Neuronavigation-Specific Parameters for Selective Access of Trigeminal Rootlets in Radiofrequency Lesioning: A Cadaveric Morphometric Study.

BACKGROUND AND OBJECTIVE: Radiofrequency lesioning (RFL) is a safe and effective treatment for medically refractory trigeminal neuralgia. Despite gaining mainstream neurosurgical acceptance in the 1970s, the technique has remained relatively unchanged, with the majority of series using lateral fluoroscopy over neuronavigation for cannula guidance. To date, there are no studies describing neuronavigation-specific parameters to help neurosurgeons selectively target individual trigeminal rootlets. In this cadaveric study, we sought to provide a neuronavigation-specific morphometric roadmap for selective targeting of individual trigeminal rootlets. METHODS: Embalmed cadaveric specimens were registered to cranial neuronavigation. Frontotemporal craniotomies were then performed to facilitate direct visualization of the Gasserian ganglion. A 19-gauge cannula was retrofit to a navigation probe, permitting real-time tracking. Using preplanned trajectories, the cannula was advanced through foramen ovale (FO) to the navigated posterior clival line (nPCL). A curved electrode was inserted to the nPCL and oriented inferolaterally for V3 and superomedially for V2. For V1, the cannula was advanced 5 mm distal to the nPCL and the curved electrode was reoriented inferomedially. A surgical microscope was used to determine successful contact. Morphometric data from the neuronavigation unit were recorded. RESULTS: Twenty RFL procedures were performed (10R, 10L). Successful contact with V3, V2, and V1 was made in 95%, 90%, and 85% of attempts, respectively. Mean distances from the entry point to FO and from FO to the clival line were 7.61 cm and 1.26 cm, respectively. CONCLUSION: In this proof-of-concept study, we found that reliable access to V1-3 could be obtained with the neuronavigation-specific algorithm described above. Neuronavigation for RFL warrants further investigation as a potential tool to improve anatomic selectivity, operative efficiency, and ultimately patient outcomes.

Interhemispheric Transcallosal Resection of Large Colloid Cyst Through Nondilated Foramen with Use of Microblade Retractor: 2-Dimensional Operative Video.

Patients who present with a large colloid cyst (CC) and nondilated ventricles represent a therapeutic challenge.1-3 Although transcallosal approaches provide reliable access to the lateral ventricle and foramen of Monro, direct visualization of the vascular attachment of the CC to the roof of the third ventricle is not always possible. This can be especially true with CCs located more posteriorly and superiorly.4 Opening of the choroidal fissure can improve access and visualization to the posterior third ventricle; however, this maneuver is associated with some element of risk.5 There is a paucity of operative video in the literature illustrating the technique of gentle, microblade elevation of the fornix to improve visualization into the third ventricle and, on occasion, avoid the need to open the choroidal fissure.6 We report the case of a 28-year-old woman who presented with headaches and progressive short-term memory dysfunction (Video 1). Magnetic resonance imaging demonstrated a 17-mm CC associated with distortion and thinning of the bilateral fornices without hydrocephalus. The patient was offered interhemispheric, transcallosal resection. Intraoperatively, gentle elevation of the fornix with a microblade retractor facilitated access to the vascular attachment of the colloid cyst-obviating the need to open the choroidal fissure. The index operative video discusses the technical nuances associated with trans-callosal resection of CC with use of the microblade retractor. Special emphasis is placed on the intricate relationship of neighboring anatomic structures. The patient consented to the procedure and the publication of her image.

Evaluating mortality and 6-month functional outcomes of patients with dural venous sinus thrombosis in traumatic brain injury.

