Occipital encephalocele: a retrospective analysis and assessment of post-surgical neurodevelopmental outcome.

BACKGROUND: Encephalocele represent a group of disorders which is characterised by extracranial herniation of the leptomeninges, brain, and CSF through a structural defect in the cranium. They are usually associated with other intracranial anomalies which may impact the neurological development. AIM: This study aimed to assess the predictors of neurological development of patients undergone surgical excision of occipital encephalocele. METHODS: All patients with occipital encephaloceles operated over the last decade (2012-2022). The sac size, presence of hydrocephalous, and associated anomalies were noted. The biopsy of these patients were reviewed and categorised as those which contains mature neural tissue and those without. The neurological outcomes were assessed by social, language, cognitive, and motor milestone and has been stratified into no delay, mild (1 of 4), moderate (2 or 3 of 4), and severe development delay (4 of 4). RESULTS: Total of 35 patients were included with median age of 10 months (IQR = 5-20 months). Fifteen (42.9%) patients had sac size of ≥ 5 cm, and 23 (65.7%) patients had mature neural tissues on biopsy. The median follow-up period was 6.4 years (IQR = 4.38-10.65) years. Seventeen (49.6%) patients had moderate to severe developmental delay. The sac size of ≥ 5 cm (AOR = 33.5; 95%CI = 3.35-334.8) (p = 0.003) and presence of mature neural content in the sac (AOR = 13.32; 95%CI = 1.1-160.36) (p = 0.041) were associated with significant neurodevelopmental delay. CONCLUSION: The presence of a large sac of ≥ 5 cm and the presence of mature neural tissues on histopathological specimen of patients with encephalocele point towards the possibility of poor neurological development.

Anterior clinoidectomy in low lying internal carotid artery-posterior communicating artery aneurysm.

BACKGROUND: At times, a regulation internal carotid artery-posterior communicating artery junction (ICA-P-Comm) aneurysm becomes a surgical hurdle owing to its close proximity to the anterior clinoid process, an immovable ICA and a concealed dominant P-Comm artery arising from the aneurysm neck. METHOD: A 70 year old patient with a low lying ICA-P-Comm aneurysm underwent a "tailored" intradural clinoidectomy for aneurysm clipping. CONCLUSION: A tailored anterior clinoidectomy to expose "just enough" allows a proximal ICA control in a suitable area, mobility of an atherosclerotic ICA and exposes the P-Comm artery origin which are essential in safe clipping of these aneurysms.

Trans-temporal trans-choroidal resection of thalamic and thalamopeduncular tumors: how I do it.

BACKGROUND:  Surgical resection is the cornerstone of treatment for low-grade tumors, albeit total excision is beneficial. As the thalamus is surrounded by vital neurovascular system, lesions here present a surgical challenge. METHOD: This article aims to demonstrate the trans-temporal, trans-choroidal fissure approach's effective surgical therapy on patients with thalamic lesions. With this approach, we were able to remove the tumor completely in three patients and almost completely in six more. Here we discuss a few technical details and potential hazards of the procedure with an operative video. CONCLUSION: This approach  provides excellent access to the deep areas of brain.

Tension pneumocephalus in a patient with NF1 following ventriculoperitoneal shunt-deciphering the cause and proposed management strategy.

INTRODUCTION: Spontaneous pneumocephalus following ventriculoperitoneal shunting is a very unique complication, seen in a handful of patients. Small bony defects form as a result of chronically raised intracranial pressure, which can later lead to pneumocephalus once intracranial pressure decreases following ventriculoperitoneal shunting. CASE REPORT: Here, we present a case of a 15-year-old girl with NF1 who presented to us with pneumocephalus 10 months following shunting and our management strategy along with a literature review of this condition. CONCLUSION: NF1 & hydrocephalus can lead to skull base erosion, which needs to be looked up before proceeding with VP shunting to avoid delayed onset pneumocephalus. SOKHA with the opening of LT is a minimally invasive approach suitable to tackle both problems simultaneously.

"Undercutting of the corresponding rib": a novel technique of increasing the length of donor in intercostal to musculocutaneous nerve transfer in brachial plexus injury.

