Adjuvant immunosuppression for paradoxical deterioration in tuberculous meningitis including one case responsive to cyclosporine. A tertiary referral hospital experience.

BACKGROUND: Tuberculous meningitis (TBM) accounts for 1-4% of all tuberculosis (TB) presentations. Paradoxical deterioration in non-HIV patients is a common manifestation of anti-tuberculosis therapy, characterised by clinico-radiological deterioration. We report a case series of TBM admissions to our institution including one case with paradoxical deterioration refractory to corticosteroids who responded to adjuvant cyclosporine. METHODS: Retrospective review of 12 HIV-negative patients admitted to Liverpool Hospital, Sydney (2005-2016) with laboratory and/or radiologically confirmed TBM. RESULTS: Median patient age was 40 (range 22-81 years), M:F = 7:5. Eleven patients (92%) were of Asia-Pacific origin. Eleven initially presented with central nervous system manifestations and one had preceding miliary TB. Nine patients had extra-cranial TB involvement including eight with past or current pulmonary disease. Cerebrospinal fluid (CSF) TB PCR/culture was positive in 10 patients. Paradoxical deterioration developed in three patients despite concomitant corticosteroids in two. One patient with paradoxical deterioration was refractory to corticosteroids: A 22-year-old Vietnamese male with TBM developed worsening headaches and altered mentation after seven weeks concomitant anti-TB and corticosteroid treatment. Interval MRI brain demonstrated increased size and number of tuberculomas as well as hydrocephalus. Cyclosporine was added with gradual improvement and ultimately good outcome. CONCLUSION: Our case series highlights the seriousness of paradoxical deterioration in TBM and the potential role of adjuvant cyclosporine in patients refractory to corticosteroids.

Treatment of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome with intravenous immunoglobulin in a patient with multiple sclerosis treated with fingolimod after discontinuation of natalizumab.

We report a case of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome in a multiple sclerosis (MS) patient 3.5 months after fingolimod commencement and 4.5 months after natalizumab (NTZ) cessation. Three cerebrospinal fluid analyses were required before a definitive diagnosis of progressive multifocal leukoencephalopathy was reached. Intravenous immunoglobulin (IVIG) was subsequently given as the sole MS treatment along with mirtazapine and mefloquine. There has been improvement and subsequent clinical stabilization. The notable features are the difficult timing of fingolimod commencement in the context of previous NTZ therapy, the role of repeated cerebrospinal fluid John Cunningham virus analyses in progressive multifocal leukoencephalopathy diagnosis, and the role of IVIG.

Protective effects of transgenic human endothelial protein C receptor expression in murine models of transplantation.

Thrombosis and inflammation are major obstacles to successful pig-to-human solid organ xenotransplantation. A potential solution is genetic modification of the donor pig to overexpress molecules such as the endothelial protein C receptor (EPCR), which has anticoagulant, anti-inflammatory and cytoprotective signaling properties. Transgenic mice expressing human EPCR (hEPCR) were generated and characterized to test this approach. hEPCR was expressed widely and its compatibility with the mouse protein C pathway was evident from the anticoagulant phenotype of the transgenic mice, which exhibited a prolonged tail bleeding time and resistance to collagen-induced thrombosis. hEPCR mice were protected in a model of warm renal ischemia reperfusion injury compared to wild type (WT) littermates (mean serum creatinine 39.0 ± 2.3 µmol/L vs. 78.5 ± 10.0 µmol/L, p < 0.05; mean injury score 31 ± 7% vs. 56 ± 5%, p < 0.05). Heterotopic cardiac xenografts from hEPCR mice showed a small but significant prolongation of survival in C6-deficient PVG rat recipients compared to WT grafts (median graft survival 6 vs. 5 days, p < 0.05), with less hemorrhage and edema in rejected transgenic grafts. These data indicate that it is possible to overexpress EPCR at a sufficient level to provide protection against transplant-related thrombotic and inflammatory injury, without detrimental effects in the donor animal.

Low positive predictive value of the ABCD2 score in emergency department transient ischaemic attack diagnoses: the South Western Sydney transient ischaemic attack study.

