Viral hemorrhagic fevers: neurologic complications
Aug. 17, 2021
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This article includes discussion of histoplasmosis of the nervous system and Darling disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Histoplasmosis is an infection caused by the fungus Histoplasma capsulatum. Infection is endemic to certain areas of the United States, including the Mississippi and Ohio River Valleys, as well as parts of Central America, South America, Africa, and Southeast Asia. Organisms are spread by disturbance of ground soil contaminated by bat and avian excrement. Inhalation of spores causes infection, which primarily involves the lungs. Extrapulmonary infection can occur, though this is much less common. Immunocompromised individuals are at an increased risk for disseminated infection. In rare but serious cases, histoplasmosis affects the nervous system. Central nervous system involvement is clinically recognized in 10% to 20% of progressive, disseminated cases. CNS infection can also be isolated. Meningitis is the most common clinical manifestation of CNS histoplasmosis. Cerebral ring enhancing lesions are rarely reported. Diagnosis of histoplasmosis can be confirmed by detection of serum antigens, blood cultures, bronchoalveolar lavage, and biopsy of affected tissues. Methods for diagnosis of CNS infection are detailed below. Treatment with intravenous amphotericin B is required to penetrate the blood brain barrier, and long term use of oral itraconazole or fluconazole is necessary to prevent relapse.
Histoplasma capsulatum was first discovered in 1905 by pathologist Samuel Darling. Accordingly, histoplasmosis was once known as “Darling’s disease.” Darling described the organism as a protozoan. However, in 1912, da Rocha-Lima described the organism’s resemblance to a yeast. More than 20 years later, growth on artificial medium revealed that the organism was dimorphic: a mold at room temperature and a yeast at 37°C.
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).
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.
Histoplasma capsulatum is a dimorphic fungus with 2 variants, Histoplasma capsulatum variety capsulatum, which is encountered chiefly in America and the tropics, and histoplasma capsulatum variety duboisii, which occurs in Africa (30). H. capsulatum typically results in pulmonary infections, whereas H. duboisii affects the skin and skeleton (06).
The organism grows as a mold in the soil, and consists of hyphen-bearing large tuberculate macroconidia (8 to 14 um in diameter) and smaller microconidia (2 to 5 um). The latter is the infectious form of the fungus. Conidia inhaled into the lungs germinate into yeast-like forms and incite an immune reaction. The extent of disease depends on the number of conidia inhaled and the host’s cellular immune response (21). In patients with adequate immunity, T-lymphocytes activate against the H. capsulatum antigen and stimulate macrophages to kill the engulfed yeast. T cells are pivotal in clearance of the infection. A direct correlation exists between the CD4+ T cell count and the capacity of macrophages to bind yeast cells. As a result, patients with HIV or AIDS are more susceptible to disseminated disease (03). Involvement of the central nervous system arises following dissemination from a pulmonary source (27). Using a mouse model, the H. capsulatum protein Yps3p has been shown to interact with microglial cells, leading to TLR2 activation of nuclear factor-κB and expression of proinflammatory chemokines within the brain (02).
Histopathology. Although noncaseous granulomas are encountered occasionally, infection typically results in the formation of caseous granulomas composed of central necrotic areas surrounded by macrophages, fibroblasts, blood vessels, and multinucleated giant cells.
Organisms are present in macrophages and are recognized by periodic acid-Schiff reagent and Gomori methenamine silver nitrate technique. The meninges are usually normal in parenchymal mass lesions (34). With meningeal involvement, mononuclear infiltration is found primarily in the basilar meninges. Cranial nerves can be entrapped by basilar inflammation. Infiltration also affects blood vessels, occasionally causing fibrinoid necrosis in the media of cerebral arteries, possibly from involvement of the vasa vasorum (28; 38).
Histoplasmosis infection is endemic to the Mississippi River Valley, Ohio River Valley, and focal areas on the east coast of the United States. Infections also occur in Central America, South America, Africa, and Southeast Asia. The organism is commonly found in soil contaminated with bat and bird excrement that increase its sporulation. Humidity and temperature also play a role in its growth. Human-to-human transmission via the pulmonary route has not been reported (06; 18). Outbreaks occur when micro foci in Histoplasma-containing soil are disturbed. Individuals working in construction sites have an increased risk of exposure.