OBJECTIVE: Patients with dural venous sinus thrombosis (DVST) in select populations following traumatic brain injury (TBI), including those with blunt mechanism or depressed skull fractures, have been shown to have an increased risk of mortality. The purpose of this study was to assess these findings in a mixed population of head trauma patients. METHODS: The authors performed a case-control study using propensity score matching by reviewing 17 years (2004-2021) of data from their institutional trauma registry. Patients with imaging-confirmed DVST were matched to a control group of TBI patients without identified DVST based on age, sex, postresuscitation Glasgow Coma Scale (GCS) score, and Injury Severity Score. All age groups and injury mechanisms were included with a head Abbreviated Injury Scale score ≥ 3. Data on demographics, injury and radiographic characteristics, and patient outcomes were collected. Multivariable logistic regression was performed to identify predictors of inpatient mortality. An additional subgroup analysis of patients with concurrent DVST and blunt cerebrovascular injury (BCVI) was planned a priori. RESULTS: The authors identified 9875 patients who presented to their institution over the study period with TBIs, with a 1.64% incidence of DVST. Concurrent BCVI was diagnosed in 23.5% of patients with a DVST. Following matching, the presence of DVST itself was not significantly associated with inpatient mortality (OR 0.68, 95% CI 0.24-1.88). On regression analysis, penetrating injuries (8.19, 95% CI 1.21-80.0) and lower postresuscitation GCS scores (0.69, 95% CI 0.53-0.84) were independently associated with inpatient mortality for patients with traumatic DVST. Significantly worse functional outcomes were observed in those with DVST at 3 months, with no significant difference at 6 months. CONCLUSIONS: The authors observed a prevalence of traumatic DVST of 1.64% in a mixed population of head-injured patients, with 23.5% of patients with DVST having concurrent BCVI. Traumatic DVST alone was not associated with a significantly increased risk of inpatient mortality.

Case report of bilateral middle ear effusion requiring myringotomy and tube placement following inferior U-shaped nasopharyngeal flap elevation for endonasal odontoidectomy: investigation of causality.

We describe a patient with symptomatic os odontoideum and a previous history of C1-2 wiring who underwent successful treatment with a staged endonasal odontoidectomy and C1-2 revision of instrumentation. Access to the odontoid process was gained through the endonasal corridor using an inverted U-shaped nasopharyngeal flap (IUNF). Post-operatively, the patient experienced resolution of her presenting neurologic symptoms but developed conductive hearing loss secondary to bilateral middle ear effusion, requiring bilateral myringotomy and tube placement 3 months post-operatively. We hypothesize this dysfunction may have resulted from surgical edema, packing buttressing the IUNF, or some combination thereof. In this manuscript, we review the evolution of the nasopharyngeal exposure for odontoidectomy and whether an IUNF may predispose to this complication.

A proposed classification system for presigmoid approaches: a scoping review.

OBJECTIVE: The "presigmoid corridor" covers a spectrum of approaches using the petrous temporal bone either as a target in treating intracanalicular lesions or as a route to access the internal auditory canal (IAC), jugular foramen, or brainstem. Complex presigmoid approaches have been continuously developed and refined over the years, leading to great heterogeneity in their definitions and descriptions. Owing to the common use of the presigmoid corridor in lateral skull base surgery, a simple anatomy-based and self-explanatory classification is needed to delineate the operative perspective of the different variants of the presigmoid route. Herein, the authors conducted a scoping review of the literature with the aim of proposing a classification system for presigmoid approaches. METHODS: The PubMed, EMBASE, Scopus, and Web of Science databases were searched from inception to December 9, 2022, following the PRISMA Extension for Scoping Reviews guidelines to include clinical studies reporting the use of "stand-alone" presigmoid approaches. Findings were summarized based on the anatomical corridor, trajectory, and target lesions to classify the different variants of the presigmoid approach. RESULTS: Ninety-nine clinical studies were included for analysis, and the most common target lesions were vestibular schwannomas (60/99, 60.6%) and petroclival meningiomas (12/99, 12.1%). All approaches had a common entry pathway (i.e., mastoidectomy) but were differentiated into two main categories based on their relationship to the labyrinth: translabyrinthine or anterior corridor (80/99, 80.8%) and retrolabyrinthine or posterior corridor (20/99, 20.2%). The anterior corridor comprised 5 variations based on the extent of bone resection: 1) partial translabyrinthine (5/99, 5.1%), 2) transcrusal (2/99, 2.0%), 3) translabyrinthine proper (61/99, 61.6%), 4) transotic (5/99, 5.1%), and 5) transcochlear (17/99, 17.2%). The posterior corridor consisted of 4 variations based on the target area and trajectory in relation to the IAC: 6) retrolabyrinthine inframeatal (6/99, 6.1%), 7) retrolabyrinthine transmeatal (19/99, 19.2%), 8) retrolabyrinthine suprameatal (1/99, 1.0%), and 9) retrolabyrinthine trans-Trautman's triangle (2/99, 2.0%). CONCLUSIONS: Presigmoid approaches are becoming increasingly complex with the expansion of minimally invasive techniques. Descriptions of these approaches using the existing nomenclature can be imprecise or confusing. Therefore, the authors propose a comprehensive classification based on the operative anatomy that unequivocally describes presigmoid approaches simply, precisely, and efficiently.

