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Resume Les maladies multisystemiques, dont la plupart sont en France prises en charge en medecine interne, touchent par definition plusieurs organes ou tissus. Si les atteintes cutanees ou articulaires sont frequentes, les atteintes neurologiques sont souvent synonymes de gravite. Parmi ces dernieres, les atteintes du systeme nerveux peripherique (par exemple : neuropathies) ou du systeme nerveux central (par exemple : myelites) sont generalement de diagnostic aise, a l’aide de l’expertise clinique et d’examens complementaires adaptes. Les atteintes neuropsychologiques, c’est-a-dire touchant le fonctionnement cognitif, et notamment la memoire, l’attention, les fonctions executives ou les capacites de raisonnement, sont de diagnostic plus difficile, parfois banalisees par les cliniciens. Leurs causes sont souvent multiples et intriquees. Pourtant, ces manifestations cognitives sont cruciales dans le retentissement fonctionnel et le ressenti des patients, et sont etroitement liees a leur qualite de vie. Elles affectent ainsi l’insertion sociale, familiale et professionnelle des patients, et peuvent avoir des retentissements sur le suivi medical ou l’observance medicamenteuse. L’objectif de cette mise au point, sur les troubles cognitifs associes au lupus systemique, de leur physiopathologie a leur prise en charge, est de sensibiliser les medecins internistes aux manifestations cognitives des maladies multisystemiques, a leur prise en charge diagnostique et therapeutique, ainsi que de catalyser les futurs efforts de recherche et de mise en place de parcours de soins pour les patients suivis en medecine interne presentant des difficultes cognitives.

International audience; OBJECTIVES: To provide an overview of the spectrum, characteristics and outcomes of neurologic manifestations associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We conducted a single-centre retrospective study during the French coronavirus disease 2019 (COVID-19) epidemic in March-April 2020. All COVID-19 patients with de novo neurologic manifestations were eligible. RESULTS: We included 222 COVID-19 patients with neurologic manifestations from 46 centres in France. Median (interquartile range, IQR) age was 65 (53-72) years and 136 patients (61.3%) were male. COVID-19 was severe or critical in 102 patients (45.2%). The most common neurologic diseases were COVID-19-associated encephalopathy (67/222, 30.2%), acute ischaemic cerebrovascular syndrome (57/222, 25.7%), encephalitis (21/222, 9.5%) and Guillain-Barré syndrome (15/222, 6.8%). Neurologic manifestations appeared after the first COVID-19 symptoms with a median (IQR) delay of 6 (3-8) days in COVID-19-associated encephalopathy, 7 (5-10) days in encephalitis, 12 (7-18) days in acute ischaemic cerebrovascular syndrome and 18 (15-28) days in Guillain-Barré syndrome. Brain imaging was performed in 192 patients (86.5%), including 157 magnetic resonance imaging (70.7%). Among patients with acute ischaemic cerebrovascular syndrome, 13 (22.8%) of 57 had multiterritory ischaemic strokes, with large vessel thrombosis in 16 (28.1%) of 57. Brain magnetic resonance imaging of encephalitis patients showed heterogeneous acute nonvascular lesions in 14 (66.7%) of 21. Cerebrospinal fluid of 97 patients (43.7%) was analysed, with pleocytosis found in 18 patients (18.6%) and a positive SARS-CoV-2 PCR result in two patients with encephalitis. The median (IQR) follow-up was 24 (17-34) days with a high short-term mortality rate (28/222, 12.6%). CONCLUSIONS: Clinical spectrum and outcomes of neurologic manifestations associated with SARS-CoV-2 infection were broad and heterogeneous, suggesting different underlying pathogenic processes.

Background and ObjectivesParaneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies is a cancer-related autoimmune disease directed against neural antigens expressed by tumor cells. A putative trigger of the immune tolerance breakdown is genetic alteration of Yo antigens. We aimed to identify the tumors' genetic and immune specificities involved in Yo-PCD pathogenesis.MethodsUsing clinicopathologic data, immunofluorescence (IF) imaging, and whole-transcriptome analysis, 22 breast cancers (BCs) associated with Yo-PCD were characterized in terms of oncologic characteristics, genetic alteration of Yo antigens, differential gene expression profiles, and morphofunctional specificities of their in situ antitumor immunity by comparing them with matched control BCs.ResultsYo-PCD BCs were invasive carcinoma of no special type, which early metastasized to lymph nodes. They overexpressed human epidermal growth factor receptor 2 (HER2) but were hormone receptor negative. All Yo-PCD BCs carried at least 1 genetic alteration (variation or gain in copy number) on CDR2L, encoding the main Yo antigen that was found aberrantly overexpressed in Yo-PCD BCs. Analysis of the differentially expressed genes found 615 upregulated and 54 downregulated genes in Yo-PCD BCs compared with HER2-driven control BCs without PCD. Ontology enrichment analysis found significantly upregulated adaptive immune response pathways in Yo-PCD BCs. IF imaging confirmed an intense immune infiltration with an overwhelming predominance of immunoglobulin G–plasma cells.DiscussionThese data confirm the role of genetic alterations of Yo antigens in triggering the immune tolerance breakdown but also outline a specific biomolecular profile in Yo-PCD BCs, suggesting a cancer-specific pathogenesis.

