Statin-induced T-lymphocyte modulation and neuroprotection following experimental subarachnoid hemorrhage.

INTRODUCTION: Statins influence immune system activities through mechanisms independent of their lipid-lowering properties. T cells can be subdivided based on cytokine secretion patterns into two subsets: T-helper cells type 1 (Th1) and type 2 (Th2). Independent laboratory studies have shown statins to be potent inducers of a Th2 switch in immune cell response and be neuroprotective in several models of central nervous system (CNS) disease. This study was the first to evaluate the immune modulating effects of statins in subarachnoid hemorrhage (SAH). METHODS: Simvastatin was administered to rats intraperitoneally in two dosages (1 and 20 mg/kg) 30 min after the induction of SAH using endovascular perforation. Neurological scores were assessed 24 h later. Animals were then sacrificed, and samples of cortex and brain stem were tested for expression of the T-regulatory cell cytokine transforming growth factor (TGF) ß1, as well as interleukin (IL) 1ß, a proinflammatory cytokine associated with Th1 immune responses. The presence of TGF-ß1 secreting T cells was evaluated with the use of brain slices. RESULTS: SAH significantly impaired neurological function in all SAH groups (treated and untreated) versus sham. Animals treated with high-dose simvastatin had less neurological impairment than both untreated and low-dose groups. Cortical and brain-stem levels of TGF-ß1 were significantly elevated following SAH in the high-dose group. IL-1ß was significantly elevated following the induction of SAH but was inhibited by high-dose simvastatin. Double-labeled fluorescent immunohistochemical data demonstrated the presence of lymphocytes in the subarachnoid and perivascular spaces following SAH. Expression of TGF-ß1 by lymphocytes was markedly increased following treatment with high-dose simvastatin. CONCLUSION: The present study elucidated the potential role of a Th2 immune switch in statin provided neuroprotection following SAH.

Dual effects of melatonin on oxidative stress after surgical brain injury in rats.

The purpose of this study was to evaluate the effect of melatonin on oxidative stress occurring in the brain after routine lobectomy neurosurgery procedures. Different concentrations of melatonin (5, 15 and 150 mg/kg) were administered 1 hr before lobectomy in a rodent surgical brain injury (SBI) model. Neurological outcomes were assessed 24 hr before the killing of the rodents, for evaluation of brain water content (brain edema) and lipid peroxidation (oxidative stress). The results showed that lower doses (5 and 15 mg/kg) failed to reduce brain edema, but the 15 mg/kg dose did lower oxidative stress and improved several neurological parameters. High concentration of melatonin (150 mg/kg) significantly increased brain edema and elevated oxidative stress when compared with the vehicle-treated group. Furthermore, high-dose melatonin also worsened neurological outcomes compared with other groups. The study suggests that melatonin has dual effects: low-dose melatonin may provide neuroprotective effects against SBI but a high dose may aggravate some parameters after SBI.

Rigid Internal Fixation for Traumatic Cranio-Cervical Dissociation in Infants and Young Children.

STUDY DESIGN: Retrospective review. OBJECTIVE: Evaluate radiographic and clinical outcomes for infants and children, who underwent rigid occipito-cervical fixation for traumatic craniocervical dissociation (tCCD). SUMMARY OF BACKGROUND DATA: Traumatic craniocervical dissociation is devastating. Children are at high risk but make up a large number of survivors. Non-rigid fixation has traditionally been favored over screw and rod constructs due to inherent challenges involved with instrumenting the pediatric craniocervical junction. Therefore, outcomes for rigid occipito-cervical instrumentation in infants and young children with tCCD remain uncertain. METHODS: Retrospective review of children who survived tCCD between 2006 and 2016 and underwent rigid occipito-cervical fixation. RESULTS: Fifteen children, from 8 months to 8 years old (mean, 3.8 yr), were either a passenger (n = 11) or a pedestrian (n = 4) in a motor vehicle accident. Seven patients had weakness: five with quadriplegia, one with hemiparesis, and one with bilateral upper extremity paresis. Ten patients had concurrent C1-2 instability. At last follow-up, four patients had improved motor function: one with bilateral upper extremity paresis and one with hemiparesis regained full strength, one with quadriplegia regained function on one side while another regained function in bilateral upper extremities. All underwent rigid posterior occipito-cervical fixation, with two patients requiring additional anterior and posterior fixation at non-contiguous levels. Fourteen patients were stable on flexion-extension x-rays at a mean follow-up of 31 months (9-1 yr or longer, 7-2 yr or longer). There were no cases of deformity, growth disturbance, or subaxial instability. CONCLUSION: Children who survive tCCD may regain function after stabilization. Rigid internal rod and screw fixation in infants and young children safely provided long-term stability. We advocate using C2 translaminar screws to exploit the favorable anatomy of pediatric lamina to minimize the risks of occipitocervical (OC) instrumentation. LEVEL OF EVIDENCE: 4.

