1. A Case of Cryptococcal Meningitis Treated with Adjuvant Steroid Thearpy : Suspected as an Immune Reconstitution Inflammatory Syndrome(IRIS) Dong-geun Lee, M.D., Sang Won Yoo, M.D., Jae Young An, M.D., Sung Kyung Park, M.D., Si-Ryung Han, M.D., Ph.D. Department of Neurology, St. Vincent's Hospital, The Catholic University of Korea Background In treating meningitis, anti-inflammatory effects of steroids decrease blood-brain barrier permeability and impede penetration of antibiotics into CSF, theoretically. Decreased CSF levels of certain kind of antibiotics have been confirmed in steroid- treated animals but not in human studies. Many authorities believe that all other antibiotics achieve minimal inhibitory concentrations (MICs) in CSF regardless of steroid use. More recent studies indicate that adjunctive steroids are also beneficial in the treatment of meningitis caused by bacterial pathogens other than Hemophilus Influenzae type B. In a large cohort of patients with acute meningitis due to pneumococcus, meningococcus, and other bacteria, the administration of adjunctive dexamethasone was significantly associated with a reduction in mortality and other unfavorable outcomes. It is believed that, steroids may interrupt the cytokine-mediated neurotoxic effects of bacteriolysis, which are at maximum in the first days of antibiotic use. Cryptococcal meningitis is believed to result from dissemination of the fungus from either an observed or unappreciated pulmonary infection. Cryptococcus is an intracellular as well as an extracellular pathogen, and can survive and replicate within acidic macrophage phagolysosomes, depending on the origin and state of activation of the cells. Following intracellular replication, capsule polysaccharide accumulates in vesicles, leading to permeabilization of the phagolysosomal membrane and cytotoxicity. We thought that this series of inflammatory reaction might result in high mortality and disability of cryptococcal meningitis victims. We also thought that, if we suppress the inflammatory reaction with corticosteroids, we could expect a better prognosis. Case and Course 52 year old male was admitted our hospital because of fever, headache and myalgia. He worked in Slovakia as a resident worker for 2 years. 15 days before he came back to Korea, these symptom broke out and he was diagnosed as a certain kind of encephalitis at Slovak hospital. He had no immune deficiency, and had no other disease in his past history. On admission, the clinical data revealed the CSF counting 90cells/microliter (85% lymphocytes), protein at 76mg/dL, and glucose 64mg/dL(blood glucose 193mg/dL), and ADA 16.2IU/L. Opening pressure was over 30cmCSF. We thought that this would be a partially treated bacterial meningitis, and started ceftriaxone 2g with doxycyclin 100mg twice a day. On 8 th hospital day, the symptom and CSF findings were not improved at all and B symptoms emerged. MR revealed heterogeneous increase signal change in the both occipital lobe and right frontal lobe. So we thought this situation might not be a bacterial meningitis but a tuberculous meningitis, and we started anti-tuberculous medications with mannitol. On 12 th hospital day, symptom was more aggravated, and CSF opening pressure was 53cmCSF, we started dexamethasone to lower IICP. MRI revealed no interval changes. CSF study for cryptococcus antigen was reactive, but no cryptococcus was found in the India ink study. At that time we just considered it as a false positive. On 24 th hospital day, symptom was more aggravated. We thought that 12 days are good enough for anti-tuberculous medications to work, but the symptom was not improved at all. This implied that this was not a tuberculous, not a bacterial, but a cryptococcal infection. So we started amphotericin-B, and discontinued all the medications except steroid. On the next day, the symptom was starting improving slightly on. On 30 th hospital day, symptom was still improving, but not cleared. MRI revealed abnormal high signal intensities decreased, but remnant signal was found. We maintained amphotericin-B with steroid for 7 weeks. During this period, the patient complained of headache intermittently, and we drained CSF, then the headache was calmed soon. 7weeks later, the symptom was cleared. Preparing for discharge, we changed IV amphotericin-B to PO fluconazole, and had steroid tapered out. For 3 days, it was honeymoon period, he complained of nothing. At the 4 th day, sudden headache was burst out. MRI showed interval aggravation of leptomeningeal thickenings. CSF revealed 0cells/microliter, protein at 59mg/dL, and glucose 54mg/dL. Opening pressure was 56cmCSF. At first, we thought it should be relapse, but strangely, cryptococcal antigen was not reactive. After journal searching, we recognize that this could be immune Reconstitution Inflammatory Syndrome(IRIS), and we started steroid again, and such a symptom was not re-occurred. Discussion Immune reconstitution inflammatory syndrome is a condition seen in some cases of AIDS or immunosuppression, in which the immune system begins to recover, but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse. The suppression of CD4 T cells by HIV (or by immunosuppressive drugs) causes a decrease in the body's normal response to certain infections. Not only does this make it more difficult to fight the infection; it may mean that a level of infection that would normally produce symptoms is instead undetected. If the CD4 count rapidly increases (due to effective treatment of HIV, or removal of other causes of immunosuppression), a sudden increase in the inflammatory response produces nonspecific symptoms such as fever, and in some cases a worsening of damage to the infected tissue. There are two common IRIS scenarios. The first is the “unmasking” of an occult opportunistic infection. The second is the “paradoxical” symptomatic relapse of a prior infection despite microbiologic treatment success. Often in paradoxical IRIS, microbiologic cultures are sterile. In either scenario, there is hypothesized reconstitution of antigen-specific T cell-mediated immunity with activation of the immune system following HIV therapy against persisting antigen, whether present as intact organisms, dead organisms, or debris. The best treatment for this condition is unknown. In paradoxical IRIS reactions, the events will usually spontaneously get better with time without any additional therapy. In unmasking IRIS, the most common treatment is to administer antibiotic or antiviral drugs against the infectious organism. In some severe cases anti- inflammatory medications, such as corticosteroids are needed to suppress inflammation until the infection has been eliminated. IRIS has been described in immunocompetent hosts who have meningitis caused by Cryptococcus gattii and Cryptococcus neoformans var. grubii, which often affect immunocompetent hosts. Several weeks or even months into appropriate treatment, there is a sudden onset deterioration with worsening meningitis symptoms and progression or development of new neurological symptoms. Magnetic resonance imaging shows increase in the size of brain lesions, and CSF abnormalities (white cell count, protein, glucose) increase. CSF culture is sterile, and there is no increase in CSF cryptococcal antigen titre. The mechanism behind IRIS in cryptococcal meningitis may be local or systemic immunosuppression induced by the cryptococcal infection which resolves as the organism is killed by antifungal treatment. This is associated with increased inflammation as the recovering immune system recognizes the fungus. Treatment with systemic corticosteroids during IRIS may be beneficial in preventing death or progressive neurological deterioration. IRIS may be the cause of paradoxically worse outcomes for cryptococcal meningitis in immunocompetent compared with immunocompromised hosts, in whom Cryptococcus neoformans is the usual pathogen. Initial MRI There shows heterogenous increased SI with enhancing in the both occipital lobe. Subtle leptomeningeal enhancement is noted. After Amphotericin-B Less prominent. However remnant enhancement involving both occipital lobes is noted on the contrast enhanced scans. At IRIS There are interval increased leptomeningeal enhancement of brain.