Intercostal nerves (ICN) are often utilized as donors for various neurotization procedures in brachial plexus injuries. ICN to musculocutaneous nerve (MCN) transfer is usually a standard in pan brachial plexus injuries, in order to restore flexion at the elbow. A tensionless co-aptation of the donor-recipient nerves often necessitates either a distal dissection of the ICNs where the number of fascicles is rather low or a proximal dissection, often at the cost of dissection of the serratus anterior digitation with a risk of later fibrosis and adhesion. We report two cases of pan brachial plexus injuries where ICN-MCN transfer was performed to restore elbow function. These patients underwent clinical and electrodiagnostic evaluation before surgery. We used the standard technique of harvesting ICNs 3-5, with our technical modification of "undercutting of rib" for increasing the donor length. The procedure was applied in two patients with pan brachial plexus injury (mean age = 23). Mean duration since the injury to surgery was ten months. Both patients underwent tensionless anastomosis with a combination of suture and fibrin glue co-aptation. While one patient had some improvement in elbow flexion, another one was under active rehabilitation protocol during follow-up. We found that undercutting of the ribs near serratus digitations can allow mobilization of the ICN from its groove, which in turn lengthens the donor nerve length without violating the serratus anterior digitations and without too anterior dissection of the nerve. It can be a viable option when a tensionless co-aptation at the axilla is otherwise not feasible intraoperatively.

Insular glioblastoma: surgical challenges, survival outcomes and prognostic factors.

BACKGROUND: Insular gliomas are unique, challenging and evoke a lot of interest amongst neurosurgeons. Publications on insular glioma generally focus on the surgical intricacies and extent of resection pertaining to the low-grade gliomas. Insular glioblastomas (iGBM) have not been analysed separately before. METHODS: Histologically proven WHO grade IV gliomas involving the insula over a 9-year period were studied. Their clinical presentation, radiological features, surgical findings and survival outcomes were assessed. Statistical methods were used to determine the favourable predictors of survival. RESULTS: Out of 27 patients (M:F = 2.9:1), 18 (66%) patients had a tumour extension beyond the insula, 10 (37%) of whom had basal ganglia involvement. Total, near total and subtotal excisions were performed in 7 (26%), 9 (33%) and 11 (40.7%) patients, respectively. Twenty-three patients had glioblastoma, while four had gliosarcoma. IDH mutation was negative in six of the seven patients where it was done. Median overall survival was 5 months. Multivariate analysis showed that a female gender (p = 0.013), seizures in the preoperative period (p = 0.048) and completion of adjuvant therapy (p = 0.003) were associated with a longer survival. CONCLUSION: Insular glioblastomas have a poor prognosis. Insular location and certain tumour characteristics often limit the extent of resection of iGBMs. Moreover, postoperative complications sometimes negate the advantages of a radical resection. A female gender, presentation with seizures and completion of adjuvant chemoradiotherapy appear to be good prognostic factors.

Age-stratified adeno-associated virus serotype 3 neutralizing and total antibody prevalence in hemophilia A patients from India.

Gene therapy using an adeno-associated virus (AAV) vector offers a new treatment option for individuals with monogenetic disorders. The major bottleneck is the presence of pre-existing anti-AAV antibodies, which impacts its use. Even very low titers of neutralizing antibodies (NAb) to capsids from natural AAV infections have been reported to inhibit the transduction of intravenously administered AAV in animal models and are associated with limited efficacy in human trials. Assessing the level of pre-existing NAb is important for determining the primary eligibility of patients for AAV vector-based gene therapy clinical trials. Techniques used to screen AAV-antibodies include AAV capsid enzyme-linked immunosorbent assay (ELISA) and transduction inhibition assay (TIA) for detecting total capsid-binding (TAb) and Nab, respectively. In this study, we screened 521 individuals with hemophilia A from India for TAb and NAb using ELISA and TIA, respectively. The prevalence of TAb and NAb in hemophilia A patients from India were 96% and 77.5%, respectively. There was a significant increase in anti-AAV3 NAb prevalence with age in the hemophilia A patient group from India. There was a trend in anti-AAV3 TAb positivity between the pediatric age group (94.4%) and the adult age group (97.4%).