ObjectiveTo describe the spectrum, treatment, and outcome of cranial nerve disorders associated with immune checkpoint inhibitor (Cn-ICI).MethodsThis nationwide retrospective cohort study on Cn-ICI (2015–2019) was conducted using the database of the French Refence Center. In addition, a systematic review of the literature (MEDLINE, Scopus, and Web of Science) for records published between 2010 and 2019 was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the search terms cranial nerve or neuropathy or palsy and immune checkpoint inhibitors.ResultsAmong 67 cases with ICI-related neurologic toxicities diagnosed in our reference center, 9 patients with Cn-ICI were identified (7 men, 78%, median age 62 years [range 26–82 years]). Patients were receiving a combination of anti–cytotoxic T-lymphocyte antigen 4 and anti–programmed cell death 1 (PD-1)/PD-1 ligand (n = 5, 56%) or anti–PD-1 antibodies alone (n = 4, 44%). Cn-ICI involved optic (n = 3), vestibulocochlear (n = 3), abducens (n = 2), facial (n = 2), and oculomotor (n = 1) nerves. Two patients had involvement of 2 different cranial nerves. Treatment comprised corticosteroids (n = 8, 89%), ICI permanent discontinuation (n = 7, 78%), plasma exchange (n = 2, 22%), and IV immunoglobulin (n = 1, 11%). Median follow-up was 11 months (range 1–41 months). In 3 cases (33%), neurologic deficit persisted/worsened despite treatment: 2 optic and 1 vestibulocochlear. Among cases from the literature and the present series combined (n = 39), the most commonly affected cranial nerves were facial (n = 13, 33%), vestibulocochlear (n = 8, 21%), optic (n = 7, 18%), and abducens (n = 4, 10%). Trigeminal, oculomotor, and glossopharyngeal nerves were less frequently affected (total n = 7).ConclusionCranial nerve disorders can complicate treatment with ICIs. Approximately one-third of the patients had persisting deficits, most frequently involving hearing and vision loss.

The mechanisms underlying the chronicity of autoimmune diseases of the central nervous system (CNS) are largely unknown. In particular, it is unclear whether tissue-resident memory T cells (TRM) contribute to lesion pathogenesis during chronic CNS autoimmunity. Here, we observed that a high frequency of brain-infiltrating CD8+T cells exhibit a TRM-like phenotype in human autoimmune encephalitis. Using mouse models of neuronal autoimmunity and a combination of T single-cell transcriptomics, high-dimensional flow cytometry, and histopathology, we found that pathogenic CD8+T cells behind the blood-brain barrier adopt a characteristic TRMdifferentiation program, and we revealed their phenotypic and functional heterogeneity. In the diseased CNS, autoreactive tissue-resident CD8+T cells sustained focal neuroinflammation and progressive loss of neurons, independently of recirculating CD8+T cells. Consistently, a large fraction of autoreactive tissue-resident CD8+T cells exhibited proliferative potential as well as proinflammatory and cytotoxic properties. Persistence of tissue-resident CD8+T cells in the CNS and their functional output, but not their initial differentiation, were crucially dependent on CD4+T cells. Collectively, our results point to tissue-resident CD8+T cells as essential drivers of chronic CNS autoimmunity and suggest that therapies targeting this compartmentalized autoreactive T cell subset might be effective for treating CNS autoimmune diseases.

The mechanisms underlying the chronicity of autoimmune diseases of the central nervous system (CNS) are largely unknown. In particular, it is unclear whether tissue-resident memory T cells (T

Background and ObjectivesThere is no report on the long-term outcomes of ataxia with antibodies against Delta and Notch-like epidermal growth factor–related (DNER). We aimed to describe the clinical-immunologic features and long-term outcomes of patients with anti-DNER antibodies.MethodsPatients tested positive for anti-DNER antibodies between 2000 and 2020 were identified retrospectively. In those with available samples, immunoglobulin G (IgG) subclass analysis, longitudinal cerebellum volumetry, human leukocyte antigen isotyping, and CSF proteomic analysis were performed. Rodent brain membrane fractionation and organotypic cerebellar slices were used to study DNER cell-surface expression and human IgG binding to the Purkinje cell surface.ResultsTwenty-eight patients were included (median age, 52 years, range 19–81): 23 of 28 (82.1%) were male and 23 of 28 (82.1%) had a hematologic malignancy. Most patients (27/28, 96.4%) had cerebellar ataxia; 16 of 28 (57.1%) had noncerebellar symptoms (cognitive impairment, neuropathy, and/or seizures), and 27 of 28 (96.4%) became moderately to severely disabled. Half of the patients (50%) improved, and 32.1% (9/28) had no or slight disability at the last visit (median, 26 months; range, 3–238). Good outcome significantly associated with younger age, milder clinical presentations, and less decrease of cerebellar gray matter volumes at follow-up. No human leukocyte antigen association was identified. Inflammation-related proteins were overexpressed in the patients' CSF. In the rodent brain, DNER was enriched in plasma membrane fractions. Patients' anti-DNER antibodies were predominantly IgG1/3 and bound live Purkinje cells in vitro.DiscussionDNER ataxia is a treatable condition in which nearly a third of patients have a favorable outcome. DNER antibodies bind to the surface of Purkinje cells and are therefore potentially pathogenic, supporting the use of B-cell–targeting treatments.

OBJECTIVE Long-standing overt ventriculomegaly in adults (LOVA) is a form of chronic hydrocephalus and its pathophysiology and treatment remain debated. An analysis of CSF dynamics in this condition has rarely been reported. The aim of this study was to analyze hydrodynamic characteristics of patients with suspected LOVA to discuss its pathophysiological mechanisms and the importance of CSF dynamics analysis for diagnosis and treatment of these patients. METHODS This retrospective cohort study, conducted between May 2018 and October 2022, included adult patients aged > 18 years investigated in a department of neurosurgery through a lumbar infusion study for suspicion of LOVA (n = 23). These patients were then compared with a control cohort explored for suspicion of idiopathic normal pressure hydrocephalus (iNPH; n = 30). Clinical symptoms, radiological findings, and hydrodynamic parameters were analyzed. The authors specifically compared two hydrodynamic parameters: resistance to CSF outflow, or Rout, which relies on CSF resorption, and pressure-volume index (PVI), which reflect overall craniospinal compliance. The lumbar infusion study was considered pathological (confirming the diagnosis of chronic hydrocephalus) when at least one of these two parameters was altered. RESULTS Rout was significantly less frequently increased (cutoff ≥ 12 mm Hg/ml/min) in patients with LOVA (52%) than in those with iNPH (97%; p < 0.001). In contrast, PVI was impaired (cutoff ≤ 25 ml) in both cohorts, i.e., in 61% of patients with LOVA and in 83% of patients with iNPH. Overall, the rate of pathological lumbar infusion study in LOVA (87%) was not statistically different than in iNPH (100%). However, PVI was the only impaired parameter most frequently found in those with LOVA (35%) compared with those with iNPH (3%; p = 0.002). CONCLUSIONS This study suggests that there is a differential CSF dynamics pattern when comparing patients with LOVA versus those with iNPH. A higher proportion of patients with LOVA showed isolated compliance impairment. These findings highlight the utility of CSF dynamics analysis for the evaluation of patients with suspected chronic obstructive hydrocephalus such as LOVA. Future research with larger case series may help define diagnosis and treatment algorithms of chronic obstructive hydrocephalus based on CSF dynamics analysis, in addition to clinical and radiological criteria.

