Severe aseptic leucoencephalopathy as immune reconstitution inflammatory syndrome in Caucasian and African patients
Ringelstein, Adriana; Oelschlaeger, Christiana,b; Saleh, Andreasa,b; Mathys, Christiana,b; Dziewas, Rainera,b; Niederstadt, Thomasa,b; Reichelt, Dorisa,b; Hasselblatt, Martina,b; Husstedt, Ingo Wa,b; Arendt, Gabrielea
aDepartment of Neurology, Germany
bInstitute of Radiology, Heinrich Heine University, Moorenstrasse, Duesseldorf, Germany.
Received 14 January, 2009
Revised 28 January, 2009
Accepted 29 March, 2009
Correspondence to Dr Adrian Ringelstein, Heinrich Heine University, Institute of Radiology, Moorenstrasse 5, 40225 Duesseldorf, Germany. E-mail: firstname.lastname@example.org
Immune reconstitution inflammatory syndrome (IRIS) after HAART may become manifest in form of aseptic severe leucoencephalopathy. All HIV-1-positive patients in this case series had widespread laboratory tests and follow-up MRI in order to investigate the course and the underlying pathophysiology of IRIS-associated leucoencephalopathy. All patients were treated with corticosteroids, in spite of additional immunosuppression. Three patients were successfully treated with corticosteroids and survived up to now, one died. A neuropathological examination was performed showing massive aseptic intraparenchymal and perivascular invasion of cytotoxic CD8+ cells. It is assumed that IRIS-associated leucoencephalopathy is based on other preconditions in Africans and Caucasians.
Central nervous system (CNS) IRIS is a distinct neurological disorder described as a rare but typical consequence after HAART in HIV-1-infected patients. This disorder is characterized by inflammatory and/or autoimmune disease following the restoration of an immune response against pathogen-specific antigens that results in immunopathology and immune reconstitution-associated autoimmune disease . The pathogenesis of IRIS is considered to be an ‘immune system overreaction’ particularly attributed to reconstituted CD4+ cells triggering an effective cytotoxic CD8+ immune response cascade directed against the underlying septic infectious, in general opportunistic antigens, that is, toxoplasmosis . Neuropathological examination had revealed severe inflammatory and demyelinating brain lesions with marked intraparenchymal and perivascular infiltration preferably by CD8+ T lymphocytes and macrophages . The inflammatory response can appear in a wide spectrum of clinical manifestations such as worsening or atypical appearance of an underlying opportunistic infection . IRIS patients with brain affection had predominantly shown severe concomitant opportunistic infection like John Cunningham (JC)-virus-infection, cryptococcal meningitis, Varicella-zoster-encephalitis or tuberculosis .
We describe a case series of four patients (one male/three female; 37–46 year) with HIV 1-infection. All of them were treated with HAART. Expectedly, the CD4+ cell count in all patients increased and the viral load decreased rapidly. All of them presented with severe neurological deficits between 4 and 10 weeks after initiation of HAART. None of the patients had a history of AIDS-associated opportunistic infection. The African patient had a history of malaria 14 years ago. All revealed impressive pathological findings in brain MRI. The T2-weighted-images showed circumscribed lesions corresponding to the focal neurological deficit. A breakdown of the blood–brain barrier became detectable in the course of the disease, approximately 2 weeks after first imaging with a distinct worsening of the neurological symptoms and disappeared parallel to the clinical amelioration. The widespread cerebrospinal fluid laboratory tests for infection were negative (Table 1). Every patient was treated with 500 mg methylprednisolone whereas HAART was never interrupted. The three Caucasian patients survived with mild residual deficit. The African patient died 48 h after admission.
Infective forms of IRIS may manifest as either an inflammatory ‘unmasking’ of a previously untreated opportunistic infection, or as the paradoxical clinical deterioration of an infective process for which the patient is on appropriate antimicrobial therapy . Rare forms of malignancy associated and autoimmune IRIS are described . We did not find an autoimmune form of CNS IRIS in the current literature, but cases had been presented that showed an involvement of peripheral organs, for example, the thyroid gland  or peripheral nerves, for example, IRIS-associated Guillain-Barré-Syndrome . In patients, naive to antiretroviral drugs, HAART prompts a rapid immune recovery with an abrupt decrease of the HIV load  and an increased CD4+ cell count . The ‘reconstituted’ CD4+ cells may target infectious pathogens, or their antigens, including opportunistic germs and HIV reservoirs . In our patients, however, a preceding opportunistic infection and/or its outbreak after the initiation of HAART could not be found. One patient had a history of malaria 14 years ago. In none of our patients any of the ‘typically’ IRIS-associated opportunistic infection  could be found neither at presentation nor in the medical history. We cannot rule out the possibility that our patients benefitted from steroids and additionally had an underlying opportunistic infection that escaped the diagnostics. The negative diagnostic tests does not absolutely exclude a potential replication in a low level beyond the threshold of detection of the method used, a replicative disease caused by other germs, or a persisting antigen of latent infectious disease. We observed that three patients recovered after the initiation of corticosteroids additional to the continuously given HAART, but one died. We hypothesize that there might be a difference in the course of IRIS and the outcome of the patients depending on the ethnic origin. But neither in the neuropathological findings nor in the cerebral imaging, had we found a conclusive reason for the negative outcome of the African woman. We do not know if the negative course of this patient might be associated with the recent malaria infection, an individual genetic predisposition or an infection with another HIV subgroup than the other patients. Different incidences for IRIS after HAART for African and Caucasian AIDS patients are reported, 25% for Africans  and 15% for Caucasians , respectively. The neuropathological examination of this case revealed an aseptic T-cellular inflammatory infiltration of the brain parenchyma and the perivascular spaces. This suggests a possible positive effect of a treatment with corticosteroids . The reconstitution of the CD4+ cells could lead to a cytokine-triggered cytotoxic reaction of CD8+ cells directed against yet unknown aseptic cell components as antigens thus causing an autoimmune vasculitis and/or cerebritis . That an increased baseline CD8+ T-cell count is considered as a negative prognostic parameter  and that the latency of the occurrence of IRIS after the start of HAART is coincident with the second phase of the immune restoration when naive CD8+ cells begin to proliferate  is suggestive for the belief that the inflammation is finally determined by CD4+ triggered CD8+ cells. Methylprednisolone is an effective immunomodulatory agent especially targeting the cellular immune response. During the activation phase, CD4+ cells are triggered to divide repeatedly. During the effector phase, CD8+ cells are stimulated to target the antigen. Methylprednisolone blocks the expression of the cytokines IL-1 and IL-2. IL-2 is responsible for the CD4+ cell dependent activation of CD8+ cytotoxic T cells during the effector phase. This occurs 4–6 weeks after the activation (reconstitution) of the CD4+ Helper-T cells. It seems that a temporal coherence between the sequence of the immunomodulatory effect of the corticosteroids slowing down the effector phase and the prompt improvement of the cellular immune mechanism underlying IRIS exists. This context can be interpreted as a consideration for our hypothesis that the autoimmune form of IRIS can effectively be treated with corticosteroids, considering that probably endogenous antigens constitute the target of the immune reaction.
It appears mandatory to distinguish the infectious agent-driven type of IRIS from the autoimmune type presenting as leucoencephalopathy due to aseptic vasculitis or cerebritis. We hypothesize that there might be a difference in the course and the outcome of IRIS depending on the patient's ethnic origin.
The cytotoxic immune response in HIV-1-positive patients can present as an aseptic, autoimmune-mediated inflammation of the cerebral parenchyma and therefore should reasonably be treated with corticosteroids.
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