Identification of PMD subgroups using a myelination score for PMD.

BACKGROUND: The clinical spectrum of Pelizaeus-Merzbacher disease (PMD), a common hypomyelinating leukodystrophy, ranges between severe neonatal onset and a relatively stable presentation with later onset and mainly lower limb spasticity. In view of emerging treatment options and in order to grade severity and progression, we developed a PMD myelination score. METHODS: Myelination was scored in 15 anatomic sites (items) on conventional T2-and T1w images in controls (n = 328) and 28 PMD patients (53 MRI; n = 5 connatal, n = 3 transitional, n = 10 classic, n = 3 intermediate, n = 2 PLP0, n = 3 SPG2, n = 2 female). Items included in the score were selected based on interrater variability, practicability of scoring and importance of scoring items for discrimination between patients and controls and between patient subgroups. Bicaudate ratio, maximal sagittal pons diameter, and visual assessment of midsagittal corpus callosum were separately recorded. RESULTS: The resulting myelination score consisting of 8 T2-and 5 T1-items differentiates patients and controls as well as patient subgroups at first MRI. There was very little myelin and early loss in severely affected connatal and transitional patients, more, though still severely deficient myelin in classic PMD, ongoing myelination during childhood in classic and intermediate PMD. Atrophy, present in 50% of patients, increased with age at imaging. CONCLUSIONS: The proposed myelination score allows stratification of PMD patients and standardized assessment of follow-up. Loss of myelin in severely affected and PLP0 patients and progressing myelination in classic and intermediate PMD must be considered when evaluating treatment efficacy.

Orthogonal Peptide-Templated Labeling Elucidates Lateral ETA R/ETB R Proximity and Reveals Altered Downstream Signaling.

Fine-tuning of G protein-coupled receptor (GPCR) signaling is important to maintain cellular homeostasis. Recent studies demonstrated that lateral GPCR interactions in the cell membrane can impact signaling profiles. Here, we report on a one-step labeling method of multiple membrane-embedded GPCRs. Based on short peptide tags, complementary probes transfer the cargo (e. g. a fluorescent dye) by an acyl transfer reaction with high spatial and temporal resolution within 5 min. We applied this approach to four receptors of the cardiovascular system: the endothelin receptor A and B (ETA R and ETB R), angiotensin II receptor type 1, and apelin. Wild type-like G protein activation after N-terminal modification was demonstrated for all receptor species. Using FRET-competent dyes, a constitutive proximity between hetero-receptors was limited to ETA R/ETB R. Further, we demonstrate, that ETA R expression regulates the signaling of co-expressed ETB R. Our orthogonal peptide-templated labeling of different GPCRs provides novel insight into the regulation of GPCR signaling.

Subdural hematoma in glutaric aciduria type 1: High excreters are prone to incidental SDH despite newborn screening.

Subdural hematoma (SDH) was initially reported in 20% to 30% of patients with glutaric aciduria type 1 (GA1). A recent retrospective study found SDH in 4% of patients, but not in patients identified by newborn screening (NBS). 168 MRIs of 69 patients with GA1 (age at MRI 9 days - 73.8 years, median 3.2 years) were systematically reviewed for presence of SDH, additional MR and clinical findings in order to investigate the frequency of SDH and potential risk factors. SDH was observed in eight high-excreting patients imaged between 5.8 and 24.4 months, namely space-occupying SDH in two patients after minor accidental trauma and SDH as an incidental finding in six patients without trauma. In patients without trauma imaged at 3 to 30 months (n = 36, 25 NBS, 27/9 high/low excreters), incidence of SDH was 16.7% (16% in NBS). SDH was more common after acute (33.3%) than insidious onset of dystonia (14.3%) or in asymptomatic patients (5.9%). It was only seen in patients with wide frontoparietal CSF spaces and frontotemporal hypoplasia. High excreters were over-represented among patients with SDH (6/27 vs 0/9 low excreters), acute onset (10/12), and wide frontoparietal CSF spaces (16/19). Incidental SDH occurs despite NBS and early treatment in approximately one in six patients with GA1 imaged during late infancy and early childhood. Greater risk of high excreters is morphologically associated with more frequent enlargement of external CSF spaces including frontotemporal hypoplasia, and may be furthered aggravated by more pronounced alterations of cerebral blood volume and venous pressure.

