Lutz Harms

Attenuated Stroke Severity After Prodromal TIA A Role for Ischemic Tolerance in the Brain

BACKGROUND AND PURPOSE Ischemic tolerance has been extensively studied in experimental models of heart and brain ischemia. While there is some clinical evidence of ischemic tolerance in the heart, it is not known whether the same is true for the human brain. METHODS We conducted a retrospective case-control study in 148 stroke patients with and without antecedent TIA. RESULTS Despite no significant differences in baseline characteristics, independence (Rankin scale score of 0 to 1) and favorable outcome (Glasgow Coma Scale score of 5) were significantly associated with prior TIA in univariate analysis. After correction for other cardiovascular risk factors, TIA before stroke also was an independent predictor of mild stroke (Canadian Neurological Scale score of > or= 6.5) in multivariate models (absolute difference 21.6%; P=0.01). CONCLUSIONS Assuming that a TIA represents an adequate stimulus to elicit ischemic tolerance, our results suggest that ischemic tolerance might occur in the human brain.

Encephalitis and GABAB receptor antibodies: Novel findings in a new case series of 20 patients

Objective: To report the clinical features of 20 newly diagnosed patients with GABAB receptor (GABABR) antibodies and determine the frequency of associated tumors and concurrent neuronal autoantibodies. Methods: Clinical data were retrospectively obtained and evaluated. Serum and CSF samples were examined for additional antibodies using methods previously reported. Results: Seventeen patients presented with seizures, memory loss, and confusion, compatible with limbic encephalitis (LE), one patient presented with ataxia, one patient presented with status epilepticus, and one patient presented with opsoclonus-myoclonus syndrome (OMS). Nineteen (95%) patients eventually developed LE during the course of the disease. Small-cell lung cancer (SCLC) was identified in 10 (50%) patients, all with LE. Treatment and outcome was available from 19 patients: 15 showed complete (n = 7) or partial (n = 8) neurologic improvement after steroids, IV immunoglobulins, or plasma exchange and oncologic treatment when indicated; 1 patient died of tumor progression shortly after the first cycle of immunotherapy, and 3 were not treated. Five patients with SCLC had additional onconeuronal antibodies (Ri, amphiphysin, or SOX1), and 2 without tumor had GAD65 and NMDAR antibodies, respectively. GABABR antibodies were not detected in serum of 116 patients with SCLC without neurologic symptoms. Conclusion: Our study confirms GABABR as an autoantigen of paraneoplastic and nonparaneoplastic LE and expands the phenotype of GABABR antibodies to ataxia, OMS, and status epilepticus. The long-term prognosis is dictated by the presence of a tumor. Recognition of syndromes associated with GABABR antibodies is important because they usually respond to treatment.

Distinct lesion morphology at 7-T MRI differentiates neuromyelitis optica from multiple sclerosis

Objective: To investigate distinct white matter and cortical gray matter pathology in neuromyelitis optica spectrum disorders (NMOSDs) and multiple sclerosis (MS) at 7-T MRI in a cross-sectional study. Methods: We included 10 patients with NMOSDs and 18 patients with MS in our 7-T MRI study. The imaging protocol comprised T2*-weighted fast low angle shot and turbo inversion recovery magnitude sequences. White matter and cortical gray matter lesions were assessed with special regard to their (perivascular) localization as well as the expression of a hypointense rim. Results: In total, we detected 140 white matter lesions in 7 of 10 patients with NMOSDs. In contrast to MS plaques, which were nearly exclusively centered by a small vein (92%) and showed a characteristic hypointense rim (23%), white matter changes in patients with NMOSDs were nonspecific in appearance and were only infrequently neighbored by a blood vessel (49 lesions [35%], p = 0.003). Hypointense rims were very rarely detectable (3 lesions [2%], p < 0.001). Cortical pathology was absent in NMOSDs. In our MS cohort, we detected 36 leukocortical, 8 intracortical, and 8 subpial cortical lesions in 7 of 18 patients. Conclusion: The MRI features of white matter and the absence of cortical gray matter findings substantially differentiate NMOSDs from MS and can be used as a potential marker to distinguish these 2 entities. The fact that cortical pathology is common in MS but is not present in patients with NMOSDs may reflect the difference in the underlying pathogenesis.

