Meningeal Membranes Research Articles

Structural characterization of SLYM—a 4th meningeal membrane

Traditionally, the meninges are described as 3 distinct layers, dura, arachnoid and pia. Yet, the classification of the connective meningeal membranes surrounding the brain is based on postmortem macroscopic examination. Ultrastructural and single cell transcriptome analyses have documented that the 3 meningeal layers can be subdivided into several distinct layers based on cellular characteristics. We here re-examined the existence of a 4th meningeal membrane, Subarachnoid Lymphatic-like Membrane or SLYM in Prox1-eGFP reporter mice. Imaging of freshly resected whole brains showed that SLYM covers the entire brain and brain stem and forms a roof shielding the subarachnoid cerebrospinal fluid (CSF)-filled cisterns and the pia-adjacent vasculature. Thus, SLYM is strategically positioned to facilitate periarterial influx of freshly produced CSF and thereby support unidirectional glymphatic CSF transport. Histological analysis showed that, in spinal cord and parts of dorsal cortex, SLYM fused with the arachnoid barrier layer, while in the basal brain stem typically formed a 1–3 cell layered membrane subdividing the subarachnoid space into two compartments. However, great care should be taken when interpreting the organization of the delicate leptomeningeal membranes in tissue sections. We show that hyperosmotic fixatives dehydrate the tissue with the risk of shrinkage and dislocation of these fragile membranes in postmortem preparations.

Meningitis of hantavirus etiology

The article describes a clinical case of serous meningitis in a patient with confirmed hemorrhagic fever with renal syndrome (HFRS). Despite the moderate-severe course of the disease with moderate hemorrhagic syndrome, the patient had the development of acute renal failure with the simultaneous occurrence of a rare complication – inflammation of the meningeal membranes caused by hantavirus.

Glycation-mediated tissue-level remodeling of brain meningeal membrane by aging.

Collagen is a prominent target of nonenzymatic glycation, which is a hallmark of aging and causes functional alteration of the matrix. Here, we uncover glycation-mediated structural and functional changes in the collagen-enriched meningeal membrane of the human and mouse brain. Using an in vitro culture platform mimicking the meningeal membrane composed of fibrillar collagen, we showed that the accumulation of advanced glycation end products (AGEs) in the collagen membrane is responsible for glycation-mediated matrix remodeling. These changes influence fibroblast-matrix interactions, inducing cell-mediated ECM remodeling. The adherence of meningeal fibroblasts to the glycated collagen membrane was mediated by the discoidin domain-containing receptor 2 (DDR2), whereas integrin-mediated adhesion was inhibited. A-kinase anchoring protein 12 (AKAP12)-positive meningeal fibroblasts in the meningeal membrane of aged mice exhibited substantially increased expression of DDR2 and depletion of integrin beta-1 (ITGB1). In the glycated collagen membrane, meningeal fibroblasts increased the expression of matrix metalloproteinase 14 (MMP14) and less tissue inhibitor of metalloproteinase-1 (TIMP1). In contrast, the cells exhibited decreased expression of type I collagen (COL1A1). These results suggest that glycation modification by meningeal fibroblasts is intimately linked to aging-related structural and functional alterations in the meningeal membrane.

Spontaneous bleeding of an arachnoid cyst: a rare cause of thunderclap headache

Introduction A thunderclap headache is a severe headache that starts suddenly and may be a sign of a condition that can be life threatening. Objective To present a case of a rare cause of thunderclap headache. Case presentation A 37-year-old female patient was admitted in the neurological emergence service of a private hospital in the city of São Paulo. She had sudden, explosive, and pulsatile headache, with photophobia and phonophobia. The neurological examination had no focal signs. She had deep vein thrombosis in 2014 in the past and since then she has been irregularly using Warfarin. She underwent CT and MRI of the skull that showed enlargement of the bilateral retrovermian and retrocerebellar cerebrospinal fluid space, with thin membranes/septations inside, and heterogeneous content, with deposition of hemoglobin degradation products. Such findings are consistent with a retrovermian arachnoid cyst with hemorrhagic content. The INR was 1. Conservative and symptomatic treatment was started, and control CT was performed on the second day of hospitalization, demonstrating almost complete reabsorption of hematic material. The patient was discharged after 2 days of hospitalization with complete headache improvement. Conclusion Arachnoid cysts are collections of fluid located between the meningeal membranes. They are congenital and are formed due to a valve defect in the arachnoid membranes leading to a collection of cerebrospinal fluid (CSF) in its interior. Most arachnoid cysts are an incidental finding. About 1 to 2% of the population has an arachnoid cyst and symptoms appear when the cyst increases in size or bleeds. Our patient had a are complication of and arachnoid cyst not related with the use of anticoagulant. Keywords: Thunderclap headache, Arachnoid Cyst Bleeding, Arachnoid Cyst.

