Photophysical Characterization and In Vitro Evaluation of α-Mangostin-Loaded HDL Mimetic Nano-Complex in LN-229 Glioblastoma Spheroid Model.

Cytotoxic activity has been reported for the xanthone α-mangostin (AMN) against Glioblastoma multiforme (GBM), an aggressive malignant brain cancer with a poor prognosis. Recognizing that AMN's high degree of hydrophobicity is likely to limit its systemic administration, we formulated AMN using reconstituted high-density lipoprotein (rHDL) nanoparticles. The photophysical characteristics of the formulation, including fluorescence lifetime and steady-state anisotropy, indicated that AMN was successfully incorporated into the rHDL nanoparticles. To our knowledge, this is the first report on the fluorescent characteristics of AMN with an HDL-based drug carrier. Cytotoxicity studies in a 2D culture and 3D spheroid model of LN-229 GBM cells and normal human astrocytes showed an enhanced therapeutic index with the rHDL-AMN formulation compared to the unincorporated AMN and Temozolomide, a standard GBM chemotherapy agent. Furthermore, treatment with the rHDL-AMN facilitated a dose-dependent upregulation of autophagy and reactive oxygen species generation to a greater extent in LN-229 cells compared to astrocytes, indicating the reduced off-target toxicity of this novel formulation. These studies indicate the potential therapeutic benefits to GBM patients via selective targeting using the rHDL-AMN formulation.

Transverse myelitis after Johnson & Johnson COVID-19 vaccine: illustrative case.

BACKGROUND: Transverse myelitis is a rare neurological occurrence with varied presentation. Imaging is necessary to properly diagnose this condition; however, identifying the cause of this condition may often be difficult. OBSERVATIONS: An otherwise healthy patient presented to the clinic with peculiar neurological symptoms without an obvious underlying cause. Imaging evidenced no significant structural defects but did lead to discovery of cord enhancement compatible with a diagnosis of transverse myelitis. Corticosteroid treatment was initiated rapidly to address this pathology, and the patient recovered without deficits. To identify the underlying cause, patient medical history was reviewed thoroughly and compared with existing literature. Previous tuberculosis infection could be a less likely cause of the neurological symptoms. However, recent vaccination with the Johnson & Johnson coronavirus disease 2019 (COVID-19) vaccine could be a more likely cause of the transverse myelitis, which has been rarely reported. LESSONS: Transverse myelitis after COVID-19 infection has been an escalating phenomenon. However, transverse myelitis after COVID-19 vaccination is a rare occurrence that is also on the rise. Given the increased rates of vaccination, transverse myelitis should not be overlooked as a potential pathology, due to the severity of neurological impairment if this condition is not treated rapidly.

Branched-Chain Amino Acids Are Neuroprotective Against Traumatic Brain Injury and Enhance Rate of Recovery: Prophylactic Role for Contact Sports and Emergent Use.

Branched-chain amino acids (BCAAs) are known to be neurorestorative after traumatic brain injury (TBI). Despite clinically significant improvements in severe TBI patients given BCAAs after TBI, the approach is largely an unrecognized option. Further, TBI continues to be the most common cause of morbidity and mortality in adolescents and adults. To date, no study has evaluated whether BCAAs can be preventive or neuroprotective if taken before a TBI. We hypothesized that if BCAAs were elevated in the circulation before TBI, the brain would readily access the BCAAs and the severity of injury would be reduced. Before TBI induction with a standard weight-drop method, 50 adult mice were randomized into groups that were shams, untreated, and pre-treated, post-treated, or pre- + post-treated with BCAAs. Pre-treated mice received BCAAs through supplemented water and were dosed by oral gavage 45 min before TBI induction. All mice underwent beam walking to assess motor recovery, and the Morris water maze assessed cognitive function post-injury. On post-injury day 14, brains were harvested to assess levels of astrocytes and microglia with glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (IBA-1) immunohistochemistry, respectively. Pre-treated and pre- +post-treated mice exhibited significantly better motor recovery and cognitive function than the other groups. The pre- + post-treated group had the best overall memory performance, whereas the pre-treated and post-treated groups only had limited improvements in memory compared to untreated animals. Pre- + post-treated brains had levels of GFAP that were similar to the sham group, whereas the pre-only and post-only groups showed increases. Although trends existed, no meaningful changes in IBA-1 were detected. This is the first study, animal or human, to demonstrate that BCAA are neuroprotective and substantiates their neurorestorative benefits after TBI, most likely through the important roles of BCAAs to glutamate homeostasis.