Clinical disease course and survival outcomes following disease recurrence in adenoid cystic carcinoma with and without NOTCH signaling pathway activation.

BACKGROUND: Adenoid cystic carcinoma (ACC) is a rare salivary cancer. The highest rates of disease recurrence are in patients with NOTCH pathway activation, reported in up to 20%. Novel drugs targeting NOTCH signaling are under investigation in the recurrent/metastatic (R/M) setting. To understand their clinical utility, there is an urgent need to better characterize the disease course and outcomes following current standard of care treatment. METHODS: 120 patients with R/M ACC underwent clinical review at a single UK Cancer Centre. Patients were retrospectively assessed for tumor NOTCH pathway activation using next generation sequencing (NGS) targeting NOTCH1/2/3 genes and/or NOTCH1 intra-cellular domain (NICD1) immunohistochemistry. Demographic and treatment data were extracted from the clinical notes. Kaplan-Meier survival analysis was performed using log rank test. RESULTS: NOTCH pathway activation was identified in 13/120 patients (11 %). In 12/101 patients analyzed by NGS, NOTCH1/3 activating somatic mutations were identified, and a further patient was identified with NICD1 diffuse nuclear staining in whom NGS testing was not possible. Patients with NOTCH pathway activation had shorter median RFS (1.1 vs 3.4 years, p = 0.2032) and significantly reduced median OS from diagnosis (4.0 vs 16.3 years, p < 0.0001). There was significantly reduced median OS from time of disease recurrence/metastasis (1.9 vs 9.6 years, p < 0.0001). CONCLUSION: This study clearly demonstrates a reduction in OS from time of first confirmed disease recurrence/metastasis for patients with NOTCH pathway activated ACC. This provides support for developing new drugs for this sub-group of patients, for whom clinical outcomes are significantly worse and effective treatments are lacking.

AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling.

Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy with limited treatment options for recurrent or metastatic disease. Due to chemotherapy resistance and lack of targeted therapeutic approaches, current treatment options for the localized disease are limited to surgery and radiation, which fails to prevent locoregional recurrences and distant metastases in over 50% of patients. Approximately 20% of patients with ACC carry NOTCH-activating mutations that are associated with a distinct phenotype, aggressive disease, and poor prognosis. Given the role of NOTCH signaling in regulating tumor cell behavior, NOTCH inhibitors represent an attractive potential therapeutic strategy for this subset of ACC. AL101 (osugacestat) is a potent γ-secretase inhibitor that prevents activation of all four NOTCH receptors. While this investigational new drug has demonstrated antineoplastic activity in several preclinical cancer models and in patients with advanced solid malignancies, we are the first to study the therapeutic benefit of AL101 in ACC. Here, we describe the antitumor activity of AL101 using ACC cell lines, organoids, and patient-derived xenograft models. Specifically, we find that AL101 has potent antitumor effects in in vitro and in vivo models of ACC with activating NOTCH1 mutations and constitutively upregulated NOTCH signaling pathway, providing a strong rationale for evaluation of AL101 in clinical trials for patients with NOTCH-driven relapsed/refractory ACC.