Suilyin Disrupts the Blood-Brain Barrier by Activating Group III Secretory Phospholipase A2.

Serious diseases caused by Streptococcus suis serotype 2 (S. suis 2) include septicaemia and meningitis, which are associated with high morbidity and mortality. Proliferation in the blood can result in a breach of the blood–brain barrier (BBB) and provide entry into the cerebrospinal fluid (CSF), where bacteria cause inflammation of the meningeal membranes resulting in meningitis. The molecular mechanisms of how this pathogen crosses the BBB remain unclear. Suilysin (SLY) has been identified as an important secreted virulence factor of S. suis 2 and may play a vital role in provoking meningitis. In this investigation, we demonstrate that SLY can increase the paracellular permeability of BBB, both in vivo and in vitro, via the activation of group III secretory phospholipase A2 (PLA2G3). Our results indicate that at lower, sublytic concentrations, the toxin can stimulate cerebral microvascular endothelial cells to release TNF-α, thereby inducing high level expressions of PLA2G3. Abnormal elevations of PLA2G3 might further injure tissues through direct cytolytic effectors or other responses.

Pathogenesis and predisposing factors in drug-induced aseptic meningitis: A case study

Aseptic meningitis is the inflammation of the meningeal membranes in the absence of an identifiable pathogen. While viruses are the most common culprit, bacteria, fungi, rheumatological conditions, and neoplastic processes are also known causes. It is also an uncommon, yet increasingly reported, adverse effect of certain drugs. Due to its recurrent nature, association with a specific medication, and resolution upon drug withdrawal, DIAM is an important diagnosis of exclusion in prevention and management.

Dural architecture of the cavernous sinus. Structure of the dura mater of the sellar region

This work is devoted to the study of the topography of the cavernous sinus and the clinical and anatomical substantiation of neurosurgical operations. Aspects of the topography of the internal carotid artery, cavernous sinus, cranial nerves of the sellar and paraclinic regions, topography and structure of the dura mater on the skull base, dura mater duplicates, cerebellar nave ligament, meningeal membranes (cerebral base cistern membrane, proximal carotid ring carotid membrane) and carotid rings are revealed. The work contains a large number of topograms and diagrams based on scientific literature data, as well as the author's own observations.

Evaluation of Rat Brain Morphology Following the Induction of Acute Meningitis Treated with Ceftriaxone.

The soft and delicate tissue of the brain, which is the center of our coordination, is protected by its surrounding layers. The disruption of these layers results in complicated situations and serious health problems. The brain has three protective layers of bone or skull tissue, the blood tissue layer, and finally the meningeal layer. The layer of blood tissue contains the blood vessels that are located between the skull and the meningeal membranes. If germs or foreign matter enter the fluid through the blood vessels under any circumstances and cause infection, the bones that protect the meninges will break and cause tissue damage. The present study aimed to assess the histological and immunohistochemical characteristics of the brain of rats that underwent induced acute purulent pneumococcal meningitis after antibiotic therapy with Ceftriaxone. A number of 20 white adult male Wistar rats were assigned to three groups. The first group (n=5) regarded as the control were injected with a saline solution into the subarachnoid space in an equivalent amount. The second and third groups of rats (n=5 and 10, respectively) were infected with acute purulent meningitis by the injection of 10 μl of Streptococcus pneumoniae (S. pneumonia) suspension into the subarachnoid space of the brain using a 23-G needle. The various areas of the brains of rats after meningitis inducedby S. pneumoniae were examined after the treatment with Ceftriaxone. The S. pneumoniae culture was injected into the subarachnoid space in the area of the rhomboid fossa. Treatment started 18 h after the injection. On day 10, a repeated puncture was performed with the analysis of cerebrospinal fluid in order to confirm the absence of meningitis; thereafter, the animals were taken out of the experiment. No signs of meningitis were found on histological examination. Mild perivascular and pericellular focal edema were revealed with signs of overload of the lymphatic system in the brain and focal ischemic changes in neurons. The investigation of expression with caspase-3 revealed a positive reaction of individual neurons. A positive reaction with antibodies to NeuN and Doublecortin was detected in most neurons; moreover, Glial fibrillary acidic protein (GFAP)-positive astrocytes and their processes were visualized in all layers of the brain substance. The reaction with neuron-specific enolase (NSE), microtubule-associated protein 2 (MAP-2), CD 31, and CD 34 was negative. Typical structure and pictures pointed to an intact brain and purulent meningitis in the first and second groups. The microscopic image and the changes revealed during immunohistochemistry by dual corticosteroid antibodies and neuronal nuclear protein were characterized by predominantly cytoplasmic and perinuclear reactions, respectively. Some neurons are positive for caspase-3 and are related to changes in the characteristic of premature aging.

