Molecular Basis of Cerebral Vasospasm: What Can We Learn from Transcriptome and Temporal Gene Expression Profiling in Intracranial Aneurysm?

Cerebral vasospasm (CV) is a significant complication following aneurysmal subarachnoid hemorrhage (aSAH), and lacks a comprehensive molecular understanding. Given the temporal trajectory of intracranial aneurysm (IA) formation, its rupture, and development of CV, altered gene expression might be a molecular substrate that runs through these clinical events, influencing both disease inception and progression. Utilizing RNA-Seq, we analyzed tissue samples from ruptured IAs with and without vasospasm to identify the dysregulated genes. In addition, temporal gene expression analysis was conducted. We identified seven dysregulated genes in patients with ruptured IA with vasospasm when compared with those without vasospasm. We found 192 common genes when the samples of each clinical subset of patients with IA, that is, unruptured aneurysm, ruptured aneurysm without vasospasm, and ruptured aneurysm with vasospasm, were compared with control samples. Among these common genes, TNFSF13B, PLAUR, OSM, and LAMB3 displayed temporal expression (progressive increase) with the pathological progression of disease that is formation of aneurysm, its rupture, and consequently the development of vasospasm. We validated the temporal gene expression pattern of OSM at both the transcript and protein levels and OSM emerges as a crucial gene implicated in the pathological progression of disease. In addition, RSAD2 and ATP1A2 appear to be pivotal genes for CV development. To the best of our knowledge, this is the first study to compare the transcriptome of aneurysmal tissue samples of aSAH patients with and without CV. The findings collectively provide new insights on the molecular basis of IA and CV and new leads for translational research.

Extended Unifrontal craniotomy for midline anterior cranial fossa meningiomas: A better shot at preservation of neurovascular structures.

Numerous surgical approaches have been described for the resection of anterior cranial fossa meningioma. The common problems associated with these approaches are excessive brain retraction, injury to neurovascular structures, transection of superior sagittal sinus (SSS), and a higher risk of new-onset anosmia. The authors describe a unilateral extended frontal approach with the aim to minimize brain handling without the need for SSS transection and possibly better olfaction preservation. METHODS: Thirteen patients with anterior cranial fossa meningioma were operated on using the novel technique of unilateral extended frontal skull base approach. The clinical presentation, radiological studies, intraoperative findings, and outcome at follow-up were recorded. RESULTS: Gross total tumor resection could be achieved in 12 out of 13 patients. At least one of the olfactory tracts could be anatomically preserved in all patients, and superior sagittal sinus was preserved in all patients. Functional olfaction preservation was achieved in 8 patients. No patient developed new-onset anosmia. CONCLUSIONS: The extended unilateral frontal approach is a viable and reliable alternative for extended bifrontal technique for the resection of large midline anterior cranial fossa meningiomas with avoidance of SSS ligation, decreased brain handling with better olfaction preservation while achieving comparable tumor resection and acceptable cosmetic outcomes.

Isolated embryonal rhabdomyosarcoma of the anterior petrous bone in a young child: Focusing on the intra-operative diagnosis and differentials.

OBJECTIVE: Rhabdomyosarcoma is a common soft tissue tumor, but isolated involvement of anterior portion of petrous bone is exceedingly rare. Here, we present a case of embryonal rhabdomyosarcoma involving the anterior petrous without involvement of the mastoid and middle ear. PATIENT: A 6-year-old boy presented with a progressive right side lower motor neuron facial paresis for 1-month duration along with headache and recurrent vomiting episodes. Radiology showed a contrast-enhancing lesion involving the right petrous apex. He underwent craniotomy and excision of the lesion. Based on the frozen section, a diagnosis of rhabdomyosarcoma was rendered, and gross total resection could be achieved. Postoperative course was uneventful. CONCLUSION: Isolated petrous bone involvement of embryonal rhabdomyosarcoma is a rare presentation. Intra-operative frozen section plays a key role in decision making regarding the extent of excision. Hence, a prompt and accurate diagnosis is essential in managing these cases.

Suprasellar masquerader: Chordoid glioma.