BACKGROUND: The ABCD(2) stroke risk score is recommended in national guidelines for stratifying care in transient ischaemic attack (TIA) patients, based on its prediction of early stroke risk. We had become concerned about the score accuracy and its clinical value in modern TIA cohorts. METHODS: We identified emergency department-diagnosed TIA at two hospitals over 3 years (2004-2006). Cases were followed for stroke occurrence and ABCD(2) scores were determined from expert record review. Sensitivity, specificity and positive predictive values (PPV) of moderate-high ABCD(2) scores were determined. RESULTS: There were 827 indexed TIA diagnoses and record review was possible in 95.4%. Admitted patients had lower 30-day stroke risk (n = 0) than discharged patients (n = 7; 3.1%) (P < 0.0001). There was no significant difference in proportion of strokes between those with a low or moderate-high ABCD(2) score at 30 (1.2 vs 0.8%), 90 (2.0 vs 1.9%) and 365 days (2.4 vs 2.4%) respectively. At 30 days the sensitivity, specificity and PPV of a moderate-high score were 57% (95% confidence interval (CI) 25.0-84.2), 32.2% (95% CI 29.1-35.6) and 0.75% (95% CI 0.29-1.91) respectively. CONCLUSIONS: Early stroke risk was low after an emergency diagnosis of TIA and significantly lower in admitted patients. Moderate-high ABCD(2) scores did not predict early stroke risk. We suggest local validation of ABCD(2) before its clinical use and a review of its place in national guidelines.

Il-4 therapy prevents the development of proteinuria in active Heymann nephritis by inhibition of Tc1 cells.

The role of IL-4, a key Th2 cytokine, in promoting or inhibiting active Heymann nephritis (HN) was examined. HN is induced by immunization with Fx1A in CFA, and proteinuria in HN is associated with subepithelial IgG and C3 deposition and infiltration of CD8(+) T-cytotoxic 1 (Tc1) cells and macrophages into glomeruli, as well as induction of Abs to Crry. Treatment with rIL-4 from the time of Fx1A/CFA immunization stimulated an earlier IgG1 response to Fx1A, induced anti-Crry Abs, and up-regulated IL-4 mRNA in lymphoid tissue, but did not alter proteinuria. Treatment with MRCOx-81, an IL-4-blocking mAb, resulted in greater proteinuria, which suggests endogenous IL-4 regulated the autoimmune response. Delay of rIL-4 treatment until 4 wk post-Fx1A/CFA immunization and just before the onset of proteinuria prevented the development of proteinuria and reduced Tc1 cell infiltrate in glomeruli. Delayed treatment with IL-4 had no effect on titer or isotype of Abs to Fx1A or on Ig, C3, and C9 accumulation in glomeruli. Treatment with rIL-13, a cytokine that alters macrophage function such as rIL-4, but has no direct effect on T or B cell function, reduced glomerular macrophage infiltrate, but did not prevent proteinuria or CD8+ T cell infiltrate. Anti-Crry Abs were paradoxically only induced with rIL-4 therapy, not in HN controls with proteinuria. It was concluded that the rIL-4 effect was probably by inhibition of Tc1 cells, which normally mediate the glomerular injury that results in proteinuria.

Mycophenolate mofetil treatment accelerates recovery from experimental allergic encephalomyelitis.

Mycophenolate mofetil (MM) acts through its metabolite mycophenolic acid to inhibit inosine monophosphate dehydrogenase (IMPDH), an enzyme essential for purine synthesis in lymphocytes. Oral treatment with MM from the day of immunization for 2 weeks significantly delayed both the development of active experimental allergic encephalomyelitis (EAE) in Lewis rats and reduced the antibody response to myelin basic protein (MBP). MM did not deplete T and B cells, nor did it prevent induction of Th1 or Th2 cytokine in the regional nodes. Treatment of EAE with MM at the onset of clinical symptoms resulted in more rapid recovery from EAE than in control or cyclosporin A (CsA)-treated. MM-treated rats had less infiltration of T cells, B cells, macrophages and dendritic cells into brainstems than either the control or CsA-treated. MM-treated brainstems also had lower level of mRNA for Thl (IL-2, IL-12Rbeta2, IFN-gamma), Th2 (IL-4, IL-10) cytokines and TNF-alpha and TGF-beta compared to that in CsA and controls groups. This study shows MM was superior to CsA in the treatment of EAE and acted by reducing the inflammatory infiltrate, not by suppression of Ig response or by promotion of regulatory cells such as Th2 or Th3.