Right hemidiaphragmatic paralysis after cervical transforaminal epidural steroid injection: illustrative case.

BACKGROUND: Cervical radiculopathy is a common cause of neck pain, with radiation into the upper extremity in a dermatomal pattern. Corticosteroid injection is a conservative management option with a low risk of major adverse events. No reviewed literature or case reports have implicated phrenic nerve injury secondary to cervical transforaminal epidural steroid injection (CTFESI). OBSERVATIONS: A 45-year-old man with severe right C6 radiculopathy secondary to a large right-sided C5-6 herniated intervertebral disc presented to the pain management clinic, where he received a right-sided C6 CTFESI. An hour after injection, the patient experienced shortness of breath, which was found to be caused by right diaphragmatic paralysis. The patient underwent a C5-6 anterior cervical discectomy and fusion, which provided complete relief of his radicular symptoms. However, the right hemidiaphragmatic paralysis remained at the 1-year postoperative visit. LESSONS: Thorough literature review showed no established explanations for phrenic nerve injury after CTFESI. In this study, the authors explored the suspected mechanisms of possible injury to the phrenic nerve. Epidural corticosteroid injection is considered to be a safe option for conservative management of cervical radiculopathy. This study unveiled a unique and important adverse event that should be considered before a patient receives CTFESI.

The SR-B1 Receptor as a Potential Target for Treating Glioblastoma.

PURPOSE: The goal of these studies was to provide proof of concept for a novel targeted therapy for Glioblastoma Multiforme (GBM). Methods. These studies involve the evaluation of reconstituted high density lipoprotein (rHDL) nanoparticles (NPs) as delivery agents for the drug, mammalian Target of Rapamycin (mTOR) inhibitor Everolimus (EVR) to GBM cells. Cytotoxicity studies and assessment of downstream effects, including apoptosis, migration, and cell cycle events, were probed, in relation to the expression of scavenger receptor B type 1 (SR-B1) by GBM cells. RESULTS: Findings from cytotoxicity studies indicate that the rHDL/EVR formulation was 185 times more potent than free EVR against high SR-B1 expressing cell line (LN 229). Cell cycle analysis revealed that rHDL/EVR treated LN229 cells had a 5.8 times higher apoptotic cell population than those treated with EVR. The sensitivity of GBM cells to EVR treatment was strongly correlated with SR-B1 expression. CONCLUSIONS: These studies present strong proof of concept regarding the efficacy of delivering EVR and likely other agents, via a biocompatible transport system, targeted to the SR-B1 receptor that is upregulated in most cancers, including GBM. Targeting the SR-B1 receptor could thus lead to effective personalized therapy of GBM.

Dural laceration.

OBJECT: The authors describe 4 cases of delayed dural laceration by hydroxyapatite (HA) spacer causing tetraparesis following double-door laminoplasty. There are few reports of iatrogenic spinal cord lesions developing after double-door laminoplasty, although some complications such as postoperative C-5 paralysis or axial symptoms have been reported. The purpose of this report is to draw attention to the possibility of delayed dural laceration and its triggering mechanism. METHODS: One hundred thirty patients treated for cervical myelopathy were followed up for an average of 2 years and 9 months after laminoplasty. RESULTS: Four patients experienced aggravation of cervical myelopathy. Anterior dislodgement of HA spacers was shown on plain lateral radiographs. Follow-up T2-weighted magnetic resonance imaging demonstrated that the dislodged HA spacers were surrounded by cerebrospinal fluid at the time of aggravation. The dislodged HA spacers were removed and the dural membrane defects were repaired by patching with the fascia of the gluteus maximus muscle. The preoperative symptoms improved after the second operation in all patients. CONCLUSIONS: It is hypothesized that the loosening of the HA spacer in split spinous processes could occur with the movement of the cervical spine and/or the breakage of the suture before bone bonding. Anterior dislodgement of the HA spacer toward the spinal canal would cause dural laceration by direct friction between the dural membrane and the dislodged HA spacer, resulting in clinical aggravation. Despite the well-documented advantages of using HA spacers for double-door laminoplasty, possible laceration due to a dislodged HA spacer should be considered as a late complication.

Ganglioglioma occurring with glioblastoma multiforme: separate lesions or the same lesion?

