Major goals and needs for the management and control of neurocysticercosis.

<p>Major goals and needs for the management and control of neurocysticercosis.</p

Histological changes in corticomeningeal cysticerci before and after treatment.

<p>(A) Untreated (D0) corticomeningeal cysticercus. The figure shows IS2 in both parenchyma and meninges region. IS3 is absent from both regions. (B) Treated (D5) corticomeningeal cysticercus. Both regions present IS3, which has a larger extension in the parenchymal region than in the meningeal region. <i>P</i>: Parenchymal region. <i>M</i>: Meningeal region. <i>C</i>: Cysticercus. <i>Arrows</i>: Inflammatory stage grade 3 (IS3) limits. (All figures are from Haematoxylin and eosin stain slides. Main figures, right: 40X; bar: 500 μm. Amplified panels, left: 400X; bar: 50 μm).</p

Inflammatory stages in parenchymal and meningeal cysticerci.

<p>(A), (B), (C) and (D) are IS1, IS2, IS3 and IS4 in parenchymal tissue, respectively. Collagen and number of cells tend to increase with the degree of inflammation, as previously described by Alvarez [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0004207#pntd.0004207.ref024" target="_blank">24</a>]. (E), (F) and (G) are examples of IS1, IS2 and IS3 in meningeal tissue, respectively. The collagenous areas in meningeal tissue are usually thinner than in parenchymal tissue and the number of inflammatory cells are decreased compared to the parenchyma tissue. (H) Shows inflamed meningeal vessels—note the inflammatory cells surrounding the vessels (All pictures are from Haematoxylin and eosin stain slides: 400X; bar: 50 μm).</p

Frequencies of encapsulated brain cysts with putative REBI from untreated and PZQ-treated pigs.

<p>* compared to UT.</p><p>** compared to PZQ48.</p><p>NS: non significant.</p

Positron emission tomography measurement of ¹¹C-PBR28 binding.

<p>In the first six scans including scan 1 of patient 1 shown in Figure 1, ¹¹C-PBR28 binding was measured as total distribution volume, <i>V</i>_T, using Logan plot [12] based on radioactivity measured by the PET scanner (A, closed circles: perilesional edema in left basal ganglia, open circles: contralateral side with normal MRI) and ¹¹C-PBR28 concentration in arterial plasma measured with radio-high performance liquid chromatography (B). Brain activity decreased to half of the peak in about 60 min indicating that none of the participants including this patient was a low affinity binder [14] to ¹¹C-PBR28. Both the analyses using only area under the curve of brain radioactivity (A) and that using both brain (A) and arterial blood data (B) gave the same increase of 14% in ¹¹C-PBR28 binding indicating that arterial blood sampling was unnecessary.</p

MR and PET images of patient 2 who showed a degenerating cyst (arrow).

<p>The patient presented with a seizure 85 days (01/06/2008) before the PET scan on 03/25/2008. On 02/15/2008 when the patient was asymptomatic, MRI scan showed a Gd-enhanced degenerating cyst in right temporal cortex (arrow). On the day of the PET scan (03/25/2008), the Gd-enhanced lesion slightly shrunk, and the PET scan showed increased ¹¹C-PBR28 binding based on Logan plot (21%) and area under the curve (AUC, 17%). The color bar applies to only the PET image on the left side.</p

Characterization of REBI in muscle cysts.

<p>(<b>A</b>) A representative hematoxylin-eosin (H&E) stained section through a REBI (black arrow) on a non encapsulated muscle cyst; the solid rectangle represents the area shown in “B”; isolated, non encapsulated, muscle cysts demonstrating REBI (inset). (<b>B</b>) A high and even higher magnification view (inset) of the eosinophil-rich cellular infiltrate of the REBI shown in “A” (solid rectangle). (<b>C</b>) Uninvolved cyst wall showing identifiable structures in a region close to the REBI (inset) in two magnified views of the dashed line rectangle in panel “A”. (<b>D</b>) Bright field microscopy of an unstained deparaffinized section of the REBI of the muscle cyst in “A”, demonstrating uptake of EB by eosinophils. (<b>E</b>) Fluorescent microscopy with a rhodamine filter of the same section. (<b>F</b>) H&E staining of the same section. (<b>G</b>) Immunolocalization of eosinophils and EB in a REBI with eosinophil peroxidase (EPX)-specific antibodies (brown interior staining). (<b>H</b>) Fluorescence micrograph of the same section as shown in “G”. (<b>I</b>) Merged image of “G” and “H”. Bar: 1 µm (A inset); 400 µm (A); 200 µm (B, C); 20 µm (D — I and insets in B and C). Key: cw = cyst wall; t = tegument; st = subtegument; ir = internal region.</p

MR and PET images of patient 1 following a single perilesional edema episode.