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients.

Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.

The metastatic infiltration at the metastasis/brain parenchyma-interface is very heterogeneous and has a significant impact on survival in a prospective study.

UNLABELLED: The current approach to brain metastases resection is macroscopic removal of metastasis until reaching the glial pseudo-capsule (gross total resection (GTR)). However, autopsy studies demonstrated infiltrating metastatic cells into the parenchyma at the metastasis/brain parenchyma (M/BP)-interface. AIMS/METHODS: To analyze the astrocyte reaction and metastatic infiltration pattern at the M/BP-interface with an organotypic brain slice coculture system. Secondly, to evaluate the significance of infiltrating metastatic tumor cells in a prospective biopsy study. Therefore, after GTR, biopsies were obtained from the brain parenchyma beyond the glial pseudo-capsule and analyzed histomorphologically. RESULTS: The coculture revealed three types of cancer cell infiltration. Interestingly, the astrocyte reaction was significantly different in the coculture with a benign, neuroectodermal-derived cell line. In the prospective biopsy study 58/167 (34.7%) samples revealed infiltrating metastatic cells. Altogether, 25/39 patients (64.1%) had proven to exhibit infiltration in at least one biopsy specimen with significant impact on survival (OS) (3.4 HR; p = 0.009; 2-year OS was 6.6% versus 43.5%). Exceptionally, in the non-infiltrating cohort three patients were long-term survivors. CONCLUSIONS: Metastatic infiltration has a significant impact on prognosis. Secondly, the astrocyte reaction at the M/BP-interface is heterogeneous and supports our previous concept of the organ-specific defense against metastatic (organ-foreign) cells.

Abnormalities in the normal appearing white matter of the cerebral hemisphere contralateral to a malignant brain tumor detected by diffusion tensor imaging.

INTRODUCTION: Malignant brain tumors tend to migration and invasion of surrounding brain tissue. Histopathological studies reported malignant cells in macroscopically unsuspicious parenchyma (normal appearing white matter - NAWM) remote from the tumor localization. In early stages, diffuse interneural infiltration with changes of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) is hypothesized. MATERIAL AND METHODS: Patients' ADC and FA values from NAWM of the hemisphere contralateral to a malignant glioma were compared to age- and sex-matched normal controls. RESULTS: Apparent diffusion coefficient levels of the entire contralateral hemisphere revealed a significant increase and a decrease of FA levels. An even more pronounced ADC increase was found in a region mirroring the glioma location. CONCLUSIONS: In patients with previously untreated anaplastic astrocytoma or glioblastoma, an increase of the ADC and a reduction of FA were found in the brain parenchyma of the hemisphere contralateral to the tumor localization. In the absence of visible MRI abnormalities, this may be an early indicator of microstructural changes of the NAWM attributed to malignant brain tumor.

Area-dependent time courses of brain activation during video-induced symptom provocation in social anxiety disorder.

BACKGROUND: Previous functional imaging studies using symptom provocation in patients with social anxiety disorder (SAD) reported inconsistent findings, which might be at least partially related to different time-dependent activation profiles in different brain areas. In the present functional magnetic resonance imaging study, we used a novel video-based symptom provocation design in order to investigate the magnitude and time course of activation in different brain areas in 20 SAD patients and 20 healthy controls. RESULTS: The disorder-related videos induced increased anxiety in patients with SAD as compared to healthy controls. Analyses of brain activation to disorder-related versus neutral video clips revealed amygdala activation during the first but not during the second half of the clips in patients as compared to controls. In contrast, the activation in the insula showed a reversed pattern with increased activation during the second but not during the first half of the video clips. Furthermore, a cluster in the anterior dorsal anterior cingulate cortex showed a sustained response for the entire duration of the videos. CONCLUSIONS: The present findings suggest that different regions of the fear network show differential temporal response patterns during video-induced symptom provocation in SAD. While the amygdala is involved during initial threat processing, the insula seems to be more involved during subsequent anxiety responses. In accordance with cognitive models of SAD, a medial prefrontal region engaged in emotional-cognitive interactions is generally hyperactivated.