The most effective means of prevention is to avoid the accumulation of manure. When a colony of bats or a flock of birds is discovered roosting in a building, sealing all entry points is recommended until all animals and manure have been removed. If an accumulation of bat or bird manure is discovered in a location devoid of human activity, the material should be left alone. Before disturbing material that is potentially contaminated with H. capsulatum, workers must be informed that individuals with depressed immune systems are susceptible to severe disseminated disease. Aerosolized dust must be carefully controlled when removing bat or bird manure from a building or during construction, excavation or demolition. Respirators must be worn when disposing contaminated material, and other local and state requirements must be met (22).
In evaluating a patient with suspected CNS histoplasmosis, serious consideration for tuberculosis is necessary due to similar patterns of pulmonary and CNS involvement. Tuberculosis, like histoplasmosis, causes basilar meningitis with CSF findings indicative of chronic meningitis. Other fungal infections, such as cryptococcosis, can also mimic CNS histoplasmosis. Histoplasmomas have been misdiagnosed as neoplasms; however, response to antifungal medications clarifies the diagnosis. Sarcoidosis is another condition in the differential diagnosis. Both histoplasmosis and sarcoidosis present with diffuse pulmonary infiltrates, mediastinal adenopathy, noncaseating granulomas, erythema nodosum, elevated hepatic enzymes, and splenomegaly. Serum angiotensin converting enzymes is elevated in both conditions. Furthermore, incidental antibodies to H. capsulatum occurring in patients with sarcoidosis have incorrectly suggested a primary infection due to histoplasmosis (36). Other causes of CNS vasculitis, either primary or secondary (collagen vascular disease), are worthy of consideration in the differential diagnosis as well.
The diagnostic workup for patients with suspected disseminated histoplasmosis includes serum antigen testing as well as blood cultures. In patients with disseminated histoplasmosis, serum culture sensitivity may reach 74% (11). In 1 multicenter study, serum antigens were detected in 100% of 31 patients (13). In patients with pulmonary involvement, detection of antigen in respiratory secretions obtained by bronchoalveolar lavage can also be used for diagnosis. Cytopathologic evaluation of bronchoalveolar lavage cells combined with testing bronchoalveolar lavage for histoplasma antigen reaches 97% sensitivity (12). Blood cultures should be performed in all suspected cases. To optimize a potential definitive diagnosis, submission of multiple specimens for culture is highly recommended. Diagnosis in patients with isolated CNS involvement is more challenging. CSF culture is the gold standard for diagnosis of CNS histoplasmosis, and if necessary, culture of CNS parenchymal tissue may be used (17). However, depending on the burden of disease and the patient’s immune status, both CSF and serum culture sensitivity may be low and results may take 2 to 8 weeks.
In patients with meningeal involvement, sensitivity of histoplasma polysaccharide antigen testing has a range of 40% to 65% (37).
Cerebrospinal fluid demonstrates a lymphocytic pleocytosis, high protein concentration, and low to normal glucose concentration is indicative of CNS infection. In patients with isolated meningitis, detection of the histoplasma polysaccharide antigen or antibody in the CSF is diagnostic (38; 12). It is important to note that cross reactions occur with blastomycosis, paracoccidioidomycosis, and Penicillium marneffei infections (36). Interfering substances such as human anti-rabbit antibodies, rheumatoid factor, and heterophil antibodies also cause false positive results (39). CSF is also used for fungal culture, and culture of 10 to 20 mL on 2 or more occasions is recommended. However, negative CSF cultures do not exclude CNS histoplasmosis. For these patients, repeat lumbar puncture, or high cervical aspiration, or a biopsy of an infected extra-CNS site may be diagnostic.
In patients with suspected CNS histoplasmosis, submission of 3 samples of blood is recommended. Samples are cultured and assayed for histoplasma polysaccharide antigen and anti-histoplasma antibody. Doing both helps determine if CSF antigen positivity was caused by contamination of the CSF with blood (40). Clinicians must be mindful that immunosuppression impairs antibody production and lowers the sensitivity of serologic tests.