To compare CSF biomarkers’ levels in patients suffering from anti-Leucine-rich Glioma-Inactivated 1 (LGI1) encephalitis to neurodegenerative [Alzheimer’s disease (AD), Creutzfeldt–Jakob’s disease (CJD)] and primary psychiatric (PSY) disorders. Patients with LGI1 encephalitis were retrospectively selected from the French Reference Centre database between 2010 and 2019 and enrolled if CSF was available for biomarkers analysis including total tau (T-tau), phosphorylated tau (P-tau), amyloid-beta Aβ1-42, and neurofilaments light chains (Nf L). Samples sent for biomarker determination as part of routine practice, and formally diagnosed as AD, CJD, and PSY, were used as comparators. Twenty-four patients with LGI1 encephalitis were compared to 39 AD, 20 CJD and 20 PSY. No significant difference was observed in T-tau, P-tau, and Aβ1-42 levels between LGI1 encephalitis and PSY patients. T-Tau and P-Tau levels were significantly lower in LGI1 encephalitis (231 and 43 ng/L) than in AD (621 and 90 ng/L, p

ObjectiveThe contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS.MethodsA panel of experts developed by consensus a modified set of diagnostic PNS criteria for clinical decision making and research purposes. The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project.ResultsThe panel proposed to substitute “classical syndromes” with the term “high-risk phenotypes” for cancer and introduce the concept of “intermediate-risk phenotypes.” The term “onconeural antibody” was replaced by “high risk” (>70% associated with cancer) and “intermediate risk” (30%–70% associated with cancer) antibodies. The panel classified 3 levels of evidence for PNS: definite, probable, and possible. Each level can be reached by using the PNS-Care Score, which combines clinical phenotype, antibody type, the presence or absence of cancer, and time of follow-up. With the exception of opsoclonus-myoclonus, the diagnosis of definite PNS requires the presence of high- or intermediate-risk antibodies. Specific recommendations for similar syndromes triggered by immune checkpoint inhibitors are also provided.ConclusionsThe proposed criteria and recommendations should be used to enhance the clinical care of patients with PNS and to encourage standardization of research initiatives addressing PNS.

To compare CSF biomarkers' levels in patients suffering from anti-Leucine-rich Glioma-Inactivated 1 (LGI1) encephalitis to neurodegenerative [Alzheimer's disease (AD), Creutzfeldt-Jakob's disease (CJD)] and primary psychiatric (PSY) disorders.Patients with LGI1 encephalitis were retrospectively selected from the French Reference Centre database between 2010 and 2019 and enrolled if CSF was available for biomarkers analysis including total tau (T-tau), phosphorylated tau (P-tau), amyloid-beta Aβ1-42, and neurofilaments light chains (Nf L). Samples sent for biomarker determination as part of routine practice, and formally diagnosed as AD, CJD, and PSY, were used as comparators.Twenty-four patients with LGI1 encephalitis were compared to 39 AD, 20 CJD and 20 PSY. No significant difference was observed in T-tau, P-tau, and Aβ1-42 levels between LGI1 encephalitis and PSY patients. T-Tau and P-Tau levels were significantly lower in LGI1 encephalitis (231 and 43 ng/L) than in AD (621 and 90 ng/L, p 0.001) and CJD patients (4327 and 55 ng/L, p 0.001 and p 0.01). Nf L concentrations of LGI1 encephalitis (2039 ng/L) were similar to AD (2,765 ng/L) and significantly higher compared to PSY (1223 ng/L, p 0.005), but significantly lower than those of CJD (13,457 ng/L, p 0.001). Higher levels of Nf L were observed in LGI1 encephalitis presenting with epilepsy (3855 ng/L) compared to LGI1 without epilepsy (1490 ng/L, p = 0.02). No correlation between CSF biomarkers' levels and clinical outcome could be drawn.LGI encephalitis patients showed higher Nf L levels than PSY, comparable to AD, and even higher when presenting epilepsy suggesting axonal or synaptic damage linked to epileptic seizures.

Limbic encephalitis with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leucocyte antigen and CSF proteomic profiles. Patients with anti-AK5 limbic encephalitis were mostly male (20/26, 76.9%) with a median age of 66 years (range 48–94). The predominant symptom was severe episodic amnesia in all patients, and this was frequently associated with depression (17/25, 68.0%). Weight loss, asthenia and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%) and increased Tau (11/14, 78.6%). Temporal lobe hyperintensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably towards severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with the highest titres in nine CSF-serum paired samples. A temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T cells, intense granzyme B expression and abundant macrophages/microglia. Human leucocyte antigen (HLA) analysis in 11 patients showed a striking association with HLA-B*08:01 [7/11, 63.6%; odds ratio (OR) = 13.4, 95% confidence interval (CI): 3.8–47.4], C*07:01 (8/11, 72.7%; OR = 11.0, 95% CI: 2.9–42.5), DRB1*03:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7–55.7), DQB1*02:01 (8/11, 72.7%; OR = 13.5, 95% CI: 3.5–52.0) and DQA1*05:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7–55.7) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR = 16.5, 95% CI: 4.8–57.1). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 control subjects and 10 cases with other more common non-paraneoplastic limbic encephalitis (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed 31 and seven significantly upregulated proteins in anti-AK5 limbic encephalitis, respectively mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 limbic encephalitis result from a distinct T cell-mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy.