C1 Lateral Mass Screw Placement Through Endonasal Corridor for Purpose of O-C1 Fusion: Morphometric Analysis in Cadaveric Specimens.

BACKGROUND: Odontoidectomy may pose some risks for O-C1 and/or C1-C2 instability, with previous authors reporting techniques for endonasal C1-C2 fusion. However, no technique for endonasal O-C1 fusion currently exists. We sought to describe the feasibility of endonasal anterior C1 (AC1) screw placement for endonasal O-C1 fusion. METHODS: Seven adult cadaveric heads were studied for endonasal placement of 14 C1 screws. Using thin-cut computed tomography (CT)-based "snapshot" neuronavigation assistance, 4 mm x 22 mm screws were placed in the C1 lateral mass using a 0° driver. Post-placement CT scans were obtained to determine site-of-entry measured from C1 anterior tubercle, screw angulation in axial and sagittal planes, and screw proximity to the central canal and foramen transversarium. RESULTS: Average site-of-entry was 16.57 mm lateral, 2.23 mm rostral, and 5.53 mm deep to the anterior-most portion of the C1 ring. Average axial angulation was 19.49° lateral to midline, measured at the C1 level. Average sagittal angulation was 13.22° inferior to the palatal line, measured from the hard palate to the opisthion. Bicortical purchase was achieved in 11 screws (78.6%). Partial breach of the foramen transversarium was observed in 2 screws (14.3%), violation of the O-C1 joint space in 1 (7.1%), and violation of the central canal in 0 (0%). Average minimum screw distances from the unviolated foramen transversaria and central canal were 1.97 mm and 4.04 mm. CONCLUSIONS: Navigation-assisted endonasal placement of AC1 screws is feasible. Additional studies should investigate the biomechanical stability of anterior C1 screw-plating systems, with anterior condylar screws as superior fixation point, compared to traditional posterior O-C1 fusion.

Bone morphogenetic protein receptor inhibitors suppress the growth of glioblastoma cells.

Glioblastomas (GBMs) are aggressive brain tumors that are resistant to chemotherapy and radiation. Bone morphogenetic protein (BMP) ligand BMP4 is being examined as a potential therapeutic for GBMs because it induces differentiation of cancer stem cells (CSCs) to an astrocyte phenotype. ID1 is reported to promote self-renewal and inhibit CSC differentiation. In most cancers, ID1 is transcriptionally upregulated by BMP4 promoting invasion and stemness. This conflicting data bring into question whether BMP signaling is growth suppressive or growth promoting in GBMs. We utilized BMP inhibitors DMH1, JL5, and Ym155 to examine the role of BMP signaling on the growth of GBMs. DMH1 targets BMP type 1 receptors whereas JL5 inhibits both the type 1 and type 2 BMP receptors. Ym155 does not bind the BMP receptors but rather inhibits BMP signaling by inducing the degradation of BMPR2. We show that JL5, DMH1, and Ym155 decreased the expression of ID1 in SD2 and U87 cells. JL5 and Ym155 also decreased the expression of BMPR2 and its downstream target inhibitor of apoptosis protein XIAP. JL5 treatment resulted in significant cell death and suppressed self-renewal to a greater extent than that induced by BMP4 ligand. The lysosome inhibitor chloroquine increases the localization of BMPR2 to the plasma membrane enhancing JL5-induced downregulation of ID1 and cell death in SD2 cells. We show that BMP signaling is growth promoting in GBMs. These studies suggest the need for development of BMP inhibitors and evaluation as potential therapeutic for GBMs.

Current applications and safety profile of laser interstitial thermal therapy in the pediatric population: a systematic review of the literature.

