This minisymposium was originally published in 2017. The information provided in this minisymposium was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this minisymposium.
CNS infections in immunosuppressed patients
Central nervous system (CNS) infections in immunosuppressed patients have been impacted in recent years by many factors, including increasing numbers of immunocompromised patients due to therapeutic interventions, geographic spread, changing virulence of pathogens, emergence of new pathogens, and higher incidence of super-infections. There is a wide array of CNS
infections that are seen predominantly in immunosuppressed patients. The clinical presentations, conditions of predisposition, comorbidities, and even histopathologic appearances have evolved over the years, particularly in the context of ongoing advances in therapeutic interventions. This review focuses on emerging trends in CNS
infections among immunosuppressed patients.
Since the advent of combination antiretroviral therapy (cART) in 1996, neurologic complications of HIV infection have shifted from opportunistic infections to those associated with longevity, comorbidities, and therapeutic complications. HIV-associated neurocognitive disorders (HAND), the most prevalent group of neurologic complications, ranges from mild neurocognitive disorder to dementia. A low CD4+ T-cell count nadir is a risk factor for HAND, supporting the hypothesis that immunosuppression by itself leads to cognitive dysfunction. The hallmark lesion of HIV encephalitis (HIVe) in adults is the perivascular HIV-immunopositive multinucleated giant cell which represents macrophage merging mediated by the HIV fusion protein gp41. Microgliosis, astrogliosis, and T-lymphocyte infiltration are less specific findings (Image A). In contrast to adults, opportunistic infections in pediatric patients are rare. Most cases of pediatric HIV infection are maternally transmitted. Congenital infection is asymptomatic at birth, and manifests neurologically between two months and five years of age in two main forms: (a) progressive encephalopathy, manifesting as decreased head growth, dementia and spasticity, and (b) static encephalopathy, with motor and cognitive delay. Pathologic features include basal ganglia calcifications and are otherwise similar to adults with the quantity of perivascular calcifications correlating with viral load.
Since nearly all episodes of toxoplasmosis occur by reactivation, HIV-positive patients need screening for toxoplasma IgG antibodies. Seropositive individuals must be given prophylaxis. Neuroimaging shows single or multifocal hypodense, ring-enhancing lesions with perilesional edema. Despite serology and molecular techniques, tissue biopsy may be needed to exclude primary CNS lymphoma, another common intracranial mass lesion in HIV patients. Toxoplasma encephalitis has declined due to cART and as a side benefit of the use of trimethoprim-sulfamethoxazole for prevention of pneumocystis pneumonia.
Progressive multifocal leukoencephalopathy (PML) remains the most common infiltrative brain disease in HIV/AIDS. Features of PML include non-enhancing white matter lesions on imaging, CSF PCR positivity for JC virus, and brain biopsy showing patchy myelin loss, seen here on LFB stained section (Image B), lipid-laden macrophages, oligodendrocytic viral inclusions (arrows), and enlarged bizarre astrocytes (Image C). Viral inclusions may be detected by anti-SV40 antibody which cross-reacts with JC virus. Despite improvement in survival following cART, mortality due to PML remains high: up to 30% after one year and 50% to60% after two years.
Cryptococcus neoformans, discussed in more detail in the section on fungal infections, is the most common cause of meningitis in HIV patients. Cryptococcal encephalitis has decreased in incidence with use of cART. All patents with HIV and pulmonary cryptococcosis - even without neurologic symptoms - require serum and CSF testing for cryptococcal antigen as CSF cryptococcal antigen is positive in virtually all patients with cryptococcal meningitis.
Herpes Simplex Virus (HSV): In hospitalized patients in the United States, HSV encephalitis (HSVE) is the most common identifiable cause of viral encephalitis (approximately 14%) and accounts for approximately 22% of all encephalitis-related mortality. HSV-1 encephalitis typically affects children older than three months and adults. It produces hemorrhagic, necrotizing, asymmetric, bilateral orbitofrontal and temporal lobe lesions with potential for uncal herniation due to edema. HSV-1 encephalitis results in about 70% mortality and 97% morbidity in untreated cases. Neuroimaging plays a fundamental role in diagnosis and shows early insular involvement, patchy diffusion restriction, necrosis, and hemorrhage. PCR of CSF is the gold-standard diagnostic test because of its high sensitivity and specificity, and is recommended in any patient presenting with aseptic meningitis or encephalitis regardless of skin manifestations. Of note, negative PCR during the initial 72 hours of symptoms does not exclude HSV-1 encephalitis. If CSF sampling is difficult, PCR of plasma may provide similar diagnostic accuracy. Prompt initiation of acyclovir within 4 days of onset of symptoms in suspected HSVE with pending diagnostic tests, and continue over a 14 to 21 day course can reduce mortality to 8%. HSVE is thought to be due to primary infection (independent of latent infection) with the virus traveling via the olfactory pathway. Neonatal HSV encephalitis, usually caused by HSV-2 via vertical transmission during the first month of life, can be diffuse or focal. It is clinically challenging to diagnose as it often presents with microcephaly, hydrocephalus, and seizures in newborns. Neonatal HSVE is characterized by chronic inflammation, parenchymal loss, and rare inclusion-bearing cells.