The authors report on the first such case of ganglioglioma and a malignant variant in the same individual without prior irradiation. Gangliogliomas are frequently encountered in children and young adults and have a predilection for the temporal lobes. Sporadic cases of malignant degeneration have been reported; however, most cases have undergone radiation or subtotal resection. A 45-year-old female was seen for speech abnormalities and symptoms referable to elevated intracranial pressure. The patient had no significant past medical history and no history of neurocutaneous disorders. Two separate lesions located in the posterior and anterior temporal lobes were found on imaging. At initial surgery, she underwent gross total resection of the anterior temporal tip ganglioglioma and cyst aspiration of the posterior temporal lobe lesion. The anterior temporal lesion was a ganglioglioma and did not recur. However, the posterior temporal lesion was identified as a malignant ganglioglioma/glioblastoma multiforme variant that recurred multiple times requiring several surgeries, radiation and chemotherapy. The occurrence of these distinct entities is uncommon in patients without a history of prior radiation treatment. Even rarer, is the occurrence of these separate intracranial lesions in a patient without a history of phacomatosis. For benign gangliogliomas, gross total resection can be curative; however, more aggressive variants may be resistant to multimodal therapies.

Reactivation of dormant lumbar methicillin-resistant Staphylococcus aureus osteomyelitis after 12 years.

The adequate treatment of methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis has intrigued clinicians for some time. As the resistance of these pathogens, coupled with the increase in community-acquired cases, continues steadily to rise, clinicians are finding it useful to employ multi-modal approaches for efficacious treatment. The authors present a single case report of a patient with recurrent MRSA osteomyelitis, lumbar paraspinal and epidural abscess. He was found to have decreased muscle strength and was hyporeflexic in the involved extremity. Serum testing demonstrated MRSA bacteremia. Neuroimaging studies revealed evidence of paraspinal abscess and a presumed herniated nucleus pulposus at the L5/S1 interspace with significant nerve root compromise. Despite antimicrobials, his symptoms persisted, necessitating surgical exploration. At surgery, paraspinal and epidural abscesses were encountered and debrided; however, no herniated disc was visualized. This case demonstrates the diagnostic and therapeutic dilemmas with which these lesions present. We postulate that the MRSA osteomyelitis/discitis pathogens were walled off in the disc space and subsequently inoculated the soft tissues with ensuing bacteremia. We concur that antimicrobial treatment should be the first line of therapy for these patients; however, surgical debridements and cautious spinal instrumentation should be employed where appropriate.

Nonhemorrhagic cord contusion after percutaneous fiducial placement: case report and surgical recommendations.

STUDY DESIGN: Single case report and extensive literature review. OBJECTIVES: To present the first such report of cervical cord contusion after the percutaneous placement of gold-seed fiducials. The pathomechanics and surgical recommendations are reviewed. BACKGROUND: Spinal cord injuries are well documented in the medical literature. These injuries range from cord contusion to transection and result primarily from trauma. A single case report of a patient who was found to have a nonhemorrhagic cervical spinal cord contusion after percutaneous fiducial implantation is presented. METHODS: Single case report. RESULTS: The patient underwent percutaneous placement of fiducials for stereotactic radiosurgery for a nerve sheath tumor. Postoperatively she had primarily sensory complaints; no motor deficits were detected on neurological examination. Neuroimaging studies demonstrated nonhemorrhagic cervical cord contusion. She was treated conservatively and had complete resolution of her symptoms. CONCLUSIONS: The likely mechanism for the contusion was neck hyperextension during thrusting maneuvers during fiducial implantation. This is yet another report of normal intraoperative-evoked potentials with postoperative neurological sequelae. A dedicated team approach involving ancillary staff, anesthesiologists, and surgeons should be utilized to avert this potentially devastating complication.

Chiari malformation and odontoid panus causing craniovertebral stenosis in a child with Crouzon's syndrome.

Crouzon's disease is a well-known disorder affecting multiple organ systems, specifically a craniofacial disorder with highly variable penetrance and severity of deformity. Crouzon's patients typically have anomalies of the skull base leading to gross distortion of the cranium and in some cases the cervicocranium. We present a 5-year-old girl with Crouzon's disease who suffered from an acquired Chiari I malformation after insertion of a ventriculoperitoneal shunt and a coexistent ventral odontoid panus. Both these lesions were causing cervicomedullary compression. The literature is controversial on the surgical management of anterior and posterior compression at the craniocervical junction. We review the literature on surgical options for decompression at the craniocervical junction and offer our surgical case as a treatment option for patients in this rare clinical situation.