Quantitative assessment of brainstem distortion in vestibular schwannoma and its implication in occurrence of hydrocephalus.

PURPOSE: Anatomical distortion directly affects the clinical status of patients with vestibular schwannomas (VSs). It may vary for a given tumor size due to variability in posterior fossa anatomy. We aimed to quantitatively assess brainstem distortion (BSD) and review its role in occurrence of hydrocephalus associated with VSs. METHODS: Sixty-six patients with small (<3 cm, n= 8; 12.1%); large (3-4 cm; n= 26; 39.4%) and giant (>4 cm; n= 32; 48.5%) VSs were included. Cystic VSs were excluded. Tumor size, tumor-extent, linear displacement (LD; distance between line bisecting pons (line 1) and posterior fossa midline (line 2)) and angular distortion (AD; angle subtended between lines 1 and 2) in axial-T2-MRI section through pons, and their effect on hydrocephalus were assessed. RESULTS: Significant BSD occurred in a younger age (p value = .004/.003), larger-sized tumor (p value = .001/.002), hydrocephalus (p value = .001/.001), trigeminal (V) nerve palsy (p value = .004/.003) and long tract signs (p value = .001/.034). Tumors crossing midline had significant association with hydrocephalus (p value = .003). LD increased progressively even for 4-5 cm-sized tumors while AD stabilized. Receiver operating characteristic (ROC) curve revealed that diagnostic accuracy of LD (area under the ROC curve (AUROC): 78.9% (95% CI: 67.2%, 90.5%, p < .001)), AD (AUROC:77.6% (95% CI:65.8%, 89.5%, p < .001)) and LD × AD (AUROC:80.3% (95% CI: 69.2%, 91.2%, p < .001)) for predicting occurrence of hydrocephalus was better than tumor size (AUROC: 66.7% (95% CI: 53.5%, 79.9%, p < .05). Cut-off values of LD and AD for predicting occurrence of hydrocephalus were 6.25 mm and 14.6°, respectively. Hydrocephalus was significantly more when both LD was greater than  6.25 mm and AD was greater than 14.5° (p value = .034). The role of LD and AD in influencing hydrocephalus was greater than categorization based on tumor size (Spearman's correlation coefficient: 0.535 and 0.248, respectively). Hydrocephalus occurred at a lesser cut-off value of LD and AD when compared to long tract signs. CONCLUSIONS: LD and AD values in VSs have a significantly greater influence in the development of hydrocephalus compared to tumor size, and may aid, more reliably, in the prediction of hydrocephalus.

AAV3-miRNA vectors for growth suppression of human hepatocellular carcinoma cells in vitro and human liver tumors in a murine xenograft model in vivo.

We have previously reported that recombinant adeno-associated virus serotype 3 (AAV3) vectors transduce human liver tumors more efficiently in a mouse xenograft model following systemic administration. Others have utilized AAV8 vectors expressing miR-26a and miR-122 to achieve near total inhibition of growth of mouse liver tumors. Since AAV3 vectors transduce human hepatic cells more efficiently than AAV8 vectors, in the present studies, we wished to evaluate the efficacy of AAV3-miR-26a/122 vectors in suppressing the growth of human hepatocellular carcinoma (HCC) cells in vitro, and human liver tumors in a mouse model in vivo. To this end, a human HCC cell line, Huh7, was transduced with various multiplicities of infection (MOIs) of AAV3-miR-26a or scAAV3-miR-122 vectors, or both, which also co-expressed a Gaussia luciferase (GLuc) reporter gene. Only a modest level of dose-dependent growth inhibition of Huh7 cells (~12-13%) was observed at the highest MOI (1 × 105 vgs/cell) with each vector. When Huh7 cells were co-transduced with both vectors, the extent of growth inhibition was additive (~26%). However, AAV3-miR-26a and scAAV3-miR-122 vectors led to ~70% inhibition of growth of Huh-derived human liver tumors in a mouse xenograft model in vivo. Thus, the combined use of miR-26a and scAAV3-miR-122 delivered by AAV3 vectors offers a potentially useful approach to target human liver tumors.