OBJECTIVE: Laser interstitial thermal therapy (LITT) provides a minimally invasive alternative to open brain surgery, making it a powerful neurosurgical tool especially in pediatric patients. This systematic review aimed to highlight the indications and complications of LITT in the pediatric population. METHODS: In line with the PRISMA guidelines, the authors conducted a systematic review to summarize the current applications and safety profiles of LITT in pediatrics. PubMed and Embase were searched for studies that reported the outcomes of LITT in patients < 21 years of age. Retrospective studies, case series, and case reports were included. Two authors independently screened the articles by title and abstract followed by full text. Relevant variables were extracted from studies that met final eligibility, and results were pooled using descriptive statistics. RESULTS: The selection process captured 303 pediatric LITT procedures across 35 studies. Males comprised approximately 60% of the aggregate sample, with a mean age of 10.5 years (range 0.5-21 years). The LITT technologies used included Visualase (89%), NeuroBlate (9%), and Multilase 2100 (2%). The most common indication was treatment of seizures (86%), followed by brain tumors (16%). The mean follow-up duration was 15.6 months (range 1.3-48 months). The overall complication rate was 15.8%, which comprised transient neurological deficits, cognitive and electrolyte disturbances, hemorrhage, edema, and hydrocephalus. No deaths were reported. CONCLUSIONS: As of now, LITT's most common applications in pediatrics are focused on treating medically refractory epilepsy and brain tumors that can be difficult to resect. The safety of LITT can provide an attractive alternative to open brain surgery in the pediatric population.

Stenting in High-Grade Internal Carotid Artery Stenosis: 2-Dimensional Operative Video.

Carotid artery stenosis is implicated in up to 40% of all ischemic strokes. Accordingly, symptomatic, high-grade carotid artery stenosis portends an especially high risk of future stroke. Intervention via open or endovascular approaches drastically reduces this risk. Under the appropriate conditions, carotid artery stenting serves as a safe and effective alternative to carotid endarterectomy. We present the case of a 57-yr-old male with symptomatic, high-grade stenosis of his right internal carotid artery, for whom a history of radiation to the head and neck represented a relative contraindication to carotid endarterectomy, and thus endovascular treatment with angioplasty and stenting was performed. Informed consent was obtained prior to the procedure. Intraprocedurally, stent delivery past the area of stenosis proved somewhat challenging. However, by employing several nuanced maneuvers, we utilized our guiding catheter in a nonconventional manner in order to successfully perform the procedure. As the field of neuroendovascular surgery evolves, each case provides us unique lessons, which in turn expands our interventional capabilities and adds to the armamentarium of neuroendovascular techniques. We present this surgical video both as a means to provide a general overview of carotid artery stenting, and to share a lesson learned through the implementation of an interesting technical nuance.

Aryl Hydrocarbon Receptor Activation in Astrocytes by Laquinimod Ameliorates Autoimmune Inflammation in the CNS.

OBJECTIVE: MS is an autoimmune demyelinating disease of the CNS, which causes neurologic deficits in young adults and leads to progressive disability. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, can drive anti-inflammatory functions in peripheral immune cells and also in CNS-resident cells. Laquinimod is a drug developed for the treatment of MS known to activate AHR, but the cellular targets of laquinimod are still not completely known. In this work, we analyzed the contribution of AHR activation in astrocytes to its beneficial effects in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS. METHODS: We used conditional knockout mice, in combination with genome-wide analysis of gene expression by RNA-seq and in vitro culture systems to investigate the effects of laquinimod on astrocytes. RESULTS: We found that AHR activation in astrocytes by laquinimod ameliorates EAE, a preclinical model of MS. Genome-wide RNA-seq transcriptional analyses detected anti-inflammatory effects of laquinimod in glial cells during EAE. Moreover, we established that the Delaq metabolite of laquinimod dampens proinflammatory mediator production while activating tissue-protective mechanisms in glia. CONCLUSIONS: Taken together, these findings suggest that AHR activation by clinically relevant AHR agonists may represent a novel therapeutic approach for the treatment of MS.

