key: cord-0027876-ulvlzgae authors: Wijdicks, Eelco F. M. title: It was 40 Years Ago Today: AIDS and the Brain date: 2022-03-01 journal: Neurocrit Care DOI: 10.1007/s12028-022-01455-w sha: 585430bda1f059ef0ce6c3fe89e4d0b8de4edf08 doc_id: 27876 cord_uid: ulvlzgae nan The year 1980 marks the first case of acquired immunodeficiency syndrome (AIDS). The year 1982 marks the first case of a brain lesion in AIDS describing progressive multifocal leukoencephalopathy (PML), which was followed by central nervous system (CNS) toxoplasmosis a year later. These were the first indications that patients with AIDS could succumb from acute, highly unusual brain infections. Although these viral and parasitic infections were rarely seen, they flourished in the severely compromised immune systems of patients with AIDS. The first reporting in the Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report involved only five cases of AIDS. On that day, the CDC reported pneumocystis carinii pneumonia in previously healthy men and, later, a spike in cases of Kaposi sarcoma among gay men in New York. The CDC has since reported AIDS-related deaths of more than 32 million people worldwide since the start of the global pandemic-one of the worst pandemics in history, together with bubonic plague during the fourteenth century (estimated 50 million) and 1918 flu pandemic (100 million). On December 2, 1982, the New England Journal of Medicine reported PML in a "male homosexual with T-cell immune deficiency" (Fig. 1 ). This case report in a 39-year-old man was notable for rapid clinical progression of the disorder. The diagnosis was achieved by biopsy of a cerebellar lesion, the patient's prior history of syphilis, recent weight loss, and hepatosplenomegaly. The neurological examination revealed findings not only pertaining to cerebellar dysfunction, including lateral gaze nystagmus, but also pertaining to brainstem injury, with diminished left-sided pinprick and hand sensation on the face and left arm. Both cerebellar and brainstem findings worsened, and corticospinal tract dysfunction was also noted. The original computed tomography scan featured "a large lucent lesion" in the cerebellum without edema. Biopsy of the lesion showed microglial cell response and giant astrocytes, with electron microscopy confirming intracellular viral particles and filaments typical of the papovavirus virion. Despite treatment with intravenous vidarabine, the patient died of respiratory failure 2 months after the initial presentation. The authors noted that although infection with JC virus is common, it is rarely symptomatic and destructive, even when it affects patients in an immunocompromised state (viral DNA is detected in 20-30% of immunologically normal adults' urine [1] ). This first presentation marked the "opening salvo" of many CNS complications, which included encephalitis from cytomegaly virus infection or from toxoplasma gondii. Other neurological conditions seen were meningitis caused by Cryptococcus neoformans and Aspergillus fumigatus. A second landmark article by Whelan et al. [2] (Fig. 2 ) observed 19 patients with CNS involvement in the setting of "homosexuality, intravenous drug abuse" ranging in age from 26 to 56 (but only three patients were over the age of 40). Fourteen of these 19 patients progressed to Kaposi syndrome and pulmonary and gastrointestinal infections, which included pneumocystis carinii, cytomegaly, and parasitic and fungal infection. The lesions noted were intraparenchymal or meningeal Toxoplasma gondii, an infection previously seen in only immunocompromised hosts. Nine patients were diagnosed with cryptococcal meningitis, as demonstrated by elevated cryptococcal cerebrospinal fluid (CSF) antigen India ink stains. Patients rapidly became critically ill with seizures and decline in their level of consciousness with intermittent focal findings [2] . The multiple bilateral lesions of different sizes and significant enhancement are shown in Fig. 3 . The article also noted a poor inflammatory response, with often acellular CSF in patients with cryptococcal infection, often with unusually low CSF white blood cell counts, which ranged from 0 to 10 lymphocytes. Mortality in this group was high, but there was also clinical improvement and no recurrence several months later after adequate treatment with antitoxoplasma therapy. A third confirmatory article was by Levy et al. [3] , from the Department of Neurological Surgery at the University of California, San Francisco. The authors presented nine patients evaluated between April 1979 and July 1983. At the time, approximately 10% of the CDC's 2,000 reported cases of AIDS had CNS involvement, which now extended also to primary lymphoma, but again most were Toxoplasma gondii infections. The outcome was much worse, with eight of the nine described patients dying of unknown CNS disease [3] . All these findings of rapid neurocritical illness as a result of AIDS therefore suggest the serious impact of AIDS on the CNS. Historically, this was an unusual and unpredicted early consequence