Site-specific modifications to AAV8 capsid yields enhanced brain transduction in the neonatal MPS IIIB mouse.

Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal disease caused by defective production of the enzyme α-N-acetylglucosaminidase. It is characterized by severe and complex central nervous system degeneration. Effective therapies will likely target early onset disease and overcome the blood-brain barrier. Modifications of adeno-associated viral (AAV) vector capsids that enhance transduction efficiency have been described in the retina. Herein, we describe for the first time, a transduction assessment of two intracranially administered adeno-associated virus serotype 8 variants, in which specific surface-exposed tyrosine (Y) and threonine (T) residues were substituted with phenylalanine (F) and valine (V) residues, respectively. A double-mutant (Y444 + 733F) and a triple-mutant (Y444 + 733F + T494V) AAV8 were evaluated for their efficacy for the potential treatment of MPS IIIB in a neonatal setting. We evaluated biodistribution and transduction profiles of both variants compared to the unmodified parental AAV8, and assessed whether the method of vector administration would modulate their utility. Vectors were administered through four intracranial routes: six sites (IC6), thalamic (T), intracerebroventricular, and ventral tegmental area into neonatal mice. Overall, we conclude that the IC6 method resulted in the widest biodistribution within the brain. Noteworthy, we demonstrate that GFP intensity was significantly more robust with AAV8 (double Y-F + T-V) compared to AAV8 (double Y-F). This provides proof of concept for the enhanced utility of IC6 administration of the capsid modified AAV8 (double Y-F + T-V) as a valid therapeutic approach for the treatment of MPS IIIB, with further implications for other monogenic diseases.

The hepatocyte-specific HNF4α/miR-122 pathway contributes to iron overload-mediated hepatic inflammation.

Hepatic iron overload (IO) is a major complication of transfusional therapy. It was generally thought that IO triggers substantial inflammatory responses by producing reactive oxygen species in hepatic macrophages. Recently, a decrease in microRNA-122 (miR-122) expression was observed in a genetic knockout (Hfe-/-) mouse model of IO. Because hepatocyte-enriched miR-122 is a key regulator of multiple hepatic pathways, including inflammation, it is of interest whether hepatocyte directly contributes to IO-mediated hepatic inflammation. Here, we report that IO induced similar inflammatory responses in human primary hepatocytes and Thp-1-derived macrophages. In the mouse liver, IO resulted in altered expression of not only inflammatory genes but also >230 genes that are known targets of miR-122. In addition, both iron-dextran injection and a 3% carbonyl iron-containing diet led to upregulation of hepatic inflammation, which was associated with a significant reduction in HNF4α expression and its downstream target, miR-122. Interestingly, the same signaling pathway was changed in macrophage-deficient mice, suggesting that macrophages are not the only target of IO. Most importantly, hepatocyte-specific overexpression of miR-122 rescued IO-mediated hepatic inflammation. Our findings indicate the direct involvement of hepatocytes in IO-induced hepatic inflammation and are informative for developing new molecular targets and preventative therapies for patients with major hemoglobinopathy.

Plasmacytoid and conventional dendritic cells cooperate in crosspriming AAV capsid-specific CD8+ T cells.

Adeno-associated virus (AAV) is a replication-deficient parvovirus that is extensively used as a gene therapy vector. CD8+ T-cell responses against the AAV capsid protein can, however, affect therapeutic efficacy. Little is known about the in vivo mechanism that leads to the crosspriming of CD8+ T cells against the input viral capsid antigen. In this study, we report that the Toll-like receptor 9 (TLR9)-MyD88 pattern-recognition receptor pathway is uniquely capable of initiating this response. By contrast, the absence of TLR2, STING, or the addition of TLR4 agonist has no effect. Surprisingly, both conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) are required for the crosspriming of capsid-specific CD8+ T cells, whereas other antigen-presenting cells are not involved. TLR9 signaling is specifically essential in pDCs but not in cDCs, indicating that sensing of the viral genome by pDCs activates cDCs in trans to cross-present capsid antigen during CD8+ T-cell activation. Cross-presentation and crosspriming depend not only on TLR9, but also on interferon type I signaling, and both mechanisms can be inhibited by administering specific molecules to prevent induction of capsid-specific CD8+ T cells. Thus, these outcomes directly point to therapeutic interventions and demonstrate that innate immune blockade can eliminate unwanted immune responses in gene therapy.