Melatonin decreases mortality following severe subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease that is associated with significant morbidity and mortality. There is substantial evidence to suggest that oxidative stress is significant in the development of acute brain injury following SAH. Melatonin is a strong antioxidant that has low toxicity and easily passes through the blood-brain barrier. Previous studies have shown that melatonin provides neuroprotection in animal models of ischemic stroke. This study hypothesizes that melatonin will provide neuroprotection when administered 2 hr after SAH. The filament perforation model of SAH was performed in male Sprague-Dawley rats weighing between 300 and 380 g. Melatonin (15 or 150 mg/kg), or vehicle was given via intraperitoneal injection 2 hr after SAH. Mortality and neurologic deficits were assessed 24 hr after SAH. A significant reduction in 24-hr mortality was seen following treatment with high dose melatonin. There was no improvement in neurologic scores with treatment. Brain water content and lipid peroxidation were measured following the administration of high dose melatonin to identify a mechanism for the increased survival. High dose melatonin tended to reduce brain water content following SAH, but had no effect on the lipid peroxidation of brain samples. Large doses of melatonin significantly reduces mortality and brain water content in rats following SAH through a mechanism unrelated to oxidative stress.

Effects of melatonin in early brain injury following subarachnoid hemorrhage.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease that is associated with significant morbidity and mortality. There is substantial evidence to suggest that oxidative stress is significant in the development of acute brain injury following SAH. Melatonin is a strong antioxidant that has low toxicity and easily passes through the BBB. Previous studies have shown that melatonin provides neuroprotection in other models of CNS injury. METHODS: This experiment evaluates melatonin as a neuroprotectant against early brain injury following SAH. The endovascular perforation model of SAH was performed in male Sprague Dawley rats followed by the administration of melatonin two hours after the insult. Mortality and brain water content were assessed 24 after SAH. FINDINGS: A significant reduction in 24 h mortality was seen following treatment with 150 mg/kg of melatonin. Brain water content was evaluated in the high dose treatment group to see if a reduction in brain edema was associated with reduced mortality. High dose melatonin tended to reduce brain water content following SAH. CONCLUSIONS: Large doses of melatonin significantly reduced mortality and brain water content in rats following SAH.

Apoptosis factor EI24/PIG8 is a novel endoplasmic reticulum-localized Bcl-2-binding protein which is associated with suppression of breast cancer invasiveness.