Сучасні клініко-епідеміологічні особливості ентеровірусних менінгітів

Актуальність. Актуальність нейроінфекцій обумовлена вираженою тяжкістю перебігу та високим відсотком летальності. Кількість серозних менінгітів збільшується щодня. Серозний менінгіт є одним із найбільш частих проявів ентеровірусної інфекції. Мета. Встановлення опорних клініко-лабораторних симптомів ентеровірусної етіології менінгіту. Матеріали та методи. Проаналізували результати динамічного клінічного спостереження й обстеження 70 пацієнтів із менінгітами. За результатами полімеразної ланцюгової реакції калу та/або ліквору у 33 хворих встановлено ентеровірусну етіологію захворювання, а у решти 37 етіологія залишилася нез’ясованою. Результати. З’ясували, що ентеровірусні менінгіти мають ряд анамнестичних, клінічних і лабораторних особливостей, таких як: до ентеровірусного пошкодження менінгеальних оболонок більш схильні діти перших десяти років життя; важливим епідфактором при цьому є відпочинок на морі; серед ранніх симптомів ентеровірусного менінгіту частіше реєструється блювання; для ентеровірусного менінгіту характерна полога температурна крива з ранньої нормалізацією температури тіла (на 3–5-й день у більшості пацієнтів); у цих пацієнтів переважно має місце змішаний плеоцитоз ліквору.

Senescent accelerated prone 8 (SAMP8) mice as a model of age dependent neuroinflammation

BackgroundAging and age-related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain’s immune response, plays an important role in aged associated degeneration of central nervous system (CNS). There is a need for well characterized animal models that will allow the scientific community to understand and modulate this process.MethodsWe have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their senescence resistant control mice (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and determined the appearance of Iba1+ clustered cells with aging. To analyze specific constant brain areas, we have performed stereology measurements of Iba1+ cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m/Ch), and analyzed their response to systemic lipopolysaccharide (LPS)-driven inflammation.ResultsAged 10 months old SAMP8 mice present many of the hallmarks of aging-dependent neuroinflammation when compared with their SAMR1 control, i.e., increase of protein aggregates, presence of Iba1+ clusters, but not an increase in the number of Iba1+ cells. We have further observed an increase of main inflammatory mediator IL-1β, and an augment of border MHCII+Iba1+ cells. Isolated CD45+ bMyC from brain parenchyma (BP) and choroid plexus plus meningeal membranes (m/Ch) have been analyzed, showing that there is not a significant increase of CD45+ cells from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL-1β) transcription is enhanced in CD45+BP cells. Furthermore, LPS-driven systemic inflammation produces inflammatory cytokines mainly in border bMyC, sensed to a lesser extent by the BP bMyC, showing that IL-1β expression is further augmented in aged SAMP8 compared to control SAMR1.ConclusionOur data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of pro-inflammatory cytokines such as IL-1β, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.