Curcumin-Gene Expression Response in Hormone Dependent and Independent Metastatic Prostate Cancer Cells.

The androgen receptor is one of the key targets for prostate cancer treatment. Despite its less satisfactory effects, chemotherapy is the most common treatment option for metastatic and/or castration-resistant patients. There are constant needs for novel anti-prostate cancer therapeutic/prevention agents. Curcumin, a known chemo-preventive agent, was shown to inhibit prostate cancer cell growth. This study aimed to unravel the inhibitory effect of curcumin in prostate cancer through analyzing the alterations of expressions of curcumin targeting genes clusters in androgen-dependent LNCaP cells and androgen-independent metastatic C4-2B cells. Hierarchical clustering showed the highest number of differentially expressed genes at 12 h post treatment in both cells, suggesting that the androgen-dependent/independent manner of curcumin impacts on prostate cancer cells. Evaluation of significantly regulated top canonical pathways highlighted that Transforming growth factor beta (TGF-ß), Wingless-related integration site (Wnt), Phosphoinositide 3-kinase/Protein Kinase B/ mammalian target of rapamycin (PIK3/AKT(PKB)/mTOR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling were primarily inhibited, and Phosphatase and tensin homolog (PTEN) dependent cell cycle arrest and apoptosis pathways were elevated with curcumin treatment. The short term (3-24 h) and long term (48 h) effect of curcumin treatment revealed 31 and four genes modulated in both cell lines. TGF-ß signaling, including the androgen/TGF-ß inhibitor Prostate transmembrane protein androgen-induced 1 (PMEPA1), was the only pathway impacted by curcumin treatment after 48 h. Our findings also established that MYC Proto-Oncogene, basic helix-loop-helix (bHLH) Transcription Factor (MYC) signaling was down-regulated in curcumin-treated cell lines. This study established, for the first time, novel gene-networks and signaling pathways confirming the chemo-preventive and cancer-growth inhibitory nature of curcumin as a natural anti-prostate cancer compound.

Surgical excision of large-to-giant petroclival meningiomas focusing on the middle fossa approaches: The lessons learnt.

INTRODUCTION: Petroclival meningiomas are based on or arising from the petro-clival junction in upper two-thirds of clivus, medial to the fifth cranial nerve. This study focuses on the surgical experience in resecting large-giant tumors >3.5 in size predominantly utilizing middle fossa approaches. MATERIAL AND METHODS: 33 patients with a large or a giant petroclival meningioma (size >3.5 cm) were included. Clinical features, preoperative radiological details, operative findings, and postoperative clinical course at the follow-up visit were reviewed. Group A tumors (n = 17,51.5%) were sized 3.5cm-5cm, and Group B (n = 16,48.48%) tumors were of size >5 cm. Extent of resection was described as 'gross total' (no residual tumor), 'near total' (<10% residual tumor) and 'subtotal resection' (>10% residual tumor). Glasgow outcome scale (GOS) quantitatively scored postoperative neurological outcome (mean follow up: 35.77months; range 1-106 months). RESULTS: 25 (75.8%) patients had tumour extension into both supratentorial and infratentorial compartments. Extension into Meckel's cave (n = 25,75.8%), cavernous sinus (n = 17,48.4%], sphenoid sinus (n = 12,38.7%] and suprasellar area [12,38.7%] was often seen. In 31 (93.9%) patients, the tumor crossed the midline in the premedullary, prepontine, and interpeduncular cisterns. In 20 (60.6%) patients, the tumour extended below and posterior to the internal auditory meatus (IAM), while in 13 (39.4%) patients, the tumor was located above and anterior to the IAM. Kawase's approach was the most commonly used approach in 16 (48.48%) patients and resulted in maximum tumor resection. Other approaches included half-and-half (trans-Sylvian with subtemporal) [n = 6, 18.18%]; frontotemporal craniotomy with orbitozygomatic osteotomy [n = 1, 3%] and retromastoid suboccipital craniectomy (RMSO) [n = 7, 21.21%]. In 2 (6.06%) patients, staged anterior petrosectomy with RMSO; and, in 1, staged presigmoid with half-and-half approach was used. Gross total excision was achieved in 12 (36.36%), near-total excision in 15 (45.45%) and subtotal excision in 6 (18.18%) patients. 20 (60.6%) patients had a good functional outcome; 6 patients succumbed due to meningitis, pneumonitis, perforator injury or a large tumor recurrence. CONCLUSIONS: Half-and-half approach was used in tumors with middle and posterior cranial fossae components often extending to the suprasellar region. Kawase's anterior petrosectomy was utilized in resecting tumors with predominant posterior fossa component (along with a small middle fossa component) that was crossing the midline anterior to the brain stem, and mainly situated superomedial to the IAM. Tumors confined to the posterior fossa, that extended laterally and below the IAM were resected utilizing the RMSO approach. Occasionally, a combination of these approaches was used. Middle fossa approaches help in significantly avoiding morbidity by an early devascularisation and decompression of the tumor. In tumors lacking a plane of cleavage, a thin rim of capsule of tumor may be left to avoid brain stem signs.

