, were included in the study. Clinical and hormonal profiles, comorbidities, treatment modalities, outcome and mortality data were evaluated. The cure rate was assessed according to the present consensus criteria. RESULTS: The gender distribution was equal with the mean age (±SD) of 37.1 ± 12.3 years at diagnosis. The average lag period to diagnosis was 4.7 ± 4.2 years. The most common presenting manifestations were acral enlargement and headache followed by visual deficits. The overall mortality rate was 5%, with the perioperative mortality being 1.5%. The most prevalent comorbidities in our series were hypertension (17.7%), diabetes mellitus (16.2%), arthropathy (11.8%) and obstructive sleep apnea (10.3%). Overall, 2 patients in our series suffered from extra-pituitary neoplasms and 12 patients had apoplexy as the presenting manifestation. As per the present consensus criteria, cure rate in our series was 28.5%. The cure rate was only 7.9% when many surgeons were operating. It increased to 25.5% when surgeries were being performed by one surgeon exclusively; and, when a sub-specialty clinic exclusively for pituitary diseases was set up, the cure rates improved upto 56%. CONCLUSION: Acromegaly has wide-ranging manifestations from acral enlargement to altered sensorium; incidental diagnosis was not prevalent in our series. Majority of the cases were due to the presence of a pituitary macroadenoma. Better cure rate can be achieved only when a dedicated group of multi-disciplinary team is involved.