English

The report presents a case of rear congenital defects of occipital meningocoele in male buffalo calf of Neeli-Ravi breed. A soft fluctuating, fluid filled swelling was observed in the occipital region of skull. On the base of grass clinical examination and ultrasound examination, the case was diagnosed as occipital meningocoele and was recommended for surgical treatment under general anesthesia. An elliptical skin incision was made at the base of the swelling involving the skin. Fluid filled meningeal membranes were identified protruding out from the defect site. About one litter accumulated fluid in the sac was drained. The meninges close to the defect were resected and remaining part of meninges were sutured to close the defect. The animal got an uneventful recovery after 15 days of post-operative care. © 2021 Friends Science Publishers

Aggressive Behavior Predictors in Solitary Fibrous Tumor: Demographic, Clinical, and Histopathologic Characteristics of 81 Cases.

Solitary fibrous tumor (SFT) is a rare mesenchymal tumor with an intermediate tendency to metastasize. Meningeal hemangiopericytoma (HPC), arising in the meningeal membranes, also is considered an SFT. Although SFT is assumed to show an unpredictable behavior, the authors defined some factors associated with its aggressive behavior. This retrospective study was based on the medical records of 81 SFT patients treated surgically, with the median follow-up period of 59 months. The patients were assigned to three histopathologic groups based on the 2016 WHO classification: group 1 (SFT, 29 patients), group 2 (cellular SFT/hemangiopericytoma [HPC], 27 patients), and group 3 (malignant SFT/anaplastic HPC, 25 patients). The SFT histopathologic classification was associated with distant metastasis (DM) (p = 0.007). The multivariate analysis showed that cellular SFT had an independent impact on DM (odds ratio [OR] = 25.42; p = 0.006). Tumor diameter larger than 7.25cm was correlated with DM (p = 0.010) and the patient's disease-specific death (DSD) (p = 0.007). A 1-cm increase in tumor diameter enhanced the likelihood of metastasis by 1.26 (OR = 1.26; 95% confidence interval [CI], 1.05-1.53). Tumors originating from the central nervous system (CNS) showed a greater tendency toward local recurrence (LR) (p = 0.039) and DM (p = 0.05). Radiotherapy had no association with LR, DM, or DSD. The 10-year disease-specific survival rate was 82.7%. Tumor size and histopathologic diagnosis are the predictors of SFT's aggressive behavior. Cellular SFTs behave as aggressively as the malignant form of the tumor. A SFT grading based on SFT cellularity would contribute to anticipation of its aggressive behavior.

Dural architecture of cavernous sinus. Structural Solid Marrow of the Sellyar Region

Surgery of the base of the skull requires knowledge of the topography of the internal carotid artery, cavernous sinus, cranial nerves of the sellyar and paraclinoid regions. Equally important is knowledge of the topography and structure of the dura mater (CSF) at the base of the skull, CSF duplicates, cerebellar ligaments, meningeal membranes (tank membranes of the brain base, carotid oculomotor membrane of the proximal carotid ring) and carotid rings in neurooncology and vascular neurosurgery. The article presents the results of the study of the structure of TMO in the selvary and paraselar regions.

Next generation sequencing identifies novel potential actionable mutations for grade I meningioma treatment.

Meningiomas are common brain tumors that arise from the meningeal membranes that envelope the brain and spinal cord. The World Health Organization classifies these tumors into three histopathological grades. Because of tumor recurrence, treating meningiomas may be challenging even in well-differentiated grade I (GI) neoplasms. Indeed, around 5% of completely resected GI meningiomas relapse within 5 years. Therefore, identifying driver mutations in GI meningiomas through next generation sequencing (NGS) assays is paramount. The aim of this study was to validate the use of the 50-gene AmpliSeq Hotspot Cancer Panel v2 to identify the mutational status of 23 GI meningioma, namely, 12 non recurrent and 11 recurrent. In 18 out of the 23 GI meningiomas analyzed, we identified at least one gene mutation (78.2%). The most frequently mutated genes were c-kit (39.1%), ATM (26.1%), TP53 (26.1%), EGFR (26.1%), STK11 (21.7%), NRAS (17.4%), SMAD4 (13%), FGFR3 (13%), and PTPN11 (13%); less frequent mutations were SMARCB1 (8.7%), FLT3 (8.7%), KRAS (8.7%), FBWX7 (8.7%), ABL1 (8.7%), ERBB2 (8.7%), IDH1 (8.7%), BRAF (8.7%), MET (8.7%), HRAS (4.3%), RB1 (4.3%), CTNNB1 (4.3%), PIK3CA (4.3%), VHL (4.3%), KDR (4.3%), APC (4.3%), NOTCH1 (4.3%), JAK3 (4.3%), and SRC (4.3%). To our knowledge, mutations in all of these genes, except for TP53, STK11, SMARCB1, PIK3CA, VHL, and BRAF, have never been described before in meningiomas. Hence, these findings demonstrate the viability of NGS to detect new genetic alterations in GI meningiomas. Equally important, this technology enabled us to detect possible novel actionable mutations not previously associated with GI and for which selective inhibitors already exist.