BACKGROUND: Chordoid glioma is a rare well-circumscribed glial neoplasm arising in adults and predominantly affects females. Tanycytes of the third ventricle have been proposed as the cell of origin owing to its location. It is characterized by chordoid features with myxoid and inflammatory stroma and recurrent PRKCA p.D463H missense mutation. CASE REPORT: We present two cases (30-year-old female and 45-year-old male) with similar complaints of behavioral change and headache. Midline suprasellar homogeneously enhancing mass was seen on contrast-enhanced magnetic resonance imaging. Histopathology and immunohistochemistry was characteristic of chordoid glioma with cords and clusters of epithelioid cells arranged in a solid pattern. There were variable amounts of myxoid stroma and lymphoplasmacytic infiltrate. No mitosis, necrosis, or brain invasion was noted. The cells expressed strong diffuse positivity for glial fibrillary acid protein (GFAP) and weak nuclear thyroid transcription factor (TTF-1). Epithelial membrane antigen (EMA)and brachyury were negative. Subsequently, the lady underwent gross total excision and died soon after the operation. The male patient received radiotherapy and is currently doing well after 6 months of follow-up. CONCLUSION: The rare occurrence as well as the radiological and morphological overlaps in chordoid gliomas make them a true masquerader. Combination of GFAP and TTF-1 in the immunohistochemical panel can be useful in differential diagnosis. Mainstay of treatment is complete surgical excision, with adjuvant radiotherapy becoming increasingly important.

Immunohistochemical Surrogates for Molecular Stratification in Medulloblastoma.

BACKGROUND: The WHO classification of central nervous system neoplasms (2016) recognized 4 histologic variants and genetically defined molecular subgroups within medulloblastoma (MB). Further, in the 2021 classification, new subtypes have been provisionally added within the existing subgroups reflecting the biological diversity. YAP1, GAB1, and ß-catenin were conventionally accepted as surrogate markers to identify these genetic subgroups. OBJECTIVES: We aimed to stratify MB into molecular subgroups using 3 immunohistochemical markers. TP53 mutation was also assessed in Wingless (WNT), and Sonic Hedgehog (SHH) subgroups. Demographic profiles, imaging details, and survival outcomes were compared within these molecular subgroups. PATIENTS AND METHODS: Our cohort included 164 MB cases diagnosed over the last 10 years. The histologic variants were identified on histology, and tumors were molecularly stratified using YAP1, GAB1, and ß-catenin. Further, TP53 mutation was assessed using immunohistochemical in WNT and SHH subgroups. The clinical details and survival outcomes were retrieved from the records, and the mentioned correlates were evaluated statistically. RESULTS: The age ranged from 1 to 52 years with M:F ratio of 2:1. Group 3/group 4 constituted the majority (48.4%), followed by SHH (45.9%) and WNT subgroups (5.7%). Desmoplastic/nodular and MB with extensive nodularity had the best survival, whereas large cell/anaplastic had the worst. The follow-up period ranged from 1 to 129 months. The best outcome was observed for the WNT subgroup, followed by the SHH subgroup; group 3/group 4 had the worst. Among the SHH subgroup, TP53 mutant tumors had a significantly poorer outcome compared with SHH-TP53 wildtype. CONCLUSIONS: Molecular stratification significantly contributes to prognostication, and a panel of 3 antibodies is helpful in stratifying MB into its subgroups in centers where access to advanced molecular testing is limited. Our study reinforces the efficacy of incorporating this cost-effective, minimal panel into routine practice for stratification. Further, we propose a 3-risk stratification grouping, incorporating morphology and molecular markers.

Deceptive Appearances - Spastic Paretic Hemifacial Contractures in Cases of Seventh Nerve Involvement 'Inside' and 'Outside' the Brainstem.

Spastic paretic hemifacial contracture (SPHC) is a rare clinical phenomenon characterized by facial weakness and simultaneous well-sustained contraction of the unilateral half of the face, mimicking a paresis of the normal contralateral side on casual inspection. We present three cases with such phenomenon and have postulated the underlying mechanisms. One patient had intrinsic brainstem glioma, and the others were operated for extra-axial lesions compressing the pons. The former presented with SPHC, whereas the latter two gradually developed this phenomenon following postoperative facial paresis. This condition is possibly due to denervation hyper-excitability of the facial supranuclear pathway or an aberrant regeneration secondary to nerve injury leading to functional facial-nerve nuclear reorganization. SPHC occurrence is not limited to intra-axial lesions but can also be seen after partial injury to the facial nerve beyond its exit from the brainstem.

A Novel Pedicle Screw Design with Variable Thread Geometry: Biomechanical Cadaveric Study with Finite Element Analysis.