p53 is a critical tumor suppressor which removes cells with DNA damage by regulating expression and activity of a select group of p53-induced genes (PIG) that subsequently induce apoptosis. PIG8 was also identified as a gene induced by etoposide and named etoposide-induced gene 24 (EI24). Later experiments established EI24/PIG8 as a proapoptotic factor and suggested that it may function as a tumor suppressor. Indeed, EI24/PIG8 is relatively highly mutated in aggressive breast cancers and is located in a region which expresses frequent loss of heterozygosity. However, despite these important observations, the activity and role of EI24/PIG8 remain largely unknown. We used (immmuno)fluorescence microscopy and subcellular fractionation techniques to show that EI24/PIG8 is localized in the endoplasmic reticulum (ER). Pull-down experiments showed that it specifically binds with Bcl-2, a death regulator known to reside in mitochondria, ER, and the nuclear envelope. EI24/PIG8-Bcl-2 binding was corroborated by coimmunoprecipitation and other in vitro and in vivo protein-protein binding assays. Further analysis showed that EI24/PIG8 uses its N-terminal region to bind the BH3 domain in Bcl-2. Finally, we used immunohistochemical techniques to analyze expression of EI24/PIG8 in breast cancer tissue progression arrays and showed that loss of EI24/PIG8 is associated with tumor invasiveness but not with the development of the primary tumor. These results suggest that EI24/PIG8 is a novel, ER-localized Bcl-2-binding protein which may contribute to apoptosis by modulating the activity and/or function of Bcl-2 in this organelle. EI24/PIG8 may serve to prevent tumor spreading, consistent with its suspected role as a tumor suppressor.

Intracranial Myeloid Sarcoma Metastasis Mimicking Acute Subdural Hematoma.

Myeloid sarcoma, a rare consequence of myeloproliferative disorders, is rarely seen in the central nervous system, most commonly in the pediatric population. Although there are a handful of case reports detailing initial presentation of CNS myeloid sarcoma in the adult population, we have been unable to find any reports of CNS myeloid sarcoma presenting as a large mass lesion in a herniating patient. Here, we present the case of a patient transferred to our facility for a very large subdural hematoma. Based on imaging characteristics, it was felt to be a spontaneous hematoma secondary to coagulopathy. No coagulopathy was found. Interestingly, he did have a history of acute myeloid leukemia (AML) diagnosed 2 months previously, and intraoperatively he was found to have a confluent white mass invading both the subdural and subarachnoid spaces. There was minimal associated hemorrhage and final pathology showed myeloid sarcoma. This is the first report we are aware of in which CNS myeloid sarcoma presented as a subdural metastasis and also the first report in which we are aware of this etiology causing a herniation syndrome secondary to mass effect.

Preoperative mucosal tolerance to brain antigens and a neuroprotective immune response following surgical brain injury.

OBJECT: Intracranial surgery causes cortical injury from incisions, hemorrhage, retraction, and electrocautery. The term "surgical brain injury" (SBI) has been developed to categorize this injury inherent to the procedure. Neuroinflammation plays a significant role in SBI. Traditional antiinflammatory therapies are often limited by their immunosuppressive side effects and poor CNS penetration. This study uses mucosal tolerance to develop an immune system that is tolerant to brain myelin basic protein (MBP) so that inflammation can be suppressed in a timely and site-specific manner following surgical disruption of the blood-brain barrier. METHODS: A standard SBI model using CD57 mice was used. Nasopharyngeal mucosa was exposed to vehicle, ovalbumin, or MBP to develop mucosal tolerance to these antigens. Immunological tolerance to MBP was confirmed in vivo through hypersensitivity testing. Neurological scores, cerebral edema, and interleukin (IL)-1ß and transforming growth factor (TGF)-ß1 cytokine levels were measured 48 hours postoperatively. RESULTS: Hypersensitivity testing confirmed the development of immune tolerance to MBP. Myelin basic protein-tolerant mice demonstrated reduced neurological injury, less cerebral edema, decreased levels of IL-1ß, and increased levels of TGFß1 following SBI. CONCLUSIONS: Developing preoperative immunological tolerance to brain antigens through mucosal tolerance provides neuroprotection, reduces brain edema, and modulates neuroinflammation following SBI.

Encephalocraniocutaneous lipomatosis: a review of its clinical pathology and neurosurgical indications.

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous syndrome whose hallmark lesions are benign lipomas of the brain and spinal cord. The authors present a case of a male infant with ECCL who had extensive brainstem and spinal cord lipomas. The management of this patient's hydrocephalus, cervicomedullary compression, tethered cord, and scoliosis over the course of his first 2 years of life is described. This case report and review of the literature is presented to provide a synopsis of the problems likely to be encountered by neurosurgeons who treat patients with this syndrome.