Erratum - Effect of Albendazole Treatment in an Experimental Model of Neurocysticercosis-Induced Hydrocephalus

Hydrocephalus is a major concern in neurocysticercosis (NCC), and its management is more challenging than that of hydrocephalus caused by other etiologies. Even though albendazole is a well-established drug for the treatment of NCC, the death of the parasites may worsen the clinical symptoms and eventually, deteriorate the course of hydrocephalus. The aim of this study was to analyze the effects of treatment with albendazole on the course of hydrocephalus as well as on animal behavior in a rat model of NCC-induced hydrocephalus in order to verify whether the course of hydrocephalus and the animal behavior were changed. Ventricle volumes before and after treatment showed a slight but non-statistically significant difference (168.11 mm 3 versus 184.98 mm 3 , p = 0.45). The distribution and location of the cysts were unaffected. In addition, the behavioral patterns before and after the treatment were not significantly different, as assessed by the open field test. On histologic assessment, mononuclear leukocyte infiltration was present in diverse sites, such as the perivascular and peri-ependymal regions, choroid plexus, and meningeal membranes. A positive correlation was found between the degree of ventricle enlargement and tissue damage. Further studies with long-term comparisons are required.

Effect of Albendazole Treatment in an Experimental Model of Neurocysticercosis-Induced Hydrocephalus

AbstractHydrocephalus is a major concern in neurocysticercosis (NCC), and its management is more challenging than that of hydrocephalus caused by other etiologies. Even though albendazole is a well-established drug for the treatment of NCC, the death of the parasites may worsen the clinical symptoms and eventually, deteriorate the course of hydrocephalus. The aim of this study was to analyze the effects of treatment with albendazole on the course of hydrocephalus as well as on animal behavior in a rat model of NCC-induced hydrocephalus in order to verify whether the course of hydrocephalus and the animal behavior were changed. Ventricle volumes before and after treatment showed a slight but non-statistically significant difference (168.11 mm3 versus 184.98 mm3, p = 0.45). The distribution and location of the cysts were unaffected. In addition, the behavioral patterns before and after the treatment were not significantly different, as assessed by the open field test. On histologic assessment, mononuclear leukocyte infiltration was present in diverse sites, such as the perivascular and peri-ependymal regions, choroid plexus, and meningeal membranes. A positive correlation was found between the degree of ventricle enlargement and tissue damage. Further studies with long-term comparisons are required.

Spinal Hematomas: What a Radiologist Needs to Know.

Spinal hematomas are a frequent indication for radiologic evaluation and can be a diagnostic dilemma for many radiologists and surgeons. There are four types of spinal hematomas: epidural, subdural, subarachnoid, and intramedullary (spinal cord) hematomas. Because they differ by their location in relationship to the meningeal membranes and spinal cord, unique radiologic appearances can be recognized to distinguish these types of spinal hemorrhage. Anatomic knowledge of the spinal compartments is essential to the radiologist for confident imaging diagnosis of spinal hematomas and to specify correct locations. MRI is the modality of choice to diagnose the location of the hematoma, characterize important features such as age of the hemorrhage, and detect associated injury or disease. Each type of spinal hematoma has imaging patterns and characteristics that distinguish it from the others, as these specific spinal compartments displace and affect the adjacent anatomic structures. Early detection and accurate localization of spinal hematomas is critical for the surgeon to address the proper treatment and surgical decompression, when necessary, as neurologic deficits may otherwise become permanent. Online supplemental material is available for this article. ©RSNA, 2018.