of a rapidly emerging pandemic. Within the next few years, the CNS became the second-most affected system in patients with AIDS. Many neurologists at the time pointed out that the neurologic signs were subtle in AIDS but became apparent because of hospitalization [4] . CNS involvement added to the suffering of patients and also heightened the fear of neurosurgical teams about the risks of infection from operating on patients infected with AIDS. Looking back over 40 years, we find little to celebrate. This anniversary reminds us that even after introduction of highly active antiretroviral drugs, morbidity and mortality barely declined. Bowen et al. [5] also concluded that CNS-opportunistic infections remained a major cause of morbidity and mortality in individuals positive for human immunodeficiency virus (HIV) and those with AIDS. They also emphasized that most treatments were administered in the absence of any controlled study or even phase 2 or 3 trial. The emerging radiologic picture of CNS involvement revealed bilateral ring-enhancing lesions or solitary enhancing lesions associated with Toxoplasma gondii or Herpes simplex focal infection. The combination of Kaposi sarcoma, Toxoplasma gondii, and brain abscess was noted by Vilaseca et al. [6] . Disseminated toxoplasmosis, toxoplasmic encephalitis, and petechial hemorrhages were commonly seen. Multiple cerebral hemorrhages due to Toxoplasma gondii were found, at least in one case report, as the first AIDS-defining condition [7] . Hemorrhages were typically associated with toxoplasma, but cerebral infarcts also became more frequently described, often in the setting of nonbacterial thrombotic endocarditis or disseminated intravascular coagulopathy [8] . Mizusawa et al. [8] suggested that 33% of patients with AIDS, after detailed postmortem examination, had a cerebral infarct related to nonbacterial thrombotic endocarditis, which was countered by a series of nearly 1400 patients with asymptomatic HIV infection with no reports of intracerebral hemorrhage or cerebral infarction after a 2-year follow-up [9] . Since the initiation of antiretroviral therapy, current concern is the risk of developing immune reconstitution inflammatory syndrome (IRIS). IRIS shows worsening after initial stabilization; magnetic resonance imaging (MRI) findings typically show leptomeningeal and even perilesional enhancement and edema in patients with cryptococcal IRIS. Prevalence estimates from clinical and pathological series suggest that up to 5% of all persons infected with HIV will develop PML. The usual first step in confirming the diagnosis is to test CSF by polymerase chain reaction for the presence of JCV DNA. The assay result is positive in approximately 70-90% of patients not taking ART, for whom a positive result can be considered diagnostic in the appropriate clinical context. No specific therapy exists for JCV infection or PML. Intravenous and intrathecal cytarabine and cidofovir are neither effective nor recommended. A promising report of long-term survival of a patient with PML in the setting of hematologic malignancy treated with nivolumab [10] was shortly followed by a case series on patients with PML treated with pembrolizumab [11, 12] and nivolumab [13] , both antibodies to PD-1, suggesting stabilization or improvement in some patients. Paraclinical markers reported were also supportive of survival. A robust influx of CD4 and numerous CD8 cells may precipitate a clinical decline not explained by the natural course of PML. Similarly, the paradoxical deterioration here is from IRIS. The marked clinical and MRI worsening that occurs during IRIS remains very worrisome to clinicians, but IRIS is an unavoidable consequence of treating PML. Nevertheless, treatment cannot be delayed because delay leads to a generation of additional JC antigens and accumulation of permanent brain injury from JCV. Others have emphasized that PML IRIS may be recognized by T2 bright punctate perivascular lesions on MRI ("starry sky") [14] . During a new pandemic, it is useful to revisit prior pandemics, and certainly the AIDS epidemic has been well documented. Consultations for neurologists and, later, neurointensivists rapidly increased in these early years and to an extent we have not seen later in other outbreaks. No extramural funding supported this effort. Progressive multifocal leukoencephalopathy in a male homosexual with T-cell immune deficiency Acquired immunodeficiency syndrome: cerebral computed tomographic manifestations Central nervous system mass lesions in the acquired immunodeficiency syndrome (AIDS) Neurological complications now characterizing many AIDS victims HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment Kaposi's sarcoma and toxoplasma gondii brain abscess in a Spanish homosexual Fatal disseminated hemorrhagic toxoplasmic encephalitis as the initial manifestation of AIDS Cerebrovascular lesions in acquired immune deficiency syndrome (AIDS) Zidovudine in asymptomatic human immunodeficiency virus infection. 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