Neurofascin as a target for autoantibodies in peripheral neuropathies

ABSTRACT Objectives: We asked whether autoantibodies against neurofascin (NF)186 or NF155, both localized at the nodes of Ranvier, are present in serum of patients with inflammatory neuropathy, and whether NF-specific monoclonal antibodies are pathogenic in vivo. Methods: We cloned human NF155 and NF186, and developed an ELISA and cell-based assay to screen for antibodies to human NF in a total of 434 donors including 294 patients with Guillain-Barré syndrome variants acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy, and chronic inflammatory demyelinating polyneuropathy (CIDP). We characterized reactive samples by isotyping, tissue section staining, and epitope mapping. We also injected NF-specific monoclonal antibodies IV into rats with experimental autoimmune neuritis. Results: We detected autoantibodies to NF by ELISA in 4% of patients with AIDP and CIDP, but not in controls. Most positive samples contained immunoglobulin G (IgG)1, IgG3, or IgG4 antibodies directed to only one isoform of NF. Two patients with CIDP showed particularly high (1:10,000 dilution) NF155-specific reactivity in both assays and stained paranodes. Two other patients with CIDP who benefited from plasma exchange exhibited antibodies to NF155 by ELISA, and upon affinity purification, antibodies to both isoforms were observed by both assays. Anti-NF monoclonal antibodies enhanced and prolonged induced neuritis in rats. Conclusions: Autoantibodies to NF are detected in a very small proportion of patients with AIDP and patients with CIDP, but may nevertheless be pathogenic in these cases.

IL-17 and GM-CSF Expression Are Antagonistically Regulated by Human T Helper Cells

GM-CSF–producing T helper cells in humans follow a distinct regulation program as compared to TH17 cells and are associated with multiple sclerosis. Cytokine Rivalry In patients with autoimmune diseases, cytokines—secreted immune mediators—are a crucial cause of tissue damage. However, the interplay between different cytokines and their individual roles in disease aggravation and resolution remain poorly defined, especially in humans. Noster et al. report that T helper (TH) cell production of granulocyte-macrophage colony-stimulating factor (GM-CSF) may play a pathogenic role in the brain of patients with multiple sclerosis (MS). They found that TH17-related cytokines—thought from mouse studies to be critical for pathogenesis—actually prevented induction of GM-CSF, whereas TH1-type cytokines promoted GM-CSF. These data provide a rationale for decreasing GM-CSF in patients with MS and suggest that, for MS at least, human may know best. Although T helper 17 (TH17) cells have been acknowledged as crucial mediators of autoimmune tissue damage, the effector cytokines responsible for their pathogenicity still remain poorly defined, particularly in humans. In mouse models of autoimmunity, the pathogenicity of TH17 cells has recently been associated with their production of granulocyte-macrophage colony-stimulating factor (GM-CSF). We analyzed the regulation of GM-CSF expression by human TH cell subsets. Surprisingly, the induction of GM-CSF expression by human TH cells is constrained by the interleukin-23 (IL-23)/ROR-γt/TH17 cell axis but promoted by the IL-12/T-bet/TH1 cell axis. IL-2–mediated signal transducer and activator of transcription 5 (STAT5) signaling induced GM-CSF expression in naïve and memory TH cells, whereas STAT3 signaling blocked it. The opposite effect was observed for IL-17 expression. Ex vivo, GM-CSF+ TH cells that coexpress interferon-γ and T-bet could be distinguished by differential chemokine receptor expression from a previously uncharacterized subset of GM-CSF–only–producing TH cells that did not express TH1, TH2, and TH17 signature cytokines or master transcription factors. Our findings demonstrate distinct and counterregulatory pathways for the generation of IL-17– and GM-CSF–producing cells and also suggest a pathogenic role for GM-CSF+ T cells in the inflamed brain of multiple sclerosis (MS) patients. This provides not only a scientific rationale for depleting T cell–derived GM-CSF in MS patients but also multiple new molecular checkpoints for therapeutic GM-CSF suppression, which, unlike in mice, do not associate with the TH17 but instead with the TH1 axis.

Multiple sclerosis lesions and irreversible brain tissue damage: a comparative ultrahigh-field strength magnetic resonance imaging study.