Teaching NeuroImages: Ma2 encephalitis presenting as acute panhypopituitarism in a young man.

A 21-year-old man presented with headache, hypotonia, hypothermia, and somnolence, deteriorating to a Glasgow Coma Scale score of 3 within days. Hormonal testing revealed panhypopituitarism. His cerebral MRI showed a gadolinium-enhancing lesion in the pituitary gland with adjacent changes to the hypothalamus, midbrain, and basal ganglia (figures 1 and 2). Therapy with prednisolone resulted in rapid improvement. Ma2 antibodies were found in the patient's serum and CSF. FDG-PET demonstrated a tumor mass in the superior mediastinum and histology revealed a mediastinal seminoma. Ma2 antibody-mediated paraneoplastic disease has to be considered as a rare differential diagnosis in patients presenting with acute panhypopituitarism.(1.)

Impact of a new metal artefact reduction algorithm in the noninvasive follow-up of intracranial clips, coils, and stents with flat-panel angiographic CTA: initial results.

INTRODUCTION: Flat-panel angiographic CT after intravenous contrast agent application (ivACT) is increasingly used as a follow-up examination after coiling, clipping, or stenting. The purpose of this study was to evaluate the feasibility of a new metal artefact reduction algorithm (MARA) in patients treated for intracranial aneurysms and stenosis. METHODS: IvACT was performed on a flat-panel detector angiography system after intravenous application of 80 ml contrast media. The uncorrected raw images were transferred to a prototype reconstruction workstation where the MARA was applied. Two experienced neuroradiologists examined the corrected and uncorrected images on a commercially available workstation. RESULTS: Artefacts around the implants were detected in all 16 uncorrected cases, while eight cases showed remaining artefacts after correction with the MARA. In the cases without correction, there were 11 cases with "extensive" artefacts and five cases with "many" artefacts. After correction, seven cases showed "few" and only one case "many" artefacts (Wilcoxon test, P < 0.001). Parent vessels were characterized as "not identifiable" in 62% of uncorrected images, while the delineation of parent vessels were classified as "excellent" in 50% of the cases after correction (Wilcoxon test, P = 0.001). CONCLUSIONS: Use of the MARA in our study significantly reduced artefacts around metallic implants on ivACT images and allowed for the delineation of surrounding structures.

Evaluation of noninvasive follow-up methods for the detection of intracranial in-stent restenosis: a phantom study.

OBJECTIVES: Intra-arterial digital subtraction angiography (IA-DSA), an invasive procedure, is the current reference examination after percutaneous transluminal angioplasty and stenting for the detection of in-stent restenosis (ISR). In this phantom study, we evaluated flat-panel angiographic computed tomography after intravenous contrast agent application (IV-ACT) and multidetector computed tomographic angiography (MDCTA) as potential noninvasive follow-up alternatives after intracranial percutaneous transluminal angioplasty and stenting. MATERIALS AND METHODS: We simulated an intracranial vessel using a silicon tube placed inside a human skull. Three different stent systems were deployed inside the silicon tubes, each with diameters of 3 or 4 mm. Three grades of ISR (25%, 50%, and 75%) were simulated. The IA-DSA and IV-ACT examinations were performed on a flat-panel detector angiography system. The MDCTA images were acquired with a 128-slice computed tomographic scanner. The mean stenosis diameters, measured with each technique, were compared using the Bland-Altman plot. The difference between the known stenosis diameter and the measured stenosis diameter was calculated for each examination. RESULTS: Stenosis measurements on the IA-DSA images showed no statistically significant differences compared with the known stenosis diameters (P = 0.19). In the 3-mm stent category, when compared with the known stenosis diameter, mean (SD) differences of 0.01 (0.15) mm, 0.03 (0.24) mm and 0.16 (0.5) mm were calculated for the IA-DSA, IV-ACT, and MDCTA stenosis measurements, respectively. As for the 4-mm stents, IA-DSA and IV-ACT were again very accurate, with mean (SD) differences of -0.03 (0.11) mm and 0.07 (0.19) mm, respectively, compared with the known stenosis diameters, whereas MDCTA overestimated ISR, with a mean (SD) difference of 0.49 (0.53) mm. The Bland-Altman plots show a mean (SD) difference of 0.08 (0.2) mm between IA-DSA and IV-ACT (95% confidence interval, 0.05-0.11) and a mean (SD) difference of 0.34 (0.56) mm between IA-DSA and MDCTA measurements (95% confidence interval, 0.25-0.42). CONCLUSIONS: In our phantom study, IA-DSA was the only examination to predict accurately degrees of stenosis compared with the known stenosis diameters. The results of the IV-ACT measurements were comparable with those of IA-DSA. Multidetector computed tomographic angiography was less accurate in the quantification of stenosis, usually overestimating ISR.