BACKGROUND: Pedicle screw fixation provides one of the most stable spinal constructs. Their designs together with osseous characteristics have been known to influence the screw-bone interplay during surgical maneuvers and thereafter the fusion process. Various technical modifications to enhance screw performance have been suggested. This study evaluated the pull-out strength and axial stiffness of a novel pedicle screw design with variable thread geometry and pitch. METHODS: The newly designed triple threaded pedicle screw is tapered, and has unique out-turned flanges to hold the cancellous bone and a finer pitch at its distal and proximal end to engage the cortical bone. Five lumbar and 4 lower thoracic cadaveric vertebrae were divided into hemivertebrae. A standard cancellous pedicle screw and the newly designed pedicle screw were inserted into each hemivertebra. Axial stiffness and peak pull-out force between the screw types were compared; a finite element analysis was also performed to additionally compare the pull out under toggle forces. RESULTS: In cadaveric study, the axial stiffness of the new screw was significantly better than that of the standard screw. However, the peak load between the screws was not statistically different. Finite element analyses suggested lesser stress at bone-implant interface for the new screw along with better axial stiffness under both co-axial and toggle forces. CONCLUSIONS: Our novel pedicle screw design with variable thread geometry demonstrates greater axial stiffness compared with the standard screws, and therefore is likely to withstand a greater surgical manipulation.

Technique of C2 Nerve Root Preservation in the Presence of Anomalous Vertebral Artery in Atlantoaxial Operations.

While accessing the C1-C2 joint during posterior atlantoaxial fixation, the C2 nerve root along with its perineural venous plexus remains an obstacle for a panoramic visualization of the entry point of the C1 lateral mass and joint preparation. Therefore, many surgeons frequently advocate its intentional sectioning during this approach, with no related major complications.1,2 However, this sectioning has at times been associated with symptoms such as hypoesthesia, numbness, dysesthesia, and neuropathic ulcers.3 Thus C2 nerve root preservation during posterior approach for atlantoaxial dislocation (AAD) could potentially avoid such consequences.4 Its preservation has been described for AAD cases with relatively normal C1-C2 joint anatomy with no osseovascular abnormalities.2 In contrast, attempt at C2 nerve root preservation in patients with congenital AAD harboring bony and vascular anomalies poses a greater challenge owing to a restricted operative space and the potential for perineural venous bleeding during dissection. This is more so for young neurosurgeons in the initial part of their learning curve. Video 1 details the technique of C2 nerve root dissection and preservation in a case of congenital AAD with an anomalous vertebral artery (VA). Computed tomography (CT) of this 30-year-old male patient with spastic quadriparesis showed AAD/basilar invagination with an assimilated C1-arch and right anomalous VA on CT angiography. He underwent C1-C2 joint manipulation and short-segment fixation. At 1-year follow-up, the patient's limb weakness had improved and CT showed good bony fusion. The salient operative steps involve gentle teasing and dissection of perineural soft tissues above and below the nerve root; the key to minimize venous bleeding is to dissect, coagulate, and divide them sequentially. A thorough release of the perineural soft tissues allows adequate nerve root mobilization, which in turn provides clear visualization of the C1-C2 joint space, preventing an undue nerve stretching during the C1-lateral mass screw insertion. The anomalous VA usually lies anterior to the C2 nerve root, and careful imaging evaluation allows its anticipation.3 We do not prefer the easy alternative of C2 nerve root sacrifice because of its inherent complications we noticed in our earlier clinical practice.3.

Controlled arachnoid opening to aid endoscopic trans-sphenoidal extrarachnoidal dissection of pituitary macroadenoma.

OBJECTIVES: The arachnoid often bulges prematurely during surgical excision of large pituitary tumors obscuring the deeper regions and crevices preventing total excision. Pushing the arachnoid may not be helpful and may tear it inadvertently and extensively leading to complications. We have described controlled arachnoid opening in large pituitary macroadenomas during the final stages of excision to gain access to the hidden portions and compared our results to the conventional technique. PATIENTS AND METHODS: Patients with pituitary macroadenoma of Hardy's III and KNOSP II in whom arachnoid had bulged prematurely were considered for study. They were grouped temporally. In first group (n = 12), the arachnoid was pushed to retrieve the tumor and in the second group (n = 10) it was punctured to aid resection. The extent of resection was assessed on postoperative scans, and complications in both groups, were noted. RESULTS: In the first group where arachnoid was pushed to retrieve tumor, Gross Total Resection (GTR) could be achieved in 5 patients. Inadvertent large arachnoid tear occurred in 3 patients of which, 2 developed CSF Rhinorrhoea. No patient had neurovascular injury.In the second group, GTR could be achieved in all without any added complications. CONCLUSION: Deliberate needle puncture and controlled drainage of CSF from arachnoid that bulges prematurely while endoscopic Transsphenoidal surgery for large pituitary tumors is a safe and effective method to gain access to the hidden portions of tumor to achieve GTR.