ObjectiveTo determine the observed and expected incidence rates of paraneoplastic neurologic syndromes (PNSs) and autoimmune encephalitides (AEs) diagnosed in France between 2016 and 2018, we conducted a population-based epidemiologic study.MethodsObserved incidence rates were stratified by sex, age groups, region of care, year of diagnosis, and disease subgroups. National expected incidence rates were calculated based on rates obtained in the area directly adjacent to the Reference Center using a mixed Poisson model and compared with observed incidence rates.ResultsSix hundred thirty-two patients with definite PNS or AE met the inclusion criteria. The observed incidence rate of definite PNS and AE in France was 3.2 per million person-years (CI95%: 2.9–3.4) compared with an expected incidence rate of 7.1 per million person-years (CI95%: 3.9–11.4). The national observed incidence rate for the antibody-positive AE subgroup increased from 1.4 per million person-years (CI95%: 1.2–1.7) in 2016 to 2.1 per million person-years (CI95%: 1.7–2.4) in 2018, thus surpassing the incidence rate of classical PNS (1.2 per million person-years [CI95%: 1.0–1.5]) of 2018.ConclusionsThere was a significant widespread year-to-year increase in the incidence of diagnoses registered with the Reference Center for all subgroups of PNS and AE studied. The national observed incidence rate is likely underestimated due to underdiagnosis and underreporting.

ObjectiveTo investigate the diagnostic yield of commercial immunodots to detect onconeural antibodies associated with paraneoplastic neurologic syndromes (PNSs), we analyzed the proportion of confirmed positive results using alternative techniques.MethodsSera (n = 5,300) of patients with suspected PNS were tested by PNS+2 blot (Ravo Diagnostika; January 2016–May 2017) or EUROLINE PNS 12 Ag (Euroimmun; July 2017–November 2018). Positive samples were further explored by in-house indirect immunofluorescence and a third in-house technique (Western blot or cell-based assay) using recombinant protein. Those found negative by these 2 techniques were considered as nonconfirmed. We analyzed the relationship between band intensity and final confirmation. Clinical data were collected for all confirmed results and nonconfirmed EUROLINE immunodots.ResultsPNS+2 blot was positive in 128/1,658 (7.7%) sera and confirmed in 47/128 (36.7%). EUROLINE was positive in 186/3,626 (5.1%) and confirmed in 56/186 (30.1%). Confirmation was highly variable among the antibodies tested, from 7.2% (PNS+2 blot) and 5.8% (EUROLINE) for anti-Yo to 88.2% (PNS+2 blot) and 65.0% (EUROLINE) for anti-Hu. None of the 27 weak positive sera by EUROLINE was confirmed. Band intensity in confirmed cases was variable among the antibodies from strong positive for all anti-Yo (n = 3) and anti-Hu (n = 11) to positive (n = 19) or strong positive (n = 9) for anti-SOX1. Among patients with a nonconfirmed EUROLINE result and available clinical information, all had an alternative diagnosis, and only 6.7% had cancer.ConclusionsImmunodots may be useful for PNS screening, but a threshold should be established for each antibody, and clinical information and confirmation by other techniques are essential.Classification of evidenceThe study provides Class IV evidence that immunodot assays for onconeural antibodies accurately identify patients with paraneoplastic neurologic syndromes.

To describe autoantibodies (Abs) against tripartite motif-containing (TRIM) protein 9 and 67 in two patients with paraneoplastic cerebellar degeneration (PCD) associated with lung adenocarcinoma. Abs were characterized using immunohistochemistry, Western blotting, cultures of murine cortical, and hippocampal neurons, immunoprecipitation, mass spectrometry, knockout mice for Trim9 and 67, and cell-based assay. Control samples included sera from 63 patients with small cell lung cancer without any paraneoplastic neurological syndrome, 36 patients with lung adenocarcinoma and PNS, CSF from 100 patients with autoimmune encephalitis, and CSF from 165 patients with neurodegenerative diseases. We found Abs targeting TRIM9 and TRIM67 at high concentration in the serum and the cerebrospinal fluid (CSF) of a 78-year-old woman and a 65-year-old man. Both developed subacute severe cerebellar ataxia. Brain magnetic resonance imaging found no abnormality and no cerebellar atrophy. Both had CSF inflammation with mild pleiocytosis and a few oligoclonal bands. We identified a pulmonary adenocarcinoma, confirming the paraneoplastic neurological syndrome in both patients. They received immunomodulatory and cancer treatments without improvement of cerebellar ataxia, even though both were in remission of their cancer (for more than 10 years in one patient). Anti-TRIM9 and anti-TRIM67 Abs were specific to these two patients. All control serum and CSF samples tested were negative for anti-TRIM9 and 67. Anti-TRIM9 and anti-TRIM67 Abs appeared to be specific biomarkers of PCD and should be added to the panel of antigens tested when this is suspected.

The aim of this study was to describe specificities of patients with NMDA receptor antibody (NMDAR-Ab) encephalitis associated with a malignant tumor. Retrospective observational study of 252 patients with NMDAR-Ab encephalitis of the French Paraneoplastic Neurological Syndrome Reference Center. Patients were classified in three groups: (1) non-malignant ovarian teratomas, (2) malignant ovarian teratomas (immature), and (3) other malignant tumors. Sixty patients (23.8%) had an associated tumor and 15 (6%) were malignant. No particular neurological symptom was observed in these patients. Ovarian teratomas were the most frequent (51 cases) with 6 of them immature (11.8% of teratomas). Nine patients (3.6%) developed other malignant tumors (3 small cell lung carcinomas, 1 uterine adenocarcinoma, 1 prostate adenocarcinoma, 1 Hodgkin lymphoma, 1 pineal dysgerminoma, 1 neuroblastoma and 1 pancreatic neuroendocrine tumor). Among patients with a cancer other than teratoma, 6/9 were elderly patients (median age 65 years, representing 30% of elderly patients with such encephalitis) compared to a median age of 26 years in adult patients included herein. The clinical course was similar in the three groups, other than a higher death rate among patients with malignant tumors (86 versus 2%; p

