Presentation and course
Histoplasmosis is a mycosis that primarily affects the lungs. Of the documented cases of histoplasmosis infection in immunocompetent patients, 50% to 90% are asymptomatic. Furthermore, the symptomatic cases are typically self-limiting, and only 20% require treatment (33). Symptomatic patients often present with upper respiratory tract symptomatology, including fever, dry cough, substernal chest discomfort, and malaise. Patients with underlying lung disease are prone to chronic pulmonary histoplasmosis. Extrapulmonary manifestations are uncommon and vast, including mediastinal granulomas, mediastinal fibrosis, pericarditis, polyarteritis, symmetric arthritis, and CNS histoplasmosis (36). Erythema nodosum is another manifestation, occurring mostly in women. Disseminated histoplasmosis is rare, affecting only 1 in 2000 patients with acute H. capsulatum infection. Most patients who develop disseminated histoplasmosis are immunosuppressed (ie, HIV/AIDS patients, transplant recipients, etc.) or at the extremes of age. Patients with cellular immunity defects, whether due to an underlying malignancy (lymphoma, leukemia) or a rheumatologic disorder associated with immune dysfunction (systemic lupus erythematosus, rheumatoid arthritis), or patients receiving immunosuppressive therapies may be at risk for disseminated histoplasmosis or CNS histoplasmosis. Isolated CNS and disseminated histoplasmosis can occasionally occur in apparently immunocompetent patients (23; 25; 01). In 10% to 20% of HIV-infected patients, disseminated histoplasmosis develops as a rapid, fulminant illness. In other patients with HIV infection, the disease is chronic and is manifested by fever, sweats, weight loss, lymphadenopathy, hepatosplenomegaly, mucosal and adrenal lesions (15). Adrenal involvement is not always apparent. However, autopsy data confirms adrenal involvement in 30% to 50% of disseminated cases (24). Notably, adrenal involvement is a particular feature of the disease acquired by Europeans exposed in South and Southeast Asia (32).
CNS involvement can occur in both disseminated disease and in isolation, although isolated cases are extremely rare. In 1 autopsy series, CNS involvement occurred in 25% of disseminated cases, and only one fourth of these patients had neurologic symptoms (38). Clinical syndromes include subacute and chronic meningitis, focal brain and spinal cord lesions (histoplasmomas), stroke syndromes, and encephalitis (40; 26). Cerebritis and abscesses have also been reported (01). H. capsulatum meningoencephalitis presents with mental status changes, headaches, fever, seizures, confusion, and cranial nerve palsies, especially involving the oculomotor, abducens, and facial nerves. Focal brain lesions can cause paralysis, ataxia, and seizures. Localized brain lesions occur in one third of those with CNS involvement, and isolated spinal cord lesions have also been reported (Hagood and Ansari 2007).
Stroke syndromes can occur as a result of emboli from H. capsulatum endocarditis or arteritis from infection within Virchow-Robin spaces, although these syndromes are less common. Other unusual presentations include peroneal nerve dysfunction myelopathy or intramedullary granulomas of the spinal cord (10; 38; 07).
CNS histoplasmosis presenting with slowly progressive weakness in the lower extremities, numbness below the midthoracic area, urinary incontinence, and slurred speech has been reported (08). Interestingly, hemichorea has been reported in a patient with HIV-associated CNS histoplasmosis (09).
In HIV-infected patients, initiation of highly active antiretroviral therapy (HAART) can cause an immune reconstitution inflammatory syndrome (IRIS), with new symptoms or worsening of previous symptoms associated with histoplasmosis, along with increased CD4 count. Two different explanations have been considered: (1) A paradoxical reaction to antigens occurs despite treatment, or (2) an inflammatory reaction unmasks an undetected, active infection (05).
In subacute or chronic meningitis, MRI imaging discloses leptomeningeal thickening within the basilar meninges. Meningeal enhancement with multiple enhancing nonspecific lesions in the brain or spinal cord suggests histoplasmosis. Vascular involvement from meningeal inflammation appears as areas of infarction. Hydrocephalus can be visualized using MRI or CT, and may occur before meningitis is recognized (16).
Focal parenchymal masses are referred to as histoplasmomas. These lesions are typically small (< 2 cm) and can occur at the sites of white-gray matter junction, deep gray matter structures (eg, basal ganglia), brainstem, cerebellum, and spinal cord. The lesions are hypodense on noncontrast CT, and appear as enhancing, ring-like structures on contrast CT. Ring-enhancing lesions are also evident on MRI, with a low signal intensity on T1 sequences and a typically increased signal intensity on T2 sequences. Because histoplasmomas are abscess-like structures, depending on the stage of the abscess, inflammatory cell infiltrate, and the presence of necrosis, these may or may not show diffusion restriction on diffusion-weighted imaging (35; 31). Consequently, they may be mistaken for other conditions with lesions of similar appearance, including abscesses, necrotic tumors, toxoplasmosis, and subdural or epidural empyemas (17). Histoplasmomas found within the choroid plexus have a hyperdense appearance on CT, isointensity on MRI T1 sequences and hypointensity on T2 sequences (20). Cerebritis caused by histoplasmosis is also hypodense by noncontrast CT and enhances with the addition of contrast. This enhancement is suppressed in patients being treated with steroids (44). With MR imaging of the spinal cord, intramedullary lesions are typically isointense on T1-weighted images, hyperintense on T2-weighted images, and enhance with contrast injection. Multiple lesions are difficult to differentiate from metastatic tumors (07).
Prognosis and complications
Untreated, the course of the disease is progressive and fatal.
A 47-year-old man from Ohio presented to the local hospital complaining of severe progressively worsening headaches for the past 2 weeks. On examination, he was found to be lethargic and had nuchal rigidity and photosensitivity. Contrast-enhanced MR imaging of the brain showed diffuse meningeal enhancement as well as several ring-enhancing small lesions in the brain. On the review of symptoms, the patient also complained of chronic cough for the past 2 months. Lumbar puncture revealed 80 white blood cells with lymphocytic predominance, protein concentration of 90, and glucose concentration of 38 mg/dl. HIV and TB testing were negative. His CSF was tested for toxoplasmosis, cryptococcosis, and mycobacteria. Fungal and bacterial cultures were obtained. CT of the chest showed diffuse infiltrates, and bronchoalveolar lavage fluid was positive for histoplasma polysaccharide antigen. Serum histoplasma IgG was positive. CSF was tested for histoplasma polysaccharide antigen and was positive. Patient was started on amphotericin B for disseminated histoplasmosis. Two weeks later, H. capsulatum colonies were identified in the cultures of CSF and serum. The patient improved slowly over the next several weeks.