BACKGROUND In current clinical practice, T2-weighted magnetic resonance imaging (MRI) is commonly applied to quantify the accumulated multiple sclerosis (MS)lesion load, whereas T1-weighted sequences are used to differentiate edema, blood-brain barrier breakdown by contrast enhancement, and irreversible brain tissue damage(commonly called “black holes” owing to the loss of signal intensity in T1-weighted sequences). Black holes are histopathologically associated with axonal loss and severe tissue destruction. In addition, double inversion recovery techniques were developed to improve the sensitivity to cortical lesions. OBJECTIVE To demonstrate the potential of ultrahigh-field 3-dimensional T1-weighted imaging using magnetization-prepared rapid acquisition and multiple gradient echoes(MPRAGE) to detect and characterize white and gray matter pathology in MS. DESIGN Comparative study. SETTING The patients with MS were recruited from the outpatient clinics of the Neuro Cure Clinical Research Center and underwent 7-T brain MRI at the Berlin Ultrahigh Field Facility, both of which are in Berlin, Germany. PATIENTS Twenty patients with relapsing-remitting MS and 14 healthy controls underwent 7-T brain MRI, using a 24-channel receive head coil, and a subgroup of 18 patients with relapsing-remitting MS also underwent 1.5-T brain MRI. The imaging protocol included 2-dimensional T2-weighted fast low-angle shot (FLASH) and turbo inversion recovery magnitude (TIRM) sequences. For 3-dimensional T1-weighted imaging, the MPRAGE sequence was used. Each sequence was initially examined independently in separate analyses by an investigator blinded to all other data. In a second study, all detected lesions were retrospectively analyzed in a side-by-side comparison of all sequences. RESULTS By use of 7-T T2-weighted FLASH imaging, 604 cerebral lesions were detected in the patients with relapsing-remitting MS (mean, 30.2 lesions per patient[range, 2-107 lesions per patient]), but none were detected in healthy controls. Cortical pathology was visible in 10 patients (6 cortical lesions and 37 leukocortical lesions). Within the 7-T acquisitions, each lesion detected at T2-weighted sequences and/or double inversion recovery sequences was also clearly delineated on corresponding MPRAGE sequences in side-by-side analysis.However, at 1.5 T, the MPRAGE images depicted only 452 of 561 lesions visualized in T2-weighted sequences and/or double inversion recovery sequences. In contrast,when analyzing each sequence separately, we found that the 7-T MPRAGE depicted more lesions than the 7-TFLASH (728 lesions vs 584 lesions), and almost twice as many as the 1.5-T MPRAGE (399 lesions). The 7-TMPRAGE also improved the detection of cortical and leukocortical lesions (15 lesions vs 58 lesions). CONCLUSIONS At ultrahigh-field strength, T1-weighted MPRAGE is highly sensitive in detecting MS plaques within the white and the gray brain parenchyma. Our results indicate structural damage beyond demyelination in every lesion depicted, which is in accordance with postmortem histopathological studies. The 7-T MPRAGE clearly delineated every cortical lesion that was visualized by any other MRI sequence at 1.5 or 7 T.

Hemorrhagic transformation of ischemic stroke in diabetics on sulfonylureas.

Disability or death occurs more frequently in patients with hemorrhagic transformation (HT) after ischemic stroke. In rat models of stroke, sulfonylurea (SU) drugs such as glibenclamide (adopted US name, glyburide) confer protection against swelling and HT through actions on the novel SUR1‐regulated NCCa‐ATP channel. Here, we sought to determine whether the use of SU drugs in patients with diabetes mellitus (DM) presenting with acute ischemic stroke might influence the incidence of HT.