Autoimmune encephalitis with anti-N-methyl-d-aspartate receptor autoantibodies (NMDA-R-Abs) is a recently described disease affecting adult and pediatric patients. Symptoms of the disease are now perfectly described in the adult population but the clinical presentation is less known in young children. The aim of the present study was to describe the clinical presentation and the specificities of symptoms presented by young children with NMDA-R-Abs encephalitis to improve diagnosis of this disease, and to compare these to a series of previously published female adult patients. Fifty cases of children younger than twelve years of age diagnosed with NMDA-R-Abs encephalitis between January 1, 2007 and December 31, 2016 (27 females and 23 males) were retrospectively studied. The first neurological symptoms observed in young children with NMDA-R-Abs encephalitis were characterized by seizure (72%), especially focal seizure (42%), within a median of 15 days before other encephalitis symptoms; other patients mostly had behavioral disorders (26%). The seizures were frequently difficult to diagnose because of the transient unilateral dystonic or tonic posturing presentation or sudden unilateral pain in the absence of clonic movements. A post-ictal motor deficit was also frequently observed. This clinical presentation is different from that observed in adult females with NMDA-R-Abs encephalitis who initially present mainly psychiatric disorders (67%) or cognitive impairment (19%), and less frequently seizures (14%). The diagnosis of NMDA-R-Abs encephalitis should be systematically considered in young children of both sexes who present neurological symptoms suggesting recent seizures (focal or generalized) without obvious other etiology.

Paraneoplastic cerebellar degenerations with anti-Yo antibodies (Yo-PCD) are rare syndromes caused by an auto-immune response against neuronal antigens (Ags) expressed by tumor cells. However, the mechanisms responsible for such immune tolerance breakdown are unknown. We characterized 26 ovarian carcinomas associated with Yo-PCD for their tumor immune contexture and genetic status of the 2 onconeural Yo-Ags, CDR2 and CDR2L. Yo-PCD tumors differed from the 116 control tumors by more abundant T and B cells infiltration occasionally organized in tertiary lymphoid structures harboring CDR2L protein deposits. Immune cells are mainly in the vicinity of apoptotic tumor cells, revealing tumor immune attack. Moreover, contrary to un-selected ovarian carcinomas, 65% of our Yo-PCD tumors presented at least one somatic mutation in Yo-Ags, with a predominance of missense mutations. Recurrent gains of the CDR2L gene with tumor protein overexpression were also present in 59% of Yo-PCD patients. Overall, each Yo-PCD ovarian carcinomas carried at least one genetic alteration of Yo-Ags. These data demonstrate an association between massive infiltration of Yo-PCD tumors by activated immune effector cells and recurrent gains and/or mutations in autoantigen-encoding genes, suggesting that genetic alterations in tumor cells trigger immune tolerance breakdown and initiation of the auto-immune disease.

Les encephalites limbiques sont des pathologies rares responsables de syndromes amnesiques par atteinte inflammatoire du circuit de Papez. Nous rapportons la situation d’un patient de 62 ans, professeur de journalisme, qui installa en quelques semaines un tableau de perplexite anxieuse et d’amnesie hippocampique. Il existait au sein de l’amnesie des difficultes particulieres concernant la memoire topographique et l’identification des personnes. Cette amnesie particuliere etait due a une encephalite auto-immune associee a des auto-anticorps anti-AK5. Nous rapportons l’extraordinaire analyse que monsieur R. fait de son amnesie avec des extraits du Journal d’un oublieux, autour duquel le neurologue echange avec lui depuis quatre ans.

Objective: To assess the long-term outcomes of patients with temporal lobe epilepsy and CSF anti-glutamate decarboxylase antibodies (GAD65-Abs). Methods: We retrospectively analyzed the clinical records of 35 patients with temporal lobe epilepsy and CSF GAD65-Abs, collected from January 1993 to December 2016 and assessed cognitive impairment and seizure activity at last visit. Cognitive impairment was considered significant if impacting on daily life activities. Immunohistochemistry on rat brain slices and ELISA were used for antibody detection and titration. Results: Median age was 30years (range 2–63), 32/35 (91%) patients were female, and median follow-up was 68months (range 7–232). At presentation, 20 patients had isolated temporal lobe epilepsy and 15 patients had other limbic symptoms, including anterograde amnesia (n = 10) and behavioral disturbances (n = 5). Progressive clinical deterioration over follow-up was reported in 28/35 patients (80%), including gradual increase of memory impairment (n = 25), and apparition of behavioral disturbances (n = 4) or mood disorders (n = 18). At last follow-up, 24/35 (69%) patients had cognitive disturbances with an impact on patient’s daily life activities, and 28/35 (80%) still had active seizures. Conclusion: Most patients with temporal lobe epilepsy and CSF GAD65-Abs develop a chronic disease with progressive cognitive impairment and refractory epilepsy regardless of the presence of additional limbic symptoms at onset.

BACKGROUND Paraneoplastic cerebellar degenerations with anti-Yo antibodies (Yo-PCD) are rare syndromes associated with ovarian or breast cancers and caused by an auto-immune response against neuronal antigens expressed by tumor cells. We previously demonstrated in Yo-PCD ovarian cancers an association between massive infiltration of ovarian tumors by activated immune effector cells and recurrent gains and/or mutations of onconeural Yo genes (CDR2L and CDR2), suggesting that such genetic alterations in ovarian tumor cells may trigger immune tolerance breakdown and initiation of the auto-immune reaction against Purkinje cells. MATERIAL AND METHODS We pursued the characterization of Yo-PCD tumors and specifically studied breast cancer by IHC, FISH, CGH array and RNA sequencing analysis of 17 breast Yo-PCD tumors and by comparing their genetic characteristics with 10 sporadic breast tumors and public databases. RESULTS We confirmed that specific genetic alterations were also present in breast cancers associated with Yo-PCD. Moreover, this study provides additional evidence for a role of tumor cell specificities in PCD immunopathology by revealing peculiarities in Yo-PCD breast tumors compared to Yo-PCD ovarian cancer. Indeed, not only the CDR2L Yo gene was amplified in 8/9 breast Yo-PCD cancers but also the Erb2/Her2 gene in 15/16 (both genes are on chromosome 17q). In addition to this original Her2 and Yo antigen amplification confirmed by FISH, we observed an overexpression of these proteins by IHC analysis. These Yo-PCD breast cancers are also all negative for hormone receptors (HR). Thus, Yo-PCD breast tumors seem to belong to the molecularly and clinically distinct class of HR-negative and Her2-enriched breast cancers, which represents less than 10 % of breast cancers in the general population. Transcriptomic analysis confirmed that breast Yo-PCD tumors differ by their expression programs from classical breast cancers molecular subtypes. CONCLUSION Understanding the tumor genetic features leading to the immune breakdown and anti-tumor immune response as well as nervous tissue attack remains challenging and seems to be specific according to the tumor subtypes. Herein, our results suggest that, despite sharing common genetic alterations (copy number variations and mutations affecting Yo genes), the Yo-PCD immunopathogenesis of breast and ovarian cancers differ by involving different tumor-specific molecular pathways.