Delayed yet effective response of an endolymphatic sac tumor to radiosurgery: case report focusing on its radio-biological behavior.

Endolymphatic sac tumors (ELST), though benign are locally invasive lesions. Owing to its vascularity, complete surgical resection is often not possible and adjuvant gamma knife radiosurgery (GKRS) is advocated to control tumor growth. These lesions do not uniformly respond to radiation therapy in the initial phase and their early radiobiological course after GKRS is less understood. We discuss a case of residual ELST where a mild increase was noted at 36 months following GKRS and then regressed completely after a decade. This report possibly has the longest follow-up revealing the true efficacy of GKRS in these tumors. ELST shows a variable response in the early years after GKRS. They may remain static, regress or increase in size. One should be aware of these patterns of early radiological responses and a long term follow up is warranted as some lesions may show radiosurgical effectiveness after a long latent period.

Feasibility of awake endoscopic third ventriculostomy in selected patients of obstructive hydrocephalus.

BACKGROUND: Endoscopic third ventriculostomy (ETV) is usually performed under general anesthesia (GA) with proper head immobilization. However a few patients with hydrocephalus (HCP) may not be suitable for GA. Once the surgeon is familiar with endoscopic ventricular anatomy and gains adequate surgical experience with the procedure, ETV can be attempted under local anesthesia (LA) in selected patients. Here we discuss our experience of treating 32 patients of HCP with ETV under LA. METHODS: 32 symptomatic HCP patients with in the age range of 13 and 65 years, conscious, alert, cooperative and at high risk for GA owing to deranged liver or renal function, associated co-morbidities, pregnancy were considered for ETV under scalp block. All patients were evaluated for any discomfort during the surgical intervention. RESULT: All procedures were completed under LA. Four patients needed additional sedation prior to the scalp block to alleviate their apprehension. Four patients complained of bilateral orbital pain. In three it coincided with irrigation of fluid lower than body temperature. One patient had pain while touching the dorsum sella and needed analgesic supplement. All of them improved and none required additional CSF diversion within the average follow up of 9.5 months. CONCLUSION: ETV can be performed under local anesthesia in conscious, alert and cooperative patients in experienced hands. Unnecessary stimulation of the painful structures should be avoided and fluid for irrigation should be at body temperature. This ensures patient comfort and safety of the procedure.

A Randomized Study of Short Course (One Week) Radiation Therapy with or without Temozolomide in Elderly and/or Frail Patients with Newly Diagnosed Glioblastoma (GBM).

OBJECTIVE: Short-course radiotherapy (25 Gy in 5 fractions) has been shown to be non-inferior to standard course radiotherapy in elderly and frail patients (60 Gy in 30 fractions). The purpose of this study was to determine the effects of temozolomide combined with short-course radiotherapy on the outcome of elderly and frail patients. METHODS: Between January 2017 and November 2018, 90 patients (65 years old and KPS score of 50-70; 65 years old and KPS score of 80-100; and 65 years old and KPS score of 50-70) were assessed for eligibility. Nine patients were excluded because they did not meet the inclusion criteria, six patients declined to participate, and four patients were unable to complete the quality-of-life questionnaire. The remaining 71 patients were divided into two arms at random in a 1:1 ratio. Short-course radiotherapy with concurrent temozolomide and adjuvant temozolomide was given to Arm 1, while short-course radiotherapy alone was given to Arm 2. RESULTS: In terms of overall survival and progression-free survival, radiotherapy with concurrent temozolomide and adjuvant temozolomide outperformed short-course radiotherapy alone. The median overall survival in arm 1 was 146 days and 121 days in arm 2 (P=0.146). The median progression-free survival in arm 1 was 109.50 days, while it was 77 days in arm 2 (P=0.028). With a median follow-up time of 6 months, the quality of life at 4 weeks and 12 weeks after treatment was not different between the two arms. CONCLUSION: We concluded that adding temozolomide to short-course radiotherapy significantly improved progression-free survival and showed an increasing trend in overall survival without compromising the quality of life.