If the diagnosis remains unclear after testing CSF, blood, and urine, a sample of cisternal or ventricular fluid can aid diagnosis. Shunt aspiration is preferred for patients with ventriculoperitoneal shunts. Testing for histoplasma polysaccharide antigen and anti-histoplasma antibody as well as histopathological examination for fungi and fungal culture are all recommended (40).
If all of the above testing is negative, biopsy of the brain or meninges may be necessary to establish a diagnosis of cerebral or meningeal histoplasmosis (40).
Importantly, abnormal chest x-rays often reveal diffuse infiltrates, focal infiltrates, hilar lymphadenopathy, and calcified granulomas (38). Chest x-ray is abnormal in the majority of patients with CNS histoplasmosis.
Biopsy of non-CNS site. Non-CNS specimens are submitted for histopathological examination and cultured for fungi, especially in patients with disseminated disease. Specimens from the liver, spleen, and bone marrow are often helpful when they are involved (40).
Amphotericin B is the drug of choice for CNS histoplasmosis. Liposomal amphotericin B is preferred over the standard formulation, as the liposomal form has greater CNS penetration and lower toxicity (17). Duration of treatment depends on the patient’s immune status. In immunosuppressed patients with meningitis or focal lesions or in patients with progressive disseminated histoplasmosis, liposomal amphotericin B 5.0 mg/kg, for a total dose of 100 to 150 mg/kg given over 6 to 12 weeks is recommended. Afterward, treatment is continued with itraconazole, 200 mg 2 or 3 times a day for 1 year, or fluconazole, 600 to 800 mg once a day for 1 year. If immunodeficiency cannot be reversed, life-long treatment with itraconazole or fluconazole is recommended.
For focal lesions without complicating conditions such as coexisting meningitis, encephalitis, disseminated histoplasmosis, or underlying immunosuppression, amphotericin B, 0.7 to 1 mg/kg/day, or lipid formulation of amphotericin B, 3 to 5 mg/kg/day, is recommended for 2 to 4 weeks. Following induction therapy, itraconazole 200 mg, 2 or 3 times daily should be given for 1 year to prevent relapse. Itraconazole levels and histoplasma antigen levels should be monitored (19). For patients unable to tolerate itraconazole, fluconazole 600 to 800 mg, once daily can be substituted.
In all patients with CNS histoplasmosis, a spinal fluid examination is recommended after 1 month and 1 year of therapy or whenever a clinical deterioration occurs or a relapse is suspected. An analysis of spinal fluid is also advised when amphotericin B is changed to a triazole or whenever a decision to continue or stop treatment is under consideration. If a persistent pleocytosis or histoplasma antigen titer is found, therapy should be continued. In patients with a histoplasmoma, surgery is not recommended unless there is spinal cord compression. Treatment is with amphotericin B, and then a switch to a triazole as suggested for focal lesions without complicating conditions (40). Abnormal findings after cerebrospinal fluid analysis or imaging and abnormal antigen levels should be resolved before ending therapy (19).
If an immune reconstitution inflammatory syndrome occurs, continuation of highly active antiretroviral therapy and starting or continuing antifungal therapy is recommended (29; 05).
With treatment, patients with CNS infection have a mortality rate of 20% to 40% (04). Additionally, approximately 50% of those who respond to antifungal treatment relapse after the discontinuation of their drug (38).
Disseminated fungal infections in healthy pregnant women have been described, including histoplasmosis, coccidioidomycosis, blastomycosis, and cryptococcosis. Suppression of cell-mediated immunity is the likely explanation. Transplacental transmission of histoplasmosis has been reported in 1 patient (43). There is no sufficient evidence that histoplasmosis is more severe during pregnancy. If a patient is to be treated, azole antifungal agents should not be used because of the potential for teratogenic side effects. Amphotericin B is the drug of choice in pregnancy. The safety of the lipid preparations of amphotericin B during pregnancy, however, is unknown (41).
There are no known contraindications presented in the literature for patients with CNS histoplasmosis. Risk for anesthesia depends principally on underlying morbidities.
Elena Grebenciucova MD
Dr. Grebenciucova of Northwestern University has received honorariums from AlphaSights, Medscape, and Trinity Partners for consulting work.See Profile
Karen L Roos MD FAAN
Dr. Roos of Indiana University School of Medicine has no relevant financial relationships to disclose.See Profile
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