Frank Leypoldt

Temporal and Spatial Dynamics of Cerebral Immune Cell Accumulation in Stroke

BACKGROUND AND PURPOSE Ischemic stroke leads to significant morbidity and mortality in the Western world. Early reperfusion strategies remain the treatment of choice but can initiate and augment an inflammatory response causing secondary brain damage. The understanding of postischemic inflammation is very limited. The objectives of this study were to define the temporal and spatial infiltration of immune cell populations and their activation patterns in a murine cerebral ischemia-reperfusion injury model. METHODS Transient middle cerebral artery occlusion was induced for 1 hour followed by 12-hour to 7-day reperfusion in C57/BL6 mice. Immunohistochemistry and flow cytometry were used to quantify the infiltrating immune cell subsets. RESULTS Accumulation of microglia and infiltration of the ischemic hemisphere by macrophages, lymphocytes, and dendritic cells (DCs) preceded the neutrophilic influx. DCs were found to increase 20-fold and constituted a substantial proportion of infiltrating cells. DCs exhibited a significant upregulation of major histocompatibility complex II and major histocompatibility complex II high-expressing DCs were found 100 times more abundant than in sham conditions. Upregulation of the costimulatory molecule CD80 was observed in DCs and microglial cells but did not further increase in major histocompatibility complex II high-expressing DCs. No lymphocyte activation was observed. Additionally, regulatory immune cells (natural killer T-cells, CD4(-)/CD8(-)T lymphocytes) cumulated in the ischemic hemisphere. CONCLUSIONS This study provides a detailed analysis of the temporal dynamics of immune cell accumulation in a rodent stroke model. The peculiar activation pattern and massive increase of antigen-presenting cells in temporal conjunction with regulatory cells might provide additional insight into poststroke immune regulation.

Herpes simplex virus encephalitis is a trigger of brain autoimmunity

In 5 prospectively diagnosed patients with relapsing post–herpes simplex encephalitis (HSE), N‐methyl‐D‐aspartate receptor (NMDAR) antibodies were identified. Antibody synthesis started 1 to 4 weeks after HSE, preceding the neurological relapse. Three of 5 patients improved postimmunotherapy, 1 spontaneously, and 1 has started to improve. Two additional patients with NMDAR antibodies, 9 with unknown neuronal surface antibodies, and 1 with NMDAR and unknown antibodies, were identified during retrospective assessment of 34 HSE patients; the frequency of autoantibodies increased over time (serum, p = 0.004; cerebrospinal fluid, p = 0.04). The 3 retrospectively identified NMDAR antibody–positive patients also had evidence of relapsing post‐HSE. Overall, these findings indicate that HSE triggers NMDAR antibodies and potentially other brain autoimmunity. Ann Neurol 2014;75:317–323

Overlapping demyelinating syndromes and anti–N-methyl-D-aspartate receptor encephalitis.

To report the clinical, radiological, and immunological association of demyelinating disorders with anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis.

Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke

The devastating effect of ischemic stroke is attenuated in mice lacking conventional and unconventional T cells, suggesting that inflammation enhances tissue damage in cerebral ischemia. We explored the functional role of αβ and γδ T cells in a murine model of stroke and distinguished 2 different T cell-dependent proinflammatory pathways in ischemia-reperfusion injury. IFN-γ produced by CD4(+) T cells induced TNF-α production in macrophages, whereas IL-17A secreted by γδ T cells led to neutrophil recruitment. The synergistic effect of TNF-α and IL-17A on astrocytes resulted in enhanced secretion of CXCL-1, a neutrophil chemoattractant. Application of an IL-17A-blocking antibody within 3 hours after stroke induction decreased infarct size and improved neurologic outcome in the murine model. In autoptic brain tissue of patients who had a stroke, we detected IL-17A-positive lymphocytes, suggesting that this aspect of the inflammatory cascade is also relevant in the human brain. We propose that selective targeting of IL-17A signaling might provide a new therapeutic option for the treatment of stroke.

Autoimmune encephalopathies: Autoimmune encephalopathies

Over the past 10 years, the continual discovery of novel forms of encephalitis associated with antibodies to cell‐surface or synaptic proteins has changed the paradigms for diagnosing and treating disorders that were previously unknown or mischaracterized. We review here the process of discovery, the symptoms, and the target antigens of 11 autoimmune encephalitic disorders, grouped by syndromes and approached from a clinical perspective. Anti‐N‐methyl‐d‐aspartate receptor (NMDAR) encephalitis, several subtypes of limbic encephalitis, stiff‐person spectrum disorders, and other autoimmune encephalitides that result in psychosis, seizures, or abnormal movements are described in detail. We include a novel encephalopathy with prominent sleep dysfunction that provides an intriguing link between chronic neurodegeneration and cell‐surface autoimmunity (IgLON5). Some of the caveats of limited serum testing are outlined. In addition, we review the underlying cellular and synaptic mechanisms that for some disorders confirm the antibody pathogenicity. The multidisciplinary impact of autoimmune encephalitis has been expanded recently by the discovery that herpes simplex encephalitis is a robust trigger of synaptic autoimmunity, and that some patients may develop overlapping syndromes, including anti‐NMDAR encephalitis and neuromyelitis optica or other demyelinating diseases.