<p>Fluid-attenuated inversion recovery (FLAIR) and gadolinium (Gd)-enhanced T1-weighted MR images at three time points and ¹¹C-PBR28 PET images obtained at two time points. Two lesions are seen, the straight arrow points out a calcification with edema in the left basal ganglion and the curved arrow the edema and calcification in the right centrum semiovale. Although perilesional edema resolved by 01/14/2008, ¹¹C-PBR28 PET uptake was still present. PET images show ¹¹C-PBR28 binding in total distribution volume, <i>V</i>_T. The images are reoriented to show the two lesions on the same coronal slice. Images outside of brain parenchyma are masked.</p

TNF-α blockade suppresses pericystic inflammation following anthelmintic treatment in porcine neurocysticercosis

<div><p>Background</p><p>Neurocysticercosis (NCC) is an infection of the brain with the larval cyst of the tapeworm, <i>Taenia solium</i>. Cysticidal treatment induces parasite killing resulting in a post inflammatory response and seizures, which generally requires corticosteroid treatment to control inflammation. The nature of this response and how to best control it is unclear. We investigated the anti-inflammatory effects of pretreatment with etanercept (ETN), an anti-tumor necrosis factor agent, or dexamethasone (DEX), a high potency corticosteroid, on the post treatment inflammatory response in naturally infected pigs with neurocysticercosis after a single dose of the cysticidal drug praziquantel (PZQ).</p><p>Methodology/Principal findings</p><p>We followed the methods from a previously developed treatment model of NCC in naturally infected swine. The four study groups of infected pigs included 3 groups treated with PZQ on day 0: PZQ-treated alone (100 mg/kg PO; n = 9), pretreated with dexamethasone (DEX, 0.2 mg/kg IM administered on days -1, +1 and +3; n = 6), and pretreated with etanercept (ETN, 25 mg IM per animal on days -7 and 0; n = 6). The fourth group remained untreated (n = 3). As measured by quantitative RT-PCR, ETN pretreatment depressed transcription of a wide range of proinflammatory, regulatory and matrix protease encoding genes at 120 hr post PZQ treatment in capsules of cysts that demonstrated extravasated Evans Blue (EB) (a measure of blood brain barrier dysfunction) compared to animals not receiving ETN. Transcription was significantly depressed for the proinflammatory genes tumor necrosis factor (TNF)-α, and interferon (IFN)-γ; the inflammation regulating genes cytotoxic T-lymphocyte-associated protein (CTLA)4, interleukin (IL)-13 and transforming growth factor (TGF)-β; the tissue remodeling genes matrix metalloprotease (MMP)1 and 9, tissue inhibitors of metalloproteases (TIMP)1 and 2, and the genes regulating endothelial function vascular endothelial growth factor (VEGF)1, angiopoietin (Ang)1, Ang 2, and platelet endothelial cell adhesion molecule (PECAM)-1. In contrast, transcription was only modestly decreased in the DEX pretreated pigs compared to PZQ alone, and only for TNF-α, IL-6, IFN-γ, TGF-β and Ang1. IL-10 was not affected by either ETN or DEX pretreatments. The degree of inflammation, assessed by semi-quantitative inflammatory scores, was modestly decreased in both ETN and DEX pretreated animals compared to PZQ treated pigs whereas cyst damage scores were moderately decreased only in cysts from DEX pretreated pigs. However, the proportion of cysts with EB extravasation was not significantly changed in ETN and DEX pretreated groups.</p><p>Conclusions/Significance</p><p>Overall, TNF-α blockade using ETN treatment modulated expression of a large variety of genes that play a role in induction and control of inflammation and structural changes. In contrast the number of inflammatory cells was only moderately decreased suggesting weaker effects on cell migration into the inflammatory capsules surrounding cysts than on release of modulatory molecules. Taken together, these data suggest that TNF-α blockade may provide a viable strategy to manage post-treatment pericystic inflammation that follows antiparasitic therapy for neurocysticercosis.</p></div

Schematic outline of the schedule of treatment with anti-inflammatory agents and praziquantel (PZQ), showing number of pigs per group and necropsy time points when cyst and brain samples were collected for histopathology and analysis of gene expression by quantitative RT-PCR.

<p>The experimental groups correspond to those described in detail in Methods. EB: Evans blue; PZQ: praziquantel 100 mg/kg PO, on day 0; DEX: dexamethasone 0.2 mg/kg IM, on days –1, +1 and +3; ETN: etanercept 25 mg/pig IM on days –7 and 0.</p