A de novo interstitial deletion of 2p23.3-24.3 in a boy presenting with intellectual disability, overgrowth, dysmorphic features, skeletal myopathy, dilated cardiomyopathy.

Interstitial deletions of the distal part of chromosome 2p are rare, with only six reported cases involving regions from 2p23 to 2pter. Most of these were cytogenetic investigations. We describe a 14-year-old boy with an 8.97 Mb deletion of 2p23.3-24.3 detected by array comparative genomic hybridization (array CGH) who had intellectual disability (ID), unusual facial features, cryptorchidism, skeletal myopathy, dilated cardiomyopathy (DCM), and postnatal overgrowth (macrocephaly and tall stature). We compared the clinical features of the present case to previously described patients with an interstitial deletion within this chromosomal region and conclude that our patient exhibits a markedly different phenotype. Additional patients are needed to further delineate phenotype-genotype correlations.

Necrotizing infundibulo-hypophysitis: an entity too rare to be true?

We report a young woman with sudden and severe retroorbital headache, neck pain, and a large sellar mass extending to the suprasellar cistern. A presumptive diagnosis of non-secreting pituitary macroadenoma undergoing apoplexy was made and transphenoidal surgery performed. Histopathology revealed mononuclear infiltration and marked non-hemorrhagic necrosis of the anterior pituitary consistent with a diagnosis of necrotizing infundibulo-hypophysitis. The possible pathogenesis of this rare variant of hypophysitis is discussed.

Individual voxel-based subtype prediction can differentiate progressive supranuclear palsy from idiopathic Parkinson syndrome and healthy controls.

Voxel-based morphometry (VBM) shows a differentiated pattern in patients with atypical Parkinson syndrome but so far has had little impact in individual cases. It is desirable to translate VBM findings into clinical practice and individual classification. To this end, we examined whether a support vector machine (SVM) can provide useful accuracies for the differential diagnosis. We acquired a volumetric 3D T1-weighted MRI of 21 patients with idiopathic Parkinson syndrome (IPS), 11 multiple systems atrophy (MSA-P) and 10 progressive supranuclear palsy (PSP), and 22 healthy controls. Images were segmented, normalized, and compared at group level with SPM8 in a classical VBM design. Next, a SVM analysis was performed on an individual basis with leave-one-out cross-validation. VBM showed a strong white matter loss in the mesencephalon of patients with PSP, a putaminal grey matter loss in MSA, and a cerebellar grey matter loss in patients with PSP compared with IPS. The SVM allowed for an individual classification in PSP versus IPS with up to 96.8% accuracy with 90% sensitivity and 100% specificity. In MSA versus IPS, an accuracy of 71.9% was achieved; sensitivity, however, was low with 36.4%. Patients with IPS could not be differentiated from controls. In summary, a voxel-based SVM analysis allows for a reliable classification of individual cases in PSP that can be directly clinically useful. For patients with MSA and IPS, further developments like quantitative MRI are needed.

Comparing different MR angiography strategies of carotid stents in a vascular flow model: toward stent-specific recommendations in MR follow-up.