Cognitive disturbances in the cuprizone model of multiple sclerosis.

Cognitive problems frequently accompany neurological manifestations of multiple sclerosis (MS). However, during screening of preclinical candidates, assessments of behaviour in mouse models of MS typically focus on locomotor activity. In the present study, we analysed cognitive behaviour of 9 to 10-week-old female C57Bl/6J mice orally administered with the toxin cuprizone that induces demyelination, a characteristic feature of MS. Animals received 400 mg/kg cuprizone daily for 2 or 4 weeks, and their performance was compared with that of vehicle-treated mice. Cuprizone-treated animals showed multiple deficits in short touchscreen-based operant tasks: they responded more slowly to visual stimuli, rewards and made more errors in a simple rule-learning task. In contextual/cued fear conditioning experiments, cuprizone-treated mice showed significantly lower levels of contextual freezing than vehicle-treated mice. Diffusion tensor imaging showed treatment-dependent changes in fractional anisotropy as well as in axial and mean diffusivities in different white matter areas. Lower values of fractional anisotropy and axial diffusivity in cuprizone-treated mice indicated developing demyelination and/or axonal damage. Several diffusion tensor imaging measurements correlated with learning parameters. Our results show that translational touchscreen operant tests and fear conditioning paradigms can reliably detect cognitive consequences of cuprizone treatment. The suggested experimental approach enables screening novel MS drug candidates in longitudinal experiments for their ability to improve pathological changes in brain structure and reverse cognitive deficits.

Repeat Gamma Knife Radiosurgery for Recurrent Glossopharyngeal Neuralgia: A Systematic Review and Our Initial Experience.

BACKGROUND: Glossopharyngeal neuralgia (GPN) is a rare facial pain syndrome with debilitating symptoms. For medication-resistant GPN, stereotactic radiosurgery (SRS) is an emerging treatment option with a promising role; however, recurrence rates after SRS are fairly high. We present a patient who underwent repeat SRS for recurrent GPN and subsequently maintained over 3 years of complete pain relief. For the first time, we present a systematic review of repeat SRS for recurrent GPN. SUMMARY: Twelve cases of repeat SRS for GPN have previously been reported in the literature (13 studies including ours). Among patients with follow-up, initial pain relief was achieved in 83% (n = 10) of cases a median of 5 weeks after repeat SRS; 2 patients failed to obtain any pain relief. A favorable pain response (BNI I-IIIb) was achieved in 67 and 58% of cases at 6 and 12 months, respectively. All 13 were targeted to the glossopharyngeal meatus. Three patients (23%) experienced adverse radiation effects. Five patients (50%) experienced recurrence a median of 14 months after repeat SRS. Two patients (17%) required additional surgical intervention. At the final follow-up, 75% (n = 9) of the patients had a favorable pain outcome. Key Messages: Repeat SRS may be a viable alternative to open surgery for the treatment of recurrent GPN, albeit with an increased risk of adverse radiation effects. Though limited by a small cohort of patients, the best predictors of an effective second treatment may be a response to initial SRS for >5 months, a maximum dose >75 Gy, and a target at the glossopharyngeal meatus. Larger prospective studies are needed to better define its role.

Laser interstitial thermal therapy for in-field recurrence of brain metastasis after stereotactic radiosurgery: does treatment with LITT prevent a neurologic death?