Objective To report the induction of anti–Ma2 antibody–associated paraneoplastic neurologic syndrome (Ma2-PNS) in 6 patients after treatment with immune checkpoint inhibitors (ICIs). We also analyzed (1) patient clinical features compared with a cohort of 44 patients who developed Ma2-PNS without receiving ICI treatment and (2) the frequency of neuronal antibody detection before and after ICI implementation. Methods Retrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018. Results Our series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving nivolumab (n = 3), pembrolizumab (n = 2), or a combination of nivolumab and ipilimumab (n = 1) for treatment of neoplasms that included lung (n = 4) and kidney (n = 1) cancers and pleural mesothelioma (n = 1). Clinical syndromes comprised a combination of limbic encephalitis and diencephalitis (n = 3), isolated limbic encephalitis (n = 2), and a syndrome characterized by ophthalmoplegia and head drop (n = 1). No significant clinical difference was observed between our 6 patients and the overall cohort of Ma2-PNS cases. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017–2018 biennium. Eight cases had been detected in the preceding biennium 2015–2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. Despite ICI withdrawal and immunotherapy, 4/6 patients died, and the remaining 2 showed a moderate to severe disability. Conclusions We show a clear association between ICI use and increased diagnosis of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS because clinical presentation can be challenging.

To determine the incidence and main characteristics of cerebrovascular events as the presenting manifestations of myeloproliferative neoplasm (MPN).The Hematology in Lyon (HEMILY) registry is a prospective database (763 patients) of all cases of MPN diagnosed since 2005 in the Rhône-Alpes district of France. The MPN cases were divided into four groups: polycythemia vera (PV); essential thrombocythemia (ET); myelofibrosis (MF); and atypical MPN. The ischemic stroke subtype was classified according to TOAST criteria.A stroke history revealed MPN in 35 (4.3%) patients: 22 (63%) had an ischemic stroke; eight (23%) had a transient ischemic attack; four (11%) had cerebral venous thrombosis; and one (3%) had hemorrhagic stroke. All patients had hemoglobin and/or platelet count abnormalities. In addition, 12 (34%) patients had PV, 21 (60%) had ET, one (3%) had MF and one (3%) had atypical/unclassified MPN. The JAK2 V617F mutation was found in 83% of patients. In 18 (51%) patients, an additional mechanism of stroke was present (atherosclerosis in 10 patients, atrial fibrillation in one patient and dissection in another). The median NIHSS score at entry was 2, and the median modified Rankin Scale score at 3 months was 0. Compared with the general MPN population, stroke-MPN patients presented with significantly higher levels of hemoglobin (P0.001) and were more frequently positive for the JAK2 V617F mutation (P=0.044).Stroke revealing MPN is rare. However, careful attention should still be paid to blood counts even in patients with obvious stroke etiologies, as early diagnosis permits prompt treatment and decreases the risk of recurrence, thus limiting morbidity and mortality.

Objective: To identify the clinical and radiologic features that should raise suspicion for the pseudotumoral presentation of cerebral amyloid angiopathy–related inflammation (CAA-I). Methods: We retrospectively reviewed the characteristics of 5 newly diagnosed and 23 previously reported patients in whom the CAA-I imaging findings were initially interpreted as CNS neoplasms. Results: Most cases (85%) occurred in patients >60 years old. The clinical characteristics at presentation included subacute cognitive decline (50%), confusion (32%), focal deficits (32%), seizures (25%), and headaches (21%). Brain MRI demonstrated infiltrative white matter lesions that exhibited a loco-regional mass effect without parenchymal enhancement (93%). In general, these findings were interpreted as low-grade glioma or lymphoma. Eighteen patients (64%) underwent a biopsy, which was nondiagnostic in 4 patients (14%), and 6 patients (21%) underwent a surgical resection. The primary reason for the misinterpretation of the imaging findings was the absence of T2*-weighted gradient recalled echo (T2*-GRE) sequences on initial imaging (89%). When subsequently performed (39%), the T2*-GRE sequences demonstrated multiple characteristic cortical and subcortical microhemorrhages in all cases. Perfusion MRI and magnetic resonance spectroscopy (MRS), which were performed on a subset of patients, indicated markedly reduced relative cerebral blood flow and a normal metabolic ratio. Conclusion: The identification of one or several nonenhancing space-occupying lesions, especially in elderly patients presenting with cognitive impairment, should raise suspicion for the pseudotumoral presentation of CAA-I and lead to T2*-GRE sequences. Perfusion MRI and MRS appear to be useful techniques for the differential diagnosis of this entity.