INTRODUCTION: Carotid artery stenting (CAS) requires adequate follow-up imaging to assess complications such as in-stent stenosis or occlusion. Options include digital subtraction angiography, CT angiography, ultrasound, and MR angiography (MRA), which may offer a non-invasive option for CAS follow-up imaging. The aim of this study was to assess contrast-enhanced MRA (CE-MRA) and three-dimensional time-of-flight MRA (3D-TOF) for visualization of the in-stent lumen in different carotid stents. METHODS: In this study, we compared CE-MRA and 3D-TOF of five different carotid stents (Guidant Acculink®, Cordis Precise®, Boston Wallstent®, Abbot Vascular Xact®, Cook Zilver®) in three diameters (4, 6, and 8 mm) using a vascular flow model at 3.0 T with the help of a recently developed carotid surface coil. Stent-related artifacts were objectively assessed by calculating artificial lumen narrowing (ALN) and relative in-stent signal (RIS). RESULTS: RIS and ALN depended heavily on stent type, stent diameter, and the employed MR sequence. ALN and RIS were relatively favorable for Acculink®, Precise®, and Zilver® stents with both CE-MRA and 3D-TOF. CE-MRA provided better results for the Wallstent, while the Xact stent was difficult to visualize with both MRA protocols. CONCLUSION: Both CE-MRA and 3D-TOF are viable options for depicting the in-stent lumen in carotid stents. For specific stents, 3D-TOF provided image quality comparable to CE-MRA and may thus be suitable for in vivo assessment. Development of stent-specific pathways for follow-up imaging seems advisable to address stent-related differences in image quality.

Task-dependent neural correlates of the processing of verbal threat-related stimuli in social phobia.

The neural basis of abnormal processing of phobia-related linguistic cues in individuals suffering from social phobia is unknown, particularly in respect to different task conditions. Using event-related functional magnetic resonance imaging, this study investigated brain activation to phobia-related and phobia-unrelated words in 19 socially phobic patients and 18 healthy control subjects (HC) while subjects had to attend either to social meaning or to grammatical category of words (direct or indirect task). During the indirect task, patients, compared to HC, showed an increased activation of the amygdala and orbitofrontal cortex (OFC) in response to phobia-related vs. phobia-unrelated words. Activation of the insula was positively correlated with patients' symptom severity during the direct task. The results suggest a specific role of the amygdala and OFC during the processing of verbal phobia-relevant distracting information. In contrast, insula activation seems to be more important for direct processing of disorder-related words, especially in more severe cases of social phobia.

Polymicrogyria in fetal alcohol syndrome.

BACKGROUND: Intrauterine exposure to alcohol may result in a distinct pattern of craniofacial abnormalities and central nervous system dysfunction, designated fetal alcohol syndrome (FAS). The spectrum of malformations of the brain associated with maternal alcohol abuse during pregnancy is much broader than the relatively uniform clinical phenotype of FAS. Among these malformations the most striking abnormalities involve the impairment of neuronal cell migration. However, polymicrogyria (PMG) has so far been reported only once in a human autopsy study of a child with FAS. CASE: A 16-year-old girl with confirmed maternal alcohol consumption during pregnancy and full phenotype of FAS presented after two generalized epileptic seizures for neurologic assessment. Cranial magnetic resonance imaging revealed bilateral PMG in the superior frontal gyrus with asymmetric distribution. History, clinical features, and genetic investigations provided no evidence for any of the known genetic or acquired causes of PMG. Therefore, we propose that prenatal alcohol exposure is the cause of PMG in this patient rather than a mere coincidence. CONCLUSION: Our observation represents only the second patient of PMG in FAS and confirms the phenotypic variability of cerebral malformations associated with maternal alcohol abuse during pregnancy. In patients with clinical features of FAS and neurologic deficits or seizures neuroimaging is recommended. Furthermore, FAS should be considered as a differential diagnosis for PMG.

Evaluation of angiographic computed tomography in the follow-up after endovascular treatment of cerebral aneurysms--a comparative study with DSA and TOF-MRA.

Following coil embolization of intracranial aneurysms, many centers perform at least one digital subtraction angiography (DSA) continuing with time-of-flight magnetic resonance angiography (TOF-MRA). Angiographic computed tomography (ACT) provides high-resolution data from a rotational acquisition of a c-arm-mounted flat panel detector. This study evaluates possible advantages of applying ACT in aneurysm follow-up. In 22 patients DSA examinations with a rotational acquisition were performed. Rotational data were processed into an isotropic high-resolution volume. TOF-MRA was performed the day before DSA. Three experienced neuroradiologists performed a rating of the occlusion rate and a subjective method comparison. Weighted kappa statistics were calculated to assess the level of interobserver agreement. Compared to DSA, the diagnostic value of ACT as well as of TOF-MRA was rated to be inferior, although the sensitivity of detecting residual necks was higher with both techniques. Compared to TOF-MRA, ACT achieves favorable ratings only in aneurysms after stent-remodeling. Interobserver agreement was high for all techniques. Ratings of the occlusion rate correlated highly between all observers (r>0.85, p<0.001, respectively). In selected patients ACT can add valuable diagnostic information to DSA. TOF-MRA remains a highly sensitive method for aneurysm follow-up.