Varicella-Zoster Virus (VZV): Neurologic involvement by VZV, mostly in immunocompromised and elderly patients, typically includes meningoencephalitis, transverse myelitis, and vasculitis. Most cases are self-limited. Myelitis is uncommon, and the location typically corresponds to a dermatomal skin rash.
Cytomegalovirus (CMV): CMV encephalitis is another entity seen in immunocompromised adults. Prenatal transplacental infection by cytomegalovirus (part of the TORCH group) remains the commonest neonatal viral infection occurring in 1% of live births. Among CNS-related manifestations, intracranial calcifications, microcephaly, hearing defects, chorioretinitis, and seizures occur in decreasing frequency. Periventricular germinal matrix cells are most susceptible, resulting in neuronal migrational defects and tissue destruction evident as periventricular leukomalacia with calcifications. Markedly enlarged cells with prominent intranuclear Cowdry type A inclusions (arrows) are a characteristic feature (Image D) accompanied by acute and chronic inflammatory cells.
The incidence of intracranial fungal infections has increased due to AIDS, bone marrow/organ transplants, chemotherapy, improvement in radiologic and microbiological testing, and advances in care of debilitated patients. This parallels the incidence of systemic fungal infections. Clinical presentation may be fulminant, acute, chronic, or indolent. Features that may be detected by neuroimaging include hydrocephalus, mass effect, hemorrhage, meningitis, empyema, abscess, ventriculitis, and cerebral infarction. Unlike bacterial lesions, fungal abscesses are more likely to be multiple and involve the basal ganglia. CSF analysis serves as the diagnostic gold standard; enzyme immunoassay, latex agglutination as well as serum biomarkers from fungal cell wall components (galactomannan and 1,3-beta-D-glucan), and detection of fungal DNA by PCR may be useful in early diagnosis. Pathologically, fungal infections tend to cause a variable admixture of granulomatous and suppurative inflammation. Cryptococcus, Aspergillus, Mucor, and dimorphic fungi are the most common fungal infections in immunosuppressed patients. Histologic diagnosis can be facilitated by PAS, GMS, mucicarmine, or melanin-binding Masson-Fontana stains.
Cryptococcus spreads hematogenously, typically from lungs, and often leads to meningitis (thick gelatinous exudates) and/or parenchymal granulomas (such as cryptococcoma in basal ganglia). Histologically, the fungal yeasts are round, 4 to 7 micron in diameter, surrounded by a mucoid capsule, and exhibit budding. Organisms are readily identified with GMS, PAS, or mucicarmine stains as in Image E, within the subarachnoid space, and Image F in the parenchyma.
Aspergillus frequently reaches the CNS via the blood stream, often originating from a pulmonary focus or locally from paranasal sinuses. It appears as 3 to 6 micron in diameter, septate and branching hyphae with roughly parallel walls. In contrast, Mucor is usually too large to penetrate meningeal microcirculation and instead reaches the CNS by local spread from paranasal sinuses, orbit, or spine. Mucormycosis is characterized by broad (5 to 20 micron in diameter), non-septate hyphae with irregular diameters and right angle branching. Infection by Aspergillus or Mucor results in vascular involvement, yielding hemorrhagic cerebral infarcts and/or mycotic aneurysms. Mucormycosis is additionally predisposed by diabetic ketoacidosis, and has a more aggressive course than Aspergillosis.
One dematiaceous (pigmented) fungus, Cladophialophora, is a rare CNS pathogen regardless of immune status. It has a known, unexplained neurotropism, resulting in brain abscesses with a characteristic darkly pigmented gross appearance.
Dimorphic fungi can exist as either mold or yeast form. Candida is ubiquitous and is the second most common cause of brain micro-abscesses in adults (after Staphylococcus aureus). The remaining dimorphic fungi that cause CNS infections tend to follow a geographic distribution: Blastomyces around the Great Lakes; Histoplasma around the Ohio and Mississippi River basins; and Coccidioides in the arid southwestern United States. Clinical presentations are varied, and diagnosis requires culture of serial high-volume CSF or histology.
