Highlights on Cerebral Arteriovenous Malformation Treatment Using Combined Embolization and Stereotactic Radiosurgery: Why Outcomes are Controversial?

Cerebral arteriovenous malformations (AVMs) are abnormal tangling between brain arteries and veins causing an arteriovenous shunt called nidus with an intervening network of vessels from the region of formation and spans through the brain. AVM effect is debilitating to the affected individual due to associated persistent intracerebral hemorrhage, resulting in significant occurrences of seizures and neurological damage. Recent innovative treatments involve a combination of embolization (Embo) procedures followed by stereotactic radiosurgery (SRS), designed to optimize less-invasive practice for the obliteration of the AVMs. Three groups of investigators reported different outcomes based on obliteration rates and adverse events, making the effectiveness of options for therapy, controversial. We have taken the case-oriented-approach to highlight on varying outcomes from various studies and provide insights as to why findings from different operation settings could be so conflicting. We chose 18 articles for systematic analysis based on initial electronic database selection of 40 key papers already identified for inclusion, followed by independent blinding assessment by two co-authors. Our evaluation was based first on our specific inclusion criteria, examining method quality, obliteration rates, serious adverse events (SAEs) and mortality rates. Second, we made a comparison between SRS or embo alone treatments versus combined embo/SRS procedures, relative to AVM sizes, following Spetzler-Martin (SM) method. Third, we considered publications which had concrete statistics with well-defined P-values and clarified outcomes for accurate evaluation. We found that patients with small to medium-sized AVM were susceptible to either embo alone or SRS alone treatments, yielding obliteration rates from 71%-100%. Except for one report, giant sizes AVMs were not amenable to these single treatments, subjecting patients to embo/SRS procedures, which yielded mixed results: One group reported 52%-65% obliteration rates, compared to 23%-28% embo alone treatment. A second group contradicted this apparent beneficial outcome, obtaining obliteration rates of 53% with combined treatment compared to 71% with SRS alone, four-year postoperative. A third group reported there was no difference between single and combined treatments and obtained complete obliteration of 70%-82%, ranging from three-five-years postoperative follow-up. In all the cases analyzed, obliteration rates improved with time. SAEs, such as persistent hemorrhage and permanent neurologic deficits (P-NDs), as well as mortality, were minimal during intraoperative and postoperative follow-ups. The problem of conflicting outcomes in combined treatments of AVM by EMBO/SRS exists. Previous investigators, however, have overlooked to address this issue satisfactorily. Our analysis found that the reported inconsistencies in AVM treatment outcomes are attributable to key factors making therapy unpredictable, which includes: the size of the AVM, nidus localization and accessibility of either Embo or radiation dose applied, certain Embo materials lowering obliteration rates by masking radioactive effect on the nidus during SRS and follow-up timing for obtaining obliteration rates determine the extent of obliteration. We have indicated critical factors which require consideration when planning strategies for treatment of AVM patients and have made suggestions of how to overcome such hurdles.

Humoral autoimmunity to basement membrane antigens is regulated in C57BL/6 and MRL/MpJ mice transgenic for anti-laminin Ig receptors.

Basement membrane proteins are targeted in organ-limited and systemic autoimmune nephritis, yet little is known about the origin or regulation of immunity to these complex extracellular matrices. We used mice transgenic for a nephrotropic systemic lupus erythematosus (SLE) Ig H chain to test the hypothesis that humoral immunity to basement membrane is actively regulated. The LamH-Cmu Ig H chain transgene combines with diverse L chains to produce nephrotropic Ig reactive with murine laminin alpha1. To determine the fate of transgene-bearing B cells in vivo, transgenic mice were outcrossed onto nonautoimmune B6 and SLE-prone MRL backgrounds and exposed to potent mitogen or Ag in adjuvant. In this work we demonstrate that transgenic autoantibodies are absent in serum from M6 and M29 lineage transgenic mice and transgenic B cells hypoproliferate and fail to increase Ig production upon exposure to endotoxin or when subjected to B cell receptor cross-linking. Administration of LPS or immunization with autologous or heterologous laminin, maneuvers that induce nonoverlapping endogenous anti-laminin IgG responses, fails to induce a transgenic anti-laminin response. The marked reduction in splenic B cell number suggests that selected LamH-Cmu H chain and endogenous L chain combinations generate autospecificities that lead to B cell deletion. It thus appears that SLE-like anti-laminin B cells have access to and engage a tolerizing self-Ag in vivo. Failure to induce autoimmunity by global perturbations in immune regulation introduced by the MRL autoimmune background and exposure to potent environmental challenge suggests that humoral immunity to nephritogenic basement membrane epitopes targeted in systemic autoimmunity is tightly regulated.

Kappa editing rescues autoreactive B cells destined for deletion in mice transgenic for a dual specific anti-laminin Ig.

We explored mechanisms involved in B cell self-tolerance in a double- and triple-transgenic mouse model bearing the LamH-C mu Ig H chain conventional transgene and a gene-targeted replacement for a functional V kappa 8J kappa 5 L chain gene. Whereas the H chain is known to generate anti-laminin Ig in combination with multiple L chains, the H + L Ig binds ssDNA in addition to laminin. Immune phenotyping indicates that H + L transgenic B cells are regulated by clonal deletion, receptor editing via secondary rearrangements at the nontargeted kappa allele, and anergy. Collectively, the data suggest that multiple receptor-tolerogen interactions regulate autoreactive cells in the H + L double-transgenic mice. Generation of H + LL triple-transgenic mice homozygous for the targeted L chain to exclude secondary kappa rearrangements resulted in profound B cell depletion with absence of mature B cells in the bone marrow. We propose that the primary tolerogen of dual reactive B cells in this model is not ssDNA, but a strongly cross-linking tolerogen, presumably basement membrane laminin, that triggers recombination-activating gene activity, L chain editing, and deletion.