Brain-stem hemangioblastomas: The seemingly innocuous lesion in a perilous location.

INTRODUCTION: Hemangioblastomas [75% sporadic, 25% with Von Hippel Lindau (VHL) disease] are highly vascular, benign lesions. The surgical nuances, management, and complication avoidance in brain-stem hemangioblastomas (BHs) have been studied. MATERIAL AND METHODS: Over 18 years, 27(mean age: 29 years; range 15-60 years) consecutive cases of BH underwent microsurgical excision. All patients were assessed clinico-radiologically for neurological deficits and screened for VHL disease. Outcome of the patients was based on Karnofsky Performance Status scale (KPS). RESULTS: 12 out of 19 (70.4%) patients with hydrocephalus underwent a cerebrospinal fluid (CSF) diversion procedure. Lower cranial nerve palsy was present in 10 (37%) patients and motor weakness in 13 (48%). The tumours [mean size 3.34 ± 1.06 cm, range: 1.4-5.5 cm; 11 solid, rest solid-cystic; 18 (66.7%) subpial and 9 (33.33%) intramedullary] were divided into four categories based on size: A: <2 cm (n = 5,18.5%); B: 2-3 cm (n = 10,37%); C: 3-4 cm (n = 6,22.2%); D: >4 cm (n = 6,22.2%). Their location was at posterior cervicomedullary junction (n = 12); pontomedullary junction (n = 7); pons (n = 3), medulla (n = 3) and ponto-mesencephalic region (n = 2). Multiple flow voids were seen in >50% patients with tumour >2 cm. 5 patients had syringomyelia; and, 8 had diffuse cervical cord expansion. Two patients with a large vascular tumour underwent preoperative embolization. Six patients had VHL disease; one underwent bilateral adrenalectomy for refractory hypertension; and, the another, nephrectomy for renal cell carcinoma. Twenty-six patients underwent a midline suboccipital craniectomy; and, 1 with a cerebellopontine angle tumour, a retromastoid craniectomy. 15 patients underwent total excision; 10 patients, near-total (<10% remaining) excision, and 2 patients, a subtotal (>10% remaining)) excision. Three patients (2 with VHL disease) expired due to exsanguinating hemorrhage, spreading venous thrombosis and aspiration pneumonitis, respectively. At follow-up visit (median: 25 ± interquartile range 2-56months), 17 patients had improved KPS, 4 remained in same status and 3 (recently operated, on tracheostomy) had worsened KPS. CONCLUSIONS: Significant improvement is achievable in neurological status in patients following successful extirpation of a brain-stem hemangioblastoma, despite a turbulent perioperative period. Leaving tumour capsule adherent to the brain-stem often helps in preserving brain-stem function. Postoperatively, the patients should be monitored for their respiratory and lower cranial nerve status to prevent aspiration pneumonitis.