Tuberculosis (TB) remains a major public health problem in underdeveloped nations, largely due to multiple drug-resistant strains. CNS involvement, although accounting for only 10% of TB cases, represents its most severe form with the highest morbidity and mortality. Tuberculous meningitis, the most common form of CNS TB, constituted about 6% of extrapulmonary TB in the United States in 2005. Mycobacterium tuberculosis is a slow growing, obligate aerobic, acid-fast, and Gram-positive bacillus. Droplet transmission through coughing or sneezing infects pulmonary alveolar macrophages, resulting in about 90% latent and 10% active tuberculosis. CNS TB more commonly affects the young (4 to 48 months) and the immunosuppressed. Mycobacterial meningoencephalitis manifests as a thick gelatinous exudate in the basal cisterns and may result in obstructive hydrocephalus, cranial nerve dysfunction and cerebral vasculitis with ischemia. Other common manifestations include tuberculoma and Pott’s disease affecting the spine. Microscopy or culture may identify the organism. Culture allows for drug sensitivity testing but may take one to two months. PCR can have high sensitivity and drug resistance detection.
Acanthamoeba and Balamuthia mandrillaris are known to cause granulomatous amebic encephalitis (GAE) in chronically ill and immunosuppressed patients, with infections lasting from a few weeks to years. Acanthamoeba may also involve skin, lung, kidney, liver, and cornea (keratitis). MRI shows multiple ring-enhancing lesions in the brain. Acanthamoeba and Balamuthia are not detectable in the CSF, and brain or skin biopsy is needed for diagnosis by morphology and culture. Histologically, GAE shows multiple necrotic and hemorrhagic infarcts with perivascular inflammatory cells, multinucleated giant cells, vasculitis, amebic trophozoites, and cysts. In contrast to GAE, Naegleria fowleri causes acute, hemorrhagic, primary amebic meningoencephalitis (PAM) in healthy children and young adults with a recent history of swimming in fresh water reservoirs, usually during summer months.
Take Home Points
- Combination antiretroviral therapy (cART) has altered clinical outcomes of HIV infection, shifting the burden from opportunistic infections to chronic conditions and complications of therapy.
- Progressive multifocal leukoencephalopathy (PML) continues to have a high mortality despite therapeutic interventions.
- Herpes simplex encephalitis with its characteristic pathologic features remains the most frequent cause of viral encephalitides.
- Newer techniques, such as detection of fungal components in serum and molecular methods, have facilitated early diagnosis of many infections.
- Organisms causing granulomatous amebic encephalitis (GAE) may not be detectable in CSF and often require skin or brain biopsy to confirm the diagnosis.
- Baig AM, Khan NA. A proposed cascade of vascular events leading to granulomatous amoebic encephalitis. Microb Pathog. 2015;88:48-51.
- Brancusi F, Farrar J, Heemskerk D. Tuberculous meningitis in adults: a review of a decade of developments focusing on prognostic factors for outcome. Future Microbiol. 2012;7(9):1101-1116.
- George BP, Schneider EB, Venkatesan A. Encephalitis hospitalization rates and inpatient mortality in the United States, 2000-2010. PLoS One. 2014;9(9):e104169.
- Kaewpoowat Q, Salazar L, Aguilera E, Wootton SH, Hasbun R. Herpes simplex and varicella zoster CNS infections: clinical presentations, treatments and outcomes. Infection. 2016;44(3):337-345.
- Nath A. Neurologic Complications of Human Immunodeficiency Virus Infection. Continuum (Minneap Minn). 2015;21(6):1557-1576.
- Ng LF, Solomon T. Decade in review - CNS infections: major advances against a moving target of CNS infections. Nat Rev Neurol. 2015;11(11):623-624.
- Panackal AA, Williamson PR. Fungal Infections of the Central Nervous System. Continuum (Minneap Minn). 2015;21(6):1662-1678.
- Pavlovic D, Patera AC, Nyberg F, Gerber M, Liu M; Progressive Multifocal Leukeoncephalopathy Consortium. Progressive multifocal leukoencephalopathy: current treatment options and future perspectives. Ther Adv Neurol Disord. 2015;8(6):255-273.
- Piquet AL, Cho TA. The Clinical Approach to Encephalitis. Curr Neurol Neurosci Rep. 2016;16(5):45.
- White AL, Hedlund GL, Bale JF, Jr. Congenital cytomegalovirus infection and brain clefting. Pediatr Neurol. 2014;50(3):218-223.