Basis of persistent and recurrent Cushing disease: an analysis of findings at repeated pituitary surgery.

OBJECT: The goal of this study was to establish the clinical importance of occult dural invasion--invasion of the dura mater or cavernous sinus that is not evident on imaging studies and is not obvious to the surgeon--as the basis of recurrent or persistent tumor and endocrinopathy. METHODS: The authors retrospectively reviewed the case files of patients who underwent repeated transsphenoidal surgery for resection of an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma. Patient selection required the availability of operative and pathology reports from the initial and repeated transsphenoidal surgeries. Because no determination of the cause of persistent or recurrent disease could be made if the tumor could not be localized during the repeated surgery, a pathology report confirming the presence of tumor from the second surgery was also required. Sixty-eight patients met these criteria. In 43 patients (63%) an ACTH-producing tumor was identified at the initial surgery, in 25 patients (37%) no tumor was found, and in three patients (4%) dural invasion was noted at surgery. In 49 (72%) of the 68 patients there was initial resolution of hypercortisolism and recurrent Cushing disease (CD), whereas in 19 patients (28%) there was persistent CD after the initial surgery. At repeated surgery (44 +/- 35 months after the initial surgery) in all 43 patients in whom tumor had been identified at the initial surgery, the tumor was found at the same site or contiguous to the same site. Dural invasion was noted by the surgeon in only three patients at the original surgery, whereas dural invasion by an ACTH-producing tumor was identified during repeated surgery in 42 (62%) of the 68 patients. In addition, 39 (93%) of the 42 invasive adenomas were located laterally and involved the cavernous sinus. Adenomatous invasion of the dura mater was found in 31 (54%) of the 57 microadenomas and in all 11 macroadenomas at repeated surgery. The presence of tumor was not detected in 28 of the 59 patients studied with magnetic resonance (MR) imaging and in none of these 59 patients was dural invasion evident on MR images. CONCLUSIONS: Recurrent and persistent CD consistently results from residual tumor. At repeated surgery the residual tumor can be found at or immediately contiguous to the site at which the tumor was found originally. Unappreciated dural invasion with growth of residual tumor within the cavernous sinus dura, which frequently occurs without residual tumor or dural invasion being evident on MR images or to the surgeon during surgery, is the basis of surgical failure in many patients with CD. Occult lateral dural invasion by tumor may also underlie recurrences of other types of pituitary adenomas.

The steroid-responsive hiccup reflex arc: competitive binding to the corticosteroid-receptor?

Hiccups occurring secondary to high-doses of corticosteroids are a well-recognized problem in the field of neurosurgery. Numerous reports of oral, intravenous and intraarticular corticosteroids inducing hiccups exist in the literature. To date, there is only one case of anabolic steroids inducing hiccups. We now present a case of a patient who underwent a suboccipital craniotomy for resection of a cerebellar pontine angle meningioma. Postoperatively the patient was on high doses of Decadron and Oxandrin, an anabolic-anticatabolic agent used to combat the deleterious effects of corticosteroids. The patient suffered intractable hiccups postoperative day one, resistant to Thorazine. Oxandrin was discontinued to assess the possibility of a anabolic steroid-induced singultus. The hiccups resolved within 24 hours. This report validates the previous report on anabolic steroids inducing hiccups and exemplifies the ability for steroids as a class, due to there backbone structural homology, to induce function even as competitive inhibitors.

Precocious puberty associated with a pineal cyst: is it disinhibition of the hypothalamic-pituitary axis?

Accelerated development of secondary sexual characteristics or sexual precocity is a well-known entity. Most authors recognize two groups of patients, those described as having central precocious puberty (CPP) and those with precocious pseudopuberty. CPP results from premature activation of the hypothalamic-pituitary-gonadal axis and pseudopuberty is caused by lesions that secrete gonadotropin-like substances or hormones. The onset of CPP is usually before age 8 in females and age 9 in males; however, there is contention that the age of onset is much earlier and also differs depending on the patients' race. Previously reported causes of CPP include intracranial neoplasm, infection, trauma, hydrocephalus and Angelman's syndrome. Pineal cysts are usually asymptomatic incidental findings, but have been associated with CPP. We present an interesting case of a patient with CPP and an associated pineal cyst. We review the literature on the pathogenesis of CPP and associated pineal cyst, the neuroendocrine relationship between the pineal gland and puberty and the neurosurgical role in these cases.