To describe the detailed clinical characteristics, immunotherapy, and long-term outcomes of patients with anti-NMDA receptor (NMDAR) encephalitis in China.A single-center, prospective study. Patients who met the diagnostic criteria were enrolled from 2011 to 2017 and followed up. The clinical features, treatment, and long-term outcomes were collected prospectively. Factors affecting the long-term prognosis were analyzed.The study included 220 patients. The most common clinical presentations were psychosis (82.7%) and seizures (80.9%). Of the patients, 19.5% had an underlying neoplasm; of which ovarian teratoma was 100% of tumors in females and only one male had lung cancer. Most patients (99.5%) received first-line therapy (glucocorticoids, IV immunoglobulin, or plasmapheresis alone or combined), and only 7.3% received second-line immunotherapy (rituximab, cyclophosphamide alone, or combined). Long-term immunotherapy (mycophenolate mofetil or azathioprine1 year) was administered to 53.2% of patients. During the first 12 months, 207 (94.1%) patients experienced improvement, and 5 (2.3%) died, whereas 38 (17.3%) experienced relapses. At 12-month follow-up, 92.7% had favorable clinical outcomes (modified Rankin Scale score ≤2).Patients in China present with psychosis and seizure frequently but have a low percentage of underlying neoplasms. Re-enforced first-line immunotherapy is effective in managing anti-NMDAR encephalitis in the acute phase. Although relapse is relatively common, with combined first-line and long-term immunotherapy, most patients reached favorable outcomes.

Objective: To report the clinical features and long-term outcome of 22 newly diagnosed paraneoplastic patients with GABA B receptor antibodies (GABA B R-Abs). Methods: Retrospective clinical study of CSF-confirmed cases of GABA B R-Abs encephalitis. Results: We identified 22 patients (4 female) with GABA B R-Abs, with a median age of 64years (range 55–85). All were paraneoplastic: 20 small-cell lung cancer, one malignant thymoma, and one uncharacterized lung mass. The most frequent first symptom was the isolated recurrent seizures without cognitive inter-ictal impairment in 17 patients (77%). In the other, three presented the first behavioral disorders and two presented de novo status epilepticus (SE). After a median delay of 10days (range 1–30), the recurrent seizures’ phase was followed by an encephalitic phase characterized by confusion in 100% of cases and SE in 81% (n = 17), with 53% (n = 9) non-convulsive SE. Dysautonomic episodes were frequent (36%, n = 8, bradycardia and central apnea) and killed three patients. CSF study was abnormal in 95% of the cases (n = 21). At the encephalitic phase, MRI showed a temporal FLAIR hypersignal in 73% (n = 16) of the cases. First-line immunotherapy was initiated after a median delay of 26days (range 6–65) from disease onset, and a partial response was observed in 10 out of 20 patients (50%). There was no complete response. Two years after onset, a massive anterograde amnesia affected all still alive patients. Nine patients died from cancer progression (median survival: 1.2years). Conclusion: Paraneoplastic GABA B R-Abs encephalitis is characterized by a stereotype presentation with an epilepsy phase before an encephalitic phase with dysautonomia. The functional prognosis is poor.

International audience; We report 2 cases of NMDA receptor (NMDAR) encephalitis with classic signs and symptoms of encephalitis, but in whom Balint syndrome was a predominant manifestation in the evolution of the disease.

To report the clinical features and long-term outcome of 22 newly diagnosed paraneoplastic patients with GABARetrospective clinical study of CSF-confirmed cases of GABAWe identified 22 patients (4 female) with GABAParaneoplastic GABA

Background: Paraneoplastic neurological syndromes are rare conditions where an autoimmune reaction against the nervous system appears in patients suffering from a tumour, but not linked to the spreading of the tumour. A break in the immune tolerance is thought to be the trigger. Methods: The transcriptomic profile of 12 ovarian tumours (OT) from patients suffering from paraneoplastic cerebellar degeneration (PCD) linked to anti-Yo antibodies (anti-Yo PCD OT) was compared with 733 ovarian tumours (OT control) from different public databases using linear model analysis. Results: A prominent significant transcriptomic over-representation of CD8+ and Treg cells was found in anti-Yo PCD OT, as compared to the OT control. However, the overall degree of immune cell infiltration was similar, according to the ESTIMATE immune score. We also found an under-representation of M2 macrophages in anti-Yo PCD OT. Furthermore, the differentially expressed genes were enriched for AIRE-related genes, a well-known transcription factor associated with a broad range of autoimmune diseases. Finally, we found that the differentially expressed genes were correlated to the transcriptomic profiling of the cerebellar structures. Conclusions: Our data pinpointed the enrichment of acquired immune response, particularly high density of CD8+ lymphocytes, and high-level expression of CDR-related antigens in anti-Yo PCD OT.

Objective: To report paroxysmal episodes of cerebellar ataxia in a patient with anti–contactin-associated protein-like 2 (CASPR2) antibody-related autoimmune encephalitis and to search for similar paroxysmal ataxia in a cohort of patients with anti–CASPR2 antibody-associated autoimmune encephalitis. Methods: We report a patient with paroxysmal episodes of cerebellar ataxia observed during autoimmune encephalitis with anti-CASPR2 antibodies. In addition, clinical analysis was performed in a retrospective cohort of 37 patients with anti-CASPR2 antibodies to search for transient episodes of ataxia. Paroxysmal symptoms were further specified from the referral physicians, the patients, or their relatives. Results: A 61-year-old man with limbic encephalitis and anti-CASPR2 antibodies developed stereotyped paroxysmal episodes of cerebellar ataxia, including gait imbalance, dysarthria, and dysmetria, 1 month after the onset of the encephalitis. The ataxic episodes were specifically triggered by orthostatism and emotions. Both limbic symptoms and transient ataxic episodes resolved after treatment with steroids and IV cyclophosphamide. Among 37 other patients with anti-CASPR2 antibodies, we identified 5 additional cases with similar paroxysmal ataxic episodes that included gait imbalance (5 cases), slurred speech (3 cases), limb dysmetria (3 cases), and nystagmus (1 case). All had concomitant limbic encephalitis. Paroxysmal ataxia was not observed in patients with neuromyotonia or Morvan syndrome. Triggering factors (orthostatism or anger) were reported in 4 patients. Episodes resolved with immunomodulatory treatments in 4 patients and spontaneously in 1 case. Conclusions: Paroxysmal cerebellar ataxia must be added to the spectrum of the anti-CASPR2 antibody syndrome.