Surgical Outcome Analysis of Large and Giant Petroclival Meningiomas with Special Reference to Quality of Life Issues.

Background: Management strategies for petroclival menigiomas remain controversial. Objectives: We share our experience in management of large and giant true petroclival meniongiomas with special emphasis on patient reported quality of life parameters. Methods: This is a single center study of 47 patients between 2008 and 2018. All patients were checked for tumor specific parameters, clinical parameters, extent of surgical excision, and outcome, as assessed by Karnofsky performance score (KPS), Glasgow outcome score, clinical status, and by SF-36 questionnaire. Results: 32/47 patients' data were assessed. Symptoms included headache (62.5%), involvement of 5th nerve (47%), facial nerve (40.6%), lower cranial nerves (37.5%), cerebellar signs (84%), and long tract signs in (50%) of patients. The mean preoperative KPS was 83.75+/-6.59. Surgical approaches included retromastoid suboccipital craniotomy (50%), Kawase's approach (31.25%), and others in 18.25% patients. 40.625% (n = 13) had a gross total excision, near total resection (NTR) was achieved in 53.125% (n = 17), and 6.25% (n = 2) had a subtotal excision (STE). In 13 patients who had gross total resection (GTR), there were 12 (70.5%) new neurological deficits, while among the 19 patients with NTR, only 5 (29.5%) new neurological deficits were seen. No new onset neurological deficit was seen in patients with STE of tumor. Patient assessed QoL parameters were worse in patients with GTR and best in patients with NTR/STE + GKRS. Conclusion: In patients of large/giant petroclival meningiomas, NTE/STE with adjuvant GKRS provided better preservation of quality of life.

IgG4-related Pachymeningitis as a Cause of Spinal Epidural Compression: Can Intraoperative Frozen Sections Predict the Underlying Pathology?

At times, spinal lesions are part of systemic manifestations of autoimmune disease. Awareness regarding their clinicopathological spectrum, particularly the lesions which usually respond to steroids/immunotherapy, is essential to avoid unwanted surgical morbidity. We discuss a case of a young-man presenting with thoracic spinal epidural compressive lesion which was indeed a manifestation of IgG4-related hypertrophic pachymeningitis. The mass was firmly adherent to the dura and extended into left neural foramen/paravertebral space which precluded complete excision. Frozen sections suggested fibro-inflammatory stroma with large areas of fibrosis and lymphoplasmacytic infiltrate. After subtotal excision, the patient improved with medical therapy at 1-year follow-up. Although uncommon, the case highlights the need to consider spinal presentation of this rare entity, especially in the context of autoimmune disorders or even in isolation. In this regard, intraoperative frozen section can hint the underlying inflammatory/autoimmune pathology, guide further course of surgery as well as limit unwarranted operative morbidity.

C1-C2 arthroplasty for craniovertebral junction instability: A preliminary proof of concept in human cadavers.

Background: The atlantoaxial complex contributes to significant neck movements, especially the axial rotation. Its instability is currently treated with various C1-C2 fusion techniques. This however, considerably hampers the neck movements and affects the quality of life; a C1-C2 motion preserving arthroplasty could potentially overcome this drawback. Objectives: We evaluate the range of motion (ROM) of lateral C1-C2 artificial joints in cadaveric models. Materials and Methods: This is an in vitro cadaveric biomechanical study. After C1-C2 arthroplasty through a posterior approach, the C1-C2 ROM was tested in 4 fresh-frozen human cadaveric specimens, before and after destabilization. Results: The mean axial rotation demonstrated after the placement of C1-C2 joint implants was 15.46 degrees on the right and 16.03 degrees on the left side; the prosthesis provided stability, with 46% of the baseline C1-C2 axial rotation on either side. The ROM achieved in the other axes was less compared with that of intact specimens. To initiate rotation, a higher moment of 1.5 Nm was required in the presence of joint implants compared to 0.5 NM in unimplanted specimens. Conclusions: In our preliminary ROM evaluation, the C1-C2 arthroplasty appears to be stable and provides about half of the range of atlantoaxial rotation. It has the potential for joint motion preservation in the treatment of atlantoaxial instability resulting from lateral C1-C2 joint pathologies.