Computed Tomographic Parameters Predicting Fatal Outcome in Large Middle Cerebral Artery Infarction

Background: Large middle cerebral artery (MCA) ischaemic stroke when associated with extensive mass effect can result in brain herniation and neurological death. As yet there are few guidelines to aid the selection of patients for aggressive interventional therapies, such as decompression hemicraniectomy and/or hypothermia. Methods: We studied a cohort of patients from seven centres with large MCA infarction requiring neurocritical care. The purpose of this analysis was to assess the use of early radiological signs on follow-up computed tomographic (CT) signs performed within 48 h of stroke onset for predicting mortality at 30 days. The CT parameters assessed included horizontal displacement of the septum pellucidum, pineal shift, complete or partial infarction of the temporal lobe, involvement of additional vascular territories, and the presence of hydrocephalus. The primary outcome measure was in-hospital death within 30 days. Results: One hundred and thirty-five patients who had follow-up CT scans within 48 h were identified from a total of 201 patients with large MCA infarction that received conventional medical therapy alone. The median age was 68 (range 29–99), 56% were female, and the median NIHSS category was 26–30 at 48 h. Among CT variables in univariable analysis, anteroseptal shift ≧5 mm, pineal shift ≧2 mm, complete temporal lobe infarction, involvement beyond the MCA territory, and moderate or severe hydrocephalus were equally predictive of death. Multivariable analysis adjusting for time to CT scan revealed the following predictors of fatal outcome: anteroseptal shift ≧5 mm (OR 10.9; 95% CI 3.2–37.6), NIHSS within 48 h >20 (OR 6.6; 95% CI 2.3–19.3), and infarction beyond the MCA territory (OR 4.9; 95% CI 1.6–15.0). Conclusions: We identified the role of early CT signs in predicting death following massive MCA infarction. The CT parameters anteroseptal shift (>5 versus ≤5 mm), pineal shift ≧2 mm, hydrocephalus, temporal lobe infarction, and other vascular territory infarction if present were predictive of fatal outcome. These CT parameters require prospective validation before they should be considered reliable markers for decision-making.

Morphometric and volumetric MRI changes in idiopathic intracranial hypertension

Objective We aimed at validating established imaging features of idiopathic intracranial hypertension (IIH) by using state-of-the-art MR imaging together with advanced post-processing techniques and correlated imaging findings to clinical scores. Methods Twenty-five IIH patients as well as age-, sex- and body mass index (BMI)-matched controls underwent high-resolution T1w and T2w MR imaging in a 1.5 T scanner, followed by assessment of optic nerve sheaths, pituitary gland, ventricles and Meckels cave. Imaging findings were correlated with cerebrospinal fluid (CSF) opening pressures and clinical symptom scores of visual disturbances (visual field defects or enlarged blind spot), headache, tinnitus (pulsatile and non-pulsatile) and vertigo. CSF as well as ventricle volumes were determined by using an automated MRI volumetry algorithm. Results So-called ‘empty sella’ and optic nerve sheath distension were identified as reliable imaging signs in IIH. Posterior globe flattening turned out as a highly specific but not very sensitive sign. No abnormalities of the lateral ventricles were observed. These morphometric results could be confirmed using MR volumetry (VBM). Clinical symptoms did not correlate with an increase in lumbar opening pressure. Conclusions Our study results indicate that lateral ventricle size is not affected in IIH. In contrast, abnormalities of the pituitary gland and optic nerve sheath were reliable diagnostic signs for IIH.

Venous Transcranial Doppler Ultrasound Monitoring in Acute Dural Sinus Thrombosis Report of Two Cases

BACKGROUND AND PURPOSE We sought to establish the efficacy of the Doppler technique in the evaluation of the intracranial venous system and to assess its usefulness in the monitoring of venous collateral pathways in superior sagittal sinus thrombosis. METHODS Venous Doppler ultrasound was performed with a range-gated 2-MHz transducer in 10 healthy volunteers and in two patients with superior sagittal sinus thrombosis confirmed by cerebral angiography. RESULTS In normal control subjects, a venous signal was found at a depth ranging from 40 to 72 mm, which was considered to correspond to the deep middle cerebral vein and the basal vein of Rosenthal. Mean blood flow velocities ranged from 9 to 20 cm/s. In both patients with superior sagittal sinus thrombosis, Doppler studies detected elevated mean blood flow velocities (146 and 33 cm/s), which normalized after 16 weeks and 1 week, respectively. CONCLUSIONS Venous transcranial Doppler ultrasonography provides a reliable, noninvasive, and rapid technique for intracranial venous examination. It was performed without difficulty in young health volunteers, and it can be applied as a monitoring tool in the evaluation of collateral venous flow in superior sagittal sinus thrombosis.