In vitro meningeal permeation of MnFe2O4 nanoparticles

MnFe2O4 nanoparticles (NPs) are commonly produced in some occupational settings and may reach high concentration in activities such as arc-welding or ferroalloy metallurgy. Manganese is an essential cofactor in enzyme activities but it has been demonstrated that long-term exposure to excessive levels can lead to “manganism”, a neurodegenerative disease resembling Parkinson features.Inhaled NPs deposit partially in pharynx and nasopharynx and may reach the central nervous system through the olfactory nerve, which is completely enveloped by the meningeal membranes throughout its course from the nasal cavity to the olfactory bulb or through the trigeminal nerves. This study investigated in vitro the transmeningeal absorption of 50 nm MnFe2O4NPs, using excised porcine meninges mounted on Franz diffusion cells. We tested two donor solutions: the first containing MnFe2O4NPs (2.0 g/L) and the second obtained by the ultrafiltration of the first one, in order to test only the NPs water soluble fraction. Each experiment was carried separately for 4 h. Results showed that no Mn flux permeation through the meninges occurred, since only trace of the metal was found in receivers solutions of cells exposed to MnFeNPs (5.5 ± 2.2 ng/cm2), ultrafiltered solution (3.5 ± 1.5 ng/cm2) and blank cells. (2.1 ± 0.6 ng/cm2) (mean and SE). Differences did not reach the statistical significance.Our study shows – for the first time - that MnFe2O4NPs penetrate the meningeal membrane in a negligible amount, thus making unlikely the hypothesis of a transcellular and paracellular absorption through the olfactory nerve but not excluding the hypothesis of an active intraneuronal absorption.

Fetal Myelomeningocele: Antenatal Characteristics and Pregnancy Outcomes [19R

INTRODUCTION: Spina bifida is the most common fetal anomaly of the central nervous system, which affect 1:1000 live births in the United States. Myelomeningocele is the most common presentation of spina bifida, representing half of these cases. Given the meningeal membrane sac may contain spinal cord, cerebrospinal fluid and nerve roots, this defect results in significant morbidity to infants and major life-long disabilities. In this study we aimed to identify maternal and fetal characteristics associated with expectant management or termination of pregnancy in the setting of antenatally diagnosed Myelomeningocele. METHODS: A retrospective cohort analysis was performed with patients who had presented to the Cleveland Clinic Fetal Care Center between 2005-2017. Live births then followed up at the pediatric Myelomeningocele clinic within our institution. RESULTS: Our data showed 40% of patients with antenatally diagnosed Myelomeningocele elected for second trimester terminations vs. 60% who chose to continue either by cesarean section or vaginal delivery. Based off ultrasound findings, there were no significant differences among these two groups. Maternal body mass index was significantly higher in those who continued pregnancies (p<0.05). In addition, the fetal diagnostic methods chosen by patients was significantly different. Those who elected to terminate were more likely to pursue amniocentesis instead of MRI characterization of the fetus (p<0.02). CONCLUSION: Taken together, we conclude, in the setting of antenatally diagnosed Myelomeningocele, patients often rely less on the associated ultrasonographic findings and depend more on maternal characteristics as well as fetal diagnostics in determining whether to continue or terminate pregnancy in the second trimester.

Multiple pathological mechanisms contribute to hippocampal damage in the experimental autoimmune encephalomyelitis model of multiple sclerosis.

Emotional and cognitive deficits and associated hippocampal damage observed in multiple sclerosis (MS) are now recognized as primary disease manifestations. However, the pathological substrate of these dysfunctions is unclear. In the experimental autoimmune encephalomyelitis (EAE) MS model, impaired hippocampal-dependent functions are concomitant with severe microglial reactivity and neurodegeneration, but reports vary with respect to evidence of lymphocytic infiltration, raising questions as to the nature of the underlying neurodegenerative mechanisms. Our investigations of EAE-induced inflammation across the hippocampal formation showed CD3 infiltration only in regions adjacent to inflamed meningeal membranes interposed between the ventral aspect of the hippocampus and the dorsal aspect of the mid-brain, but widespread microglial reactivity across the structure. Regions that contact the lateral ventricles do not show inflammation, but CD3 cells are observed in the adjacent ventricular space and choroid plexus, suggesting that microglial reactivity in these regions results from exposure to proinflammatory mediators released into the ventricles. These data indicate that multiple pathophysiological mechanisms underlie hippocampal damage during EAE. Treatment with the immunomodulator FTY720 eliminates microglial reactivity across the whole structure, suggesting potential benefit for neuropsychological symptoms in MS.