Brain metastasis (BM) affects up to one-third of adults with cancer and carries a historically bleak prognosis. Despite advances in stereotactic radiosurgery (SRS), rates of in-field recurrence (IFR) after SRS range from 10 to 25%. High rates of neurologic death have been reported after SRS failure, particularly for recurrences deep in the brain and surgically inaccessible. Laser interstitial thermal therapy (LITT) is an emerging option in this setting, but its ability to prevent a neurologic death is unknown. In this study, we investigate the causes of death among patients with BM who undergo LITT for IFR after SRS. We conducted a single institution retrospective case series of patients with BM who underwent LITT for IFR after SRS. Clinical and demographic data were collected via chart review. The primary endpoint was cause of death. Between 2010 and 2018, 70 patients with BM underwent LITT for IFR after SRS. Median follow-up after LITT was 12.0 months. At analysis, 49 patients died; a cause was determined in 44. Death was neurologic in 20 patients and non-neurologic in 24. The 24-month cumulative incidence of neurologic and non-neurologic death was 35.1% and 38.6%, respectively. Etiologies of neurologic death included local recurrence (n = 7), recovery failure (n = 7), distant progression (n = 5), and other (n = 1). Among our patient population, LITT provided the ability to stabilize neurologic disease in up to 2/3 of patients. For IFR after SRS, LITT may represent a reasonable treatment strategy for select patients. Additional work is necessary to determine the extent to which LITT can prevent neurologic death after recurrence of BM.

Presentation, Surgical Management, and Postoperative Outcome of a Fourth Ventricular Cavernous Malformation: Case Report and Review of Literature.

BACKGROUND: Brainstem cavernous malformations (CMs) represent dangerous clinical entities associated with high rates of rebleeding and morbidity compared with those in other locations. Particularly rare are those located within the fourth ventricle. Although fourth ventricular CMs are favorable from a surgical standpoint, there are no defined guidelines on definitive indications and optimal timing of surgery. In addition, the surgical approaches, anatomic considerations, and general observations regarding these lesions are not well reported in the literature. CASE PRESENTATION: A 27-year-old man with a known history of a CM on the floor of the fourth ventricle presented with new cranial nerve deficits and signs of increased intracranial pressure. Imaging revealed acute bleeding from a fourth ventricular CM. The patient was urgently taken to surgery for resection. Despite a noneventful surgery which resulted in gross total resection, the patient developed a unique constellation of cranial nerve deficits postoperatively, most notably of which was eight-and-a-half syndrome. CONCLUSIONS: CMs of the fourth ventricle are rare clinical entities that can be treated successfully with surgery. The indications for surgery may not always be clear-cut; therefore, the neurosurgeon's decision to proceed with surgery must reside on a case-by-case basis using a multifactorial approach. The location of these lesions presents unique challenges given their proximity to vital structures and the technical difficulty required. For these reasons, the resection of these lesions often results in new or persistent neurologic deficits. However, despite the associated risks, the potential benefits of surgery oftentimes outweigh the risks of the alternative.

Laquinimod ameliorates secondary brain inflammation.

Accumulating evidence suggests that a degenerative processes within the brain can trigger the formation of new, focal inflammatory lesions in Multiple Sclerosis (MS). Here, we used a novel pre-clinical MS animal model to test whether the amelioration of degenerative brain events reduces the secondary recruitment of peripheral immune cells and, in consequence, inflammatory lesion development. Neural degeneration was induced by a 3 weeks cuprizone intoxication period. To mitigate the cuprizone-induced pathology, animals were treated with Laquinimod (25 mg/kg) during the cuprizone-intoxication period. At the beginning of week 6, encephalitogenic T cell development in peripheral lymphoid organs was induced by the immunization with myelin oligodendrocyte glycoprotein 35-55 peptide (i.e., Cup/EAE). Demyelination, axonal injury and reactive gliosis were determined by immunohistochemistry. Positron emission tomography (PET) imaging was performed to analyze glia activation in vivo. Vehicle-treated cuprizone mice displayed extensive callosal demyelination, glia activation and enhanced TSPO-ligand binding. This cuprizone-induced pathology was profoundly ameliorated in mice treated with Laquinimod. In vehicle-treated Cup/EAE mice, the cuprizone-induced pathology triggered massive peripheral immune cell recruitment into the forebrain, evidenced by multifocal perivascular inflammation, glia activation and neuro-axonal injury. While anti myelin oligodendrocyte glycoprotein 35-55 peptide immune responses were comparable in vehicle- and Laquinimod-treated Cup/EAE mice, the cuprizone-triggered immune cell recruitment was ameliorated by the Laquinimod treatment. This study clearly illustrates that amelioration of a primary brain-intrinsic degenerative process secondary halts peripheral immune cell recruitment and, in consequence, inflammatory lesion development. These findings have important consequences for the interpretation of the results of clinical studies.