Objective:To report 10 patients with limbic encephalitis (LE) and adenylate kinase 5 autoantibodies (AK5-Abs).Methods:We conducted a retrospective study in a cohort of 50 patients with LE with uncharacterized autoantibodies and identified a specific target using immunohistochemistry, Western blotting, immunoprecipitation, mass spectrometry, and cell-based assay.Results:AK5 (a known autoantigen of LE) was identified as the target of antibodies in the CSFs and sera of 10 patients with LE (median age 64 years; range 57–80), which was characterized by subacute anterograde amnesia without seizure and sometimes preceded by a prodromal phase of asthenia or mood disturbances. Anterograde amnesia can be isolated, but some patients also complained of prosopagnosia, paroxysmal anxiety, or abnormal behavior. No associated cancer was observed. All 10 patients had bilateral hippocampal hypersignal on a brain MRI. CSF analysis generally showed a mild pleiocytosis with elevated immunoglobulin G index and oligoclonal bands, as well as high levels of tau protein with normal concentration of Aβ42 and phospho-tau, suggesting a process of neuronal death. Except for one patient, clinical response to immunotherapy was unfavorable, with persistence of severe anterograde amnesia. Two patients evolved to severe cognitive decline. Hippocampal atrophy was observed on control brain MRI. Using in vitro tests on hippocampal neurons, we did not identify clues suggesting a direct pathogenic role of AK5-Abs.Conclusions:AK5-Abs should be systematically considered in aged patients with subacute anterograde amnesia. Recognition of this disorder is important to develop new treatment strategies to prevent irreversible limbic damage.

Planagumà et al. show that infusing CSF from patients with anti-NMDAR encephalitis into the mouse brain induces progressive memory and behavioural deficits that correlate with levels of brain-bound human NMDAR-antibodies and a reduction in NMDARs. The changes, which are reversible, confirm the pathogenicity of NMDAR-antibodies and have therapeutic implications.

Gliomas account for >30% of all primary brain tumors, and each year in the United States, >20,000 individuals receive a diagnosis of the disease.1 Gliomas are heterogeneous and are typically classified according to tumor grade into pilocytic astrocytomas (World Health Organization [WHO] grade I), diffuse low-grade gliomas (WHO grade II), anaplastic gliomas (WHO grade III) and glioblastoma (GBM; WHO grade IV). Gliomas are also classified on the basis of cellular lineage: astrocytic, oligodendroglial, and mixed tumors.2 Over the past 10 years, specific tumor somatic aberrations have been shown to typify the various glioma subtypes, suggesting that different tumor genetic profiles result from different etiologic pathways. IDH (ie, IDH1 or less frequently IDH2) mutation is involved in the development of low-grade glioma and progressive GBM.3,4 The codeletion of chromosome 1p and 19q is highly correlated with oligodendroglial phenotype grade II and III and with IDH mutation. These molecular phenotypes are associated with good clinical outcome.5 In contrast, loss of chromosome 9p and 10q, homozygous deletions of the oncosuppressor CDKN2A-p16-INK4a, and the amplification of the EGFR oncogene are associated with high-grade disease and, particularly, GBM.6 Although Li-Fraumeni, Turcot, and the melanoma/glioblastoma syndromes are associated with substantive risks of glioma, all are rare and collectively account for

Recent advances in the treatment of malignant gliomas have highlighted the fact that the appearance of new contrast-enhancing lesions on magnetic resonance imaging (MRI) is not always indicative of tumor recurrence. It has been suggested that transient seizure-related MRI changes could mimic disease progression (peri-ictal pseudoprogression [PIPG]). However, the clinical and MRI features associated with this situation have not been well described. Here, we consulted the databases of 6 institutions to identify patients with brain tumor who presented during the follow-up period transient MRI lesions wrongly suggesting tumor progression in a context of epileptic seizures. Ten patients were identified. All patients but 1 were long-term survivors who had initially been treated with radiotherapy. The PIPG episode occurred after a median interval of 11 years after radiotherapy. MRI features were highly similar across patients and consisted of transient focal cortical and/or leptomeningeal enhancing lesions that erroneously suggested tumor progression. All patients improved after adjustment of their antiepileptic drugs and transient oral corticosteroids, and MRI findings were normalized 3 months after the PIPG episode. Two patients demonstrated several seizure relapses with the same clinicoradiological pattern. After a median follow-up period of 3.5 years after the initial PIPG episode, only 1 patient presented with a tumor recurrence. In conclusion, in patients with brain tumor, especially in long-term survivors of radiotherapy, the appearance of new cortical and/or leptomeningeal contrast-enhancing lesions in a context of frequent seizures should raise the suspicion of PIPG. This phenomenon is important to recognize in order to avoid futile therapeutic escalation.

Background and Purpose— MR signal changes after intravenous ultrasmall superparamagnetic iron oxide (USPIO) injection are related to inflammatory cells at the subacute stages after focal cerebral injury. However, at the early stages, the interpretation of USPIO-related MR signal alterations remains controversial. Here, we compared MR signal changes after intravenous USPIO injection with the histological iron and macrophage distribution during the first 24 hours in a rodent model of acute stroke. Methods— Multiparametric MRI at 7T and histological USPIO distribution were confronted from 6 to 24 hours after permanent middle cerebral artery occlusion in mice. Blood–brain barrier disruption was assessed using gadolinium MRI and immunoglobulin staining. Prussian blue staining was performed to depict the USPIO brain distribution. USPIO uptake by phagocytes was assessed by immunochemistry on brain tissue, peripheral blood cells, and monocyte cells derived from bone marrow culture. Results— After USPIO injection, 4 areas of early signal change were observed on every MRI. In all these areas, iron particles were mostly free whether detected in the vascular and cerebrospinal fluid compartments or in the interstitium. Within the first 24 hours, USPIO-loaded cells were not detected in the blood of injured mice or in cultured monocytic cells incubated with USPIO at plasmatic concentration. Conclusions— These results suggest that, in this model, early reproducible USPIO-related MR signal changes are mainly caused by passive diffusion of free USPIO after blood–brain barrier leakage and by intravascular trapping rather than by peripheral phagocyte infiltration.