A 59-year-old man is admitted to the hospital after experiencing several weeks of dyspnea, fatigue, weight loss, and progressive neurologic decline. He has a past medical history of autologous hematopoietic stem cell transplant and living donor allograft kidney transplant in the setting of multiple myeloma and associated immunoglobulin light chain (AL) amyloidosis. Diagnostic work-up revealed bacteremia and multifocal lesions in the lungs and brain. Magnetic resonance imaging of one of the lesions and a histologic section from this area are shown below.
The correct answer is ...
The patient, given his medical history that includes both hematopoietic stem cell transplant and solid organ transplant, had been treated with chronic immunosuppressive therapy over the course of multiple years. He was found to have disseminated infection with blood cultures returning positive for Nocardia farcinica and Nocardia kroppenstedtii. His neurologic function continued to decline as he progressed to septic shock. Despite aggressive treatment, the patient died in the hospital three weeks after admission. At autopsy, gross examination revealed numerous similarly appearing abscesses in multiple organs (lungs, brain, liver, thyroid, kidney, and heart). The example shown in the question stem was a 1.4 cm cerebral abscess involving the right hippocampus at the level of the lateral geniculate nucleus. Given the patient's clinical history, blood culture results, and autopsy findings, disseminated nocardiosis due to sequelae of multiple myeloma was determined to be the cause of death.
Nocardia spp. are Gram-positive, branching filamentous, obligate aerobic, weakly acid-fast bacilli that are ubiquitous in soil and can cause localized or disseminated infection in immunocompromised hosts. Inhalation leading to pulmonary disease is the most common route of primary infection. Hematogenous dissemination can involve any organ system, and frequently involves the central nervous system (CNS).
Within the CNS, Nocardia spp. exhibit tropism for the brain, where they can cross the blood-brain barrier and preferentially infect and replicate within astrocytes and microglia. In the brain, surface receptors on Nocardia bind to host capillary endothelial cells and glia. Virulence factors such as catalase and superoxide dismutase also facilitate CNS infection by inhibiting neutrophil killing. Impaired cell-mediated immunity is a major risk factor for CNS nocardiosis.
Nocardia spp. is one of the most common abscess-causing pathogens in the CNS. Among the common species, N. farcinica is known to be highly neurotropic and more often leads to CNS disease than N. asteroides. The microscopic appearance of Nocardia spp. can be very similar to that of Actinomyces spp., which are also Gram-positive, branching filamentous bacilli. Thus, microbiology studies are important for definitive diagnosis. In contrast to Nocardia, Actinomyces spp. are obligate anaerobes and are not acid-fast. Actinomyces infections most often occur in cervicofacial tissue or the lungs and can spread to adjacent organs, including to the CNS. However, Actinomyces spp. lack the aforementioned neurotropic virulence factors possessed by Nocardia and are thus far less likely to cause CNS infection.
On microscopy, the general evolution of a cerebral abscess is thought to occur in four stages:
Collagen deposition continues to occur; the capsule gradually thickens, and the abscess enlarges by expanding into the white matter over subsequent weeks-months. Capsular thickening occurs to a greater extent in subcortical brain tissue than in the deep white matter, where it tends to remain relatively thin. Hematogenously spreading CNS infections tend to be less encapsulated than those caused by direct local spread. Clinical presentation of cerebral abscess is variable and may include headache, fever, epilepsy, nausea, vomiting, altered sensorium, nuchal rigidity, or focal neurologic signs depending on location. The early changes of focal cerebritis may be seen on magnetic resonance imaging before any abnormality is apparent on computerized tomography. The overall mortality of cerebral abscess is approximately 20%. Of the patients who survive, approximately 50% will have persistent epilepsy, cognitive impairment, and/or focal neurologic signs as long-term complications.
David Cook, M.D.
Resident, Anatomic & Neuropathology
Ross Zumwalt, M.D.
Senior Associate Consultant, Anatomic Pathology