No advantage of time-of-flight magnetic resonance angiography at 3 Tesla compared to 1.5 Tesla in the follow-up after endovascular treatment of cerebral aneurysms.

INTRODUCTION: Long-term follow-up after coil embolization of intracranial aneurysms is mandatory to monitor coil compacting and aneurysm recurrence. Most centers perform one digital subtraction angiography (DSA) on follow-up continuing with time-of-flight magnetic resonance angiography (TOF-MRA). This study explores the diagnostic value of TOF-MRA at 1.5 T versus 3 T compared to DSA. MATERIALS AND METHODS: In 18 patients with 20 aneurysms treated with coil embolization, TOF-MRA at 1.5 and 3 T were performed the day before follow-up DSA, the latter serving as reference. Optimized diagnostic protocols were applied (1.5 T: 0.78 x 0.55 x 0.8 mm, voxel size; acquisition time (TA), 6.37 min; 3 T: 0.56 x 0.45 x 0.65 mm, voxel size; TA, 3.12 min). Three independent neuroradiologists experienced in neuroendovascular therapy rated the occlusion rate ("complete occlusion" vs. "residual neck" vs. "residual aneurysm") and compared the two methods subjectively. Weighted kappa statistics were calculated to assess the level of interobserver agreement. RESULTS: Compared to DSA, TOF-MRA was more sensitive in detecting neck remnants, with a slight advantage at 3 T. Regarding artifact load, there are advantages at 1.5 T. Ratings of the occlusion rate correlated highly between all observers (r > 0.85, p < 0.001, respectively). Interobserver agreement was high in all cases (small ka, Cyrillic (w) approximately 0.8, respectively). CONCLUSION: TOF-MRA is a reliable tool for follow-up imaging of cerebral aneurysms after endovascular treatment. Our study shows no advantage of TOF-MRA at 3 T over 1.5 T, when comparable measurement protocols are applied. TOF-MRA at 1.5 T therefore provides appropriate information regarding a therapeutic decision.

Liposomal glucocorticosteroids in treatment of chronic autoimmune demyelination: long-term protective effects and enhanced efficacy of methylprednisolone formulations.

Liposomal encapsulation leads to enhanced efficacy of glucocorticosteroids (GS) in treatment of autoimmune diseases. Here we compare liposomal prednisolone (PL) to liposomal methylprednisolone (MPL) in chronic-relapsing myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE), a model closely reflecting aspects of multiple sclerosis (MS). At the maximum of the first relapse, a single dose of PL or MPL was applied at 10 mg/kg or at 4 mg/kg and compared to classical methylprednisolone (MP) pulse therapy. PL at 10 mg/kg was superior to free MP with long-term efficacy and a sustained protection even during the second and third relapse. At the same time, in vivo magnetic resonance imaging of rat brains revealed a significant reduction of T2-lesions after PL application. Comparison of PL and MPL at 10 mg/kg disclosed superior effects for MPL with an enhanced reduction of inflammatory infiltration as well as preservation of myelin and axons. Dose titration experiments underscored a dose-dependent efficacy of liposomal GS with a sustained efficacy especially of the higher dosage. In histological analyses, PL10 was superior in reducing macrophage and T cell infiltration as well as demyelination and axonal loss while the lower dosages were still at least as effective as free MP. FACS analyses revealed an effect of liposome formulations on T cell numbers, the CD4/CD8 ratio, frequencies of regulatory T cells and adhesion molecule expression. In summary, liposomal GS and especially methylprednisolone formulations display an enhanced efficacy not only in acute inflammatory, but also in chronic demyelinating models of MS and confer long-term protection from relapses. These findings lay the groundwork for applying liposomal GS in clinical MS trials in the near future.