Herpes simplex virus–1 encephalitis can trigger anti-NMDA receptor encephalitis: Case report

Relapsing symptoms post herpes simplex virus-1 (HSV) encephalitis (HSVE) usually occur a few weeks after viral therapy and represent either 1) a true viral relapse of HSVE (CSF PCR positive for HSV, new necrotic lesions on brain MRI, and response to acyclovir therapy) or 2) a disorder postulated to be immune-mediated (CSF negative for HSV, no new necrotic lesions, and no response to acyclovir).1,2 It has been suggested that this immune-mediated disorder may be related to NMDA receptor (NMDAR) antibodies,3 and we recently reported a child in whom relapsing symptoms post HSVE were the presentation of anti-NMDAR encephalitis.4 We report an adult with this disorder, demonstrate that synthesis of NMDAR antibodies began after HSVE, and show that relapsing symptoms were due to steroid-responsive anti-NMDAR encephalitis.

Functional and structural brain changes in anti-N-methyl-D-aspartate receptor encephalitis.

Anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis with a characteristic neuropsychiatric syndrome and severe and prolonged clinical courses. In contrast, standard clinical magnetic resonance imaging (MRI) remains normal in the majority of patients. Here, we investigated structural and functional brain changes in a cohort of patients with anti‐NMDAR encephalitis.

Fluorodeoxyglucose positron emission tomography in anti-N-methyl-D-aspartate receptor encephalitis: distinct pattern of disease

Background Patients with encephalitis associated with antibodies against N-methyl-D-aspartate-receptor antibody (NMDAR-ab) encephalitis frequently show psychotic symptoms, amnesia, seizures and movement disorders. While brain MRI in NMDAR-ab encephalitis is often normal, abnormalities of cerebral glucose metabolism have been demonstrated by positron emission tomography (PET) with 18F-fluorodeoxyglucose(FDG) in a few usually isolated case reports. However, a common pattern of FDG-PET abnormalities has not been reported. Methods The authors retrospectively identified six patients with NMDAR-ab encephalitis in two large German centres who underwent at least one whole-body FDG-PET for tumour screening between January 2007 and July 2010. They analysed the pattern of cerebral uptake derived from whole-body PET data for characteristic changes of glucose metabolism compared with controls, and the changes of this pattern during the course of the disease. Results Groupwise analysis revealed that patients with NMDAR-ab encephalitis showed relative frontal and temporal glucose hypermetabolism associated with occipital hypometabolism. Cross-sectional analysis of the group demonstrated that the extent of these changes is positively associated with clinical disease severity. Longitudinal analysis of two cases showed normalisation of the pattern of cerebral glucose metabolism with recovery. Conclusions A characteristic change in cerebral glucose metabolism during NMDAR-ab encephalitis is an increased frontotemporal-to-occipital gradient. This pattern correlates with disease severity. Similar changes have been observed in psychosis induced by NMDAR antagonists. Thus, this pattern might be a consequence of impaired NMDAR function.

HEMORRHAGING FOCAL ENCEPHALITIS UNDER FINGOLIMOD (FTY720) TREATMENT: A CASE REPORT

Several new treatments for relapsing-remitting multiple sclerosis (RRMS) are currently being tested in phase III clinical trials. Fingolimod (FTY720) is an oral sphingosine 1 phosphate receptor (SP1PR) agonist inhibiting lymphocyte egress from lymph nodes.1,2 Fingolimod has shown efficacy in experimental autoimmune encephalitis3 and during phase II testing in RRMS.4 An orally available and well-tolerated drug would be a milestone in MS treatment. Known side effects are upper respiratory tract infections, dyspnea, bradycardia, diarrhea, nausea, and liver enzyme elevation. Severe adverse events included cases of facial herpes zoster,4 enterocolitis,4 macular edema,5 and posterior leukencephalopathy.4 ### Case report. We present a case of severe hemorrhagic focal encephalitis in a 28-year-old woman with mild RRMS during treatment with fingolimod in the FREEDOMS II trial. Within the previous 48 months, she had had three clinical episodes (paresthesias, optic neuritis) and only been treated with steroids. Seven T2-weighted lesions—one gadolinium (Gd) enhancing—were noticed at time of inclusion on cranial MRI (cMRI) and oligoclonal bands were positive. Visual acuity was 0.95 (20/21) (Expanded Disability Status Scale 2.0). She was recruited into the trial 7 months before admission and no disease activity had occurred since. On admission, she presented with a 1-day history of headache, nausea, and vomiting. Lumbar puncture revealed mild pleocytosis (29 cells/μL) and elevated CSF protein (571 mg/L). Neither acute-phase proteins (C-reactive protein and fibrinogen) nor leukocytes were elevated. …

Autoimmune encephalitis as differential diagnosis of infectious encephalitis.

PURPOSE OF REVIEW This review describes the main types of autoimmune encephalitis with special emphasis on those associated with antibodies against neuronal cell surface or synaptic proteins, and the differential diagnosis with infectious encephalitis. RECENT FINDINGS There is a continuous expansion of the number of cell surface or synaptic proteins that are targets of autoimmunity. The most recently identified include the metabotropic glutamate receptor 5 (mGluR5), dipeptidyl-peptidase-like protein-6 (DPPX), and γ-aminobutyric acid-A receptor (GABAAR). In these and previously known types of autoimmune encephalitis [N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), γ-aminobutyric acid-B receptor (GABABR), leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein-like 2 (CASPR2)], the prodromal symptoms or types of presentations often suggest a viral encephalitis. We review here clues that help in the differential diagnosis with infectious encephalitis. Moreover, recent investigations indicate that viral encephalitis (e.g., herpes simplex) can trigger synaptic autoimmunity. In all these disorders, immunotherapy is usually effective. SUMMARY Autoimmune encephalitis comprises an expanding group of potentially treatable disorders that should be included in the differential diagnosis of any type of encephalitis. VIDEO ABSTRACT http://links.lww.com/CONR/A25,