Reversal of experimental allergic encephalomyelitis with non-mitogenic, non-depleting anti-CD3 mAb therapy with a preferential effect on T(h)1 cells that is augmented by IL-4.

This study examined whether therapy with a non-mitogenic, non-activating anti-CD3 mAb (G4.18) alone, or in combination with the T(h)2 cytokines, could inhibit induction or facilitate recovery from experimental allergic encephalomyelitis (EAE) in Lewis rats. G4.18, but not rIL-4, rIL-5 or anti-IL-4 mAb, reduced the severity and accelerated recovery from active EAE. A combination of rIL-4 with G4.18 was more effective than G4.18 alone. The infiltrate of CD4(+) and CD8(+) T cells, B cells, dendritic cells, and macrophages in the brain stem was less with combined G4.18 and IL-4 than G4.18 therapy or no treatment. Residual cells had preferential sparing of T(r)1 cytokines IL-5 and transforming growth factor-beta with loss of T(h)1 markers IL-2, IFN-gamma and IL-12Rbeta2, and the T(h)2 cytokine IL-4 as well as macrophage cytokines IL-10 and tumor necrosis factor-alpha. Lymph nodes draining the site of immunization had less mRNA for T(h)1 cytokines, but T(h)2 and T(r)1 cytokine expression was spared. Treatment with G4.18, rIL-4 or rIL-5 from the time of immunization had no effect on the course of active EAE. MRC OX-81, a mAb that blocks IL-4, delayed onset by 2 days, but had no effect on severity of active EAE. G4.18 also inhibited the ability of activated T cells from rats with active EAE to transfer passive EAE. This study demonstrated that T cell-mediated inflammation was rapidly reversed by a non-activating anti-CD3 mAb that blocked effector T(h)1 cells, and spared cells expressing T(h)2 and T(r)1 cytokines.

Transfer of experimental allergic neuritis by intra neural injection of sensitized lymphocytes.

The final mediators of immune injury in EAN were investigated by intraneural injection of sensitized lymphocytes. Unfractionated specifically sensitized cells caused conduction block which was evident within 24 h after injection, reached significance within 3 days and remained depressed for over 12 days. Pathological changes at the site of injection showed infiltrating lymphoid and mononuclear cells and significant demyelination. The latter was only evident several days after the electrophysiological changes. These effects were shown to be specific, as injection of LNC from normal rats or those immunized with CFA alone did not induce the changes. Fractionation of sensitized LNC into the CD4+ and CD8+ subsets of T-cells showed only the former caused a drop in the amplitude ratio of nerve conduction. These changes in conduction were comparable to those observed in rats immunized with myelin/CFA to induce active EAN. Cyclosporin A (CSA) was given to host animals to block production of cytokines by the injected cells. This inhibited macrophage accumulation at the site of injection, but did not stop the electrophysiological changes. This result suggested that there was direct T-cell damage rather than damage consequent upon macrophage activation. These studies developed a model in which the cellular and molecular mechanisms of conduction block and demyelination in EAN can be studied by direct injection of specifically sensitized LNC.

Cyclosporin A in the treatment of chronic demyelinating polyradiculoneuropathy.

Eight patients with chronic inflammatory demyelinating polyneuropathy, five of whom had an associated paraproteinaemia, were treated with cyclosporin in a pilot, uncontrolled study for periods up to three and a half years after failing to respond adequately to corticosteroid and azathioprine therapy and plasmapheresis. Three patients had an excellent response, two with complete remission. In other cases it was possible to reduce the corticosteroid therapy and frequency of plasmapheresis. There were no serious complications of the treatment.