Laquinimod Supports Remyelination in Non-Supportive Environments.

Inflammatory demyelination, which is a characteristic of multiple sclerosis lesions, leads to acute functional deficits and, in the long term, to progressive axonal degeneration. While remyelination is believed to protect axons, the endogenous-regenerative processes are often incomplete or even completely fail in many multiple sclerosis patients. Although it is currently unknown why remyelination fails, recurrent demyelination of previously demyelinated white matter areas is one contributing factor. In this study, we investigated whether laquinimod, which has demonstrated protective effects in active multiple sclerosis patients, protects against recurrent demyelination. To address this, male mice were intoxicated with cuprizone for up to eight weeks and treated with either a vehicle solution or laquinimod at the beginning of week 5, where remyelination was ongoing. The brains were harvested and analyzed by immunohistochemistry. At the time-point of laquinimod treatment initiation, oligodendrocyte progenitor cells proliferated and maturated despite ongoing demyelination activity. In the following weeks, myelination recovered in the laquinimod- but not vehicle-treated mice, despite continued cuprizone intoxication. Myelin recovery was paralleled by less severe microgliosis and acute axonal injury. In this study, we were able to demonstrate that laquinimod, which has previously been shown to protect against cuprizone-induced oligodendrocyte degeneration, exerts protective effects during oligodendrocyte progenitor differentiation as well. By this mechanism, laquinimod allows remyelination in non-supportive environments. These results should encourage further clinical studies in progressive multiple sclerosis patients.

2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Vascular Dysfunction That is Dependent on Perivascular Adipose and Cytochrome P4501A1 Expression.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is associated with hypertension in humans and animals, and studies suggest that cytochrome P4501A1 (Cyp1a1) induction and vascular dysfunction may contribute. We investigated the role of perivascular adipose tissue (PVAT) and Cyp1a1 in TCDD-induced vascular dysfunction. Cyp1a1 wild-type (WT) and knockout (KO) male mice were fed a dough pill containing 1,4-p-dioxane (TCDD vehicle control) on days 0 and 7, or 1000 ng/kg TCDD on day 0 and 250 ng/kg TCDD on day 7. mRNA expression of Cyp1a1 was assessed on days 3, 7, and 14, and of Cyp1b1, 1a2, angiotensinogen, and phosphodiesterase 5a on day 14. Dose-dependent vasoconstriction to a thromboxane A2 mimetic (U46619), and vasorelaxation to acetylcholine and a nitric oxide donor (S-nitroso-N-acetyl-DL-penicillamine, SNAP), were investigated in the aorta with and without PVAT. Cyp1a1 and 1a2 mRNA was induced in aorta of WT mice only with PVAT, and Cyp1a1 induction was sustained through day 14. TCDD significantly enhanced constriction to U46619 in WT mice and inhibited relaxation to both acetylcholine and SNAP, but only in the presence of PVAT. The effects of TCDD on U46619 constriction and SNAP relaxation were not observed in Cyp1a1 KO mice. Finally, in aorta + PVAT of WT mice TCDD significantly induced expression of angiotensinogen and phosphodiesterase 5a both of which could contribute to the TCDD-induced vascular dysfunction. These data establish PVAT as a TCDD target which is critically involved in mediating vascular dysfunction. TCDD enhances vasoconstriction via the thromboxane/prostanoid (TP) receptor and inhibits vasorelaxation via nitric oxide (NO) signaling. This TCDD-induced vascular dysfunction requires perivascular adipose (PVAT) and cytochrome P4501a1 (CYP1a1) induction.