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The development of neurologic symptoms and signs in an immunosuppressed patient should alert the clinician to the possibility of an infectious etiology. When persons with AIDS are excluded, organ transplantation patients and persons with an underlying malignancy comprise those at risk for an often life-threatening central nervous system (CNS) infection. In recent years, the incidence of CNS infection in transplant recipients has diminished because of the use of cyclosporine as the primary immunosuppressive agent. The mortality of CNS infection in immunocompromised hosts, however, ranges from 42% to 77%. Bacteria, fungi, viruses, and protozoa may be involved. Whereas the pneumococcus, meningococcus, or Haemophilus influenzae is responsible for 75% of cases of bacterial meningitis in patients with no underlying disease, the causal organisms differ widely in impaired hosts. The common bacterial agents in patients with lymphoma or leukemia are Listeria monocytogenes, gram-negative enteric rods, and the pneumococcus.
The predilection for fungal infections with Cryptococcus, Aspergillus, Mucor, and Candida species has also been emphasized. One study found that one third of patients had meningitis caused by fungi. Unusual organisms such as Blastoschizomyces capitatus, a fungus previously known as Trichosporon, may cause meningitis in bone marrow transplant recipients. In addition, viral agents such as varicella-zoster virus, herpes simplex virus, papovavirus, and measles virus should be considered, in addition to parasites, especially Toxoplasma and Strongyloides.
Progressive multifocal leukoencephalopathy, a subacute progressive demyelinating disease, is caused by the JC virus. Patients present with slowly progressive focal defects, which mimic those of a mass lesion. Diagnosis is suggested when magnetic resonance imaging shows a nonenhancing, low-density lesion of the white matter. A brain biopsy is required for definitive diagnosis. In the compromised host, the laboratory must be alerted to the possibility of a common as well as an obscure cause. The differential diagnosis should also include noninfectious problems that may mimic infectious meningitis or a brain abscess, such as carcinomatous or lymphomatous meningitis, cerebral hemorrhage, and adverse reactions to chemotherapeutic agents.
The importance of suspecting an intracranial infection in this group of patients is critical, as the majority of infections are diagnosed only at autopsy and are largely caused by unrecognized fungi. The diagnosis is difficult because the symptoms and signs are often attributed to the patient’s underlying disease rather than to a possibly new infectious complication. The clinical features may be subtle, but headache and fever are usually present, even in patients receiving corticosteroids or other immunosuppressive agents. The patient’s consciousness will usually be altered at the onset or shortly after admission. Nuchal rigidity is reported in only one third of patients. Seizures may occur, and focal neurologic findings may also be present. One report noted that cerebral metastasis was the most frequent initial diagnosis in patients with CNS infections. Thus, minimal findings of headache and fever in a compromised host should elicit a search to exclude a possible CNS infection.
Cerebrospinal fluid (CSF) analysis is a valuable aid to establishing an etiologic diagnosis. A lumbar puncture should not be performed in patients with a suspected cerebral mass lesion. An elevated pressure, pleocytosis, elevated protein, and low sugar may be found. However, the absence of cells in the CSF does not exclude an infection, and Gram’s stain, acid-fast stain, India ink preparation, serologic studies for Cryptococcus (latex agglutination test), polymerase chain reaction for suspected pathogen, and appropriate cultures are indicated. A differential cell count showing a predominance of mononuclear cells suggests Cryptococcus, Listeria, Mycobacterium, or Toxoplasma. An eosinophilic pleocytosis of the CSF rarely occurs and usually indicates a helminthic parasitic infection or lymphoma.
Clues to the specific opportunistic pathogen may be present. Cryptococcus has a predilection for patients with lymphomas (impaired cellular immunity). A pulmonary infiltrate, skin lesions, and positive blood or urine cultures are occasionally noted. Other fungi, such as Aspergillus, Mucor, and Candida, are more difficult to identify, as antemortem cultures will frequently be negative. Fever and a pulmonary infiltrate in a patient with leukemia or a lymphoma unresponsive to broad-spectrum antimicrobial agents suggest a fungal disease. Neurologic involvement usually indicates a disseminated infection.
Of the bacterial opportunists, Listeria has a predilection for hosts with impaired T-cell function, such as renal transplant recipients or those with a lymphoma. Whereas most cases of Listeria infection are sporadic and the route of infection remains unknown, food-borne outbreaks related to contaminated milk, ice cream, cheese, and coleslaw have been reported. These gram-positive rods may at times appear as gram-positive cocci or be confused with diphtheroids. Patients infected with Nocardia, another opportunistic agent, may present with pulmonary, neurologic, and, less often, skin involvement. Gram-negative enteric bacilli may cause hospital-acquired meningitis in patients with acute leukemia and granulocytopenia. Toxoplasmosis is a treatable parasitic infection that presents with any one of three patterns of CNS involvement: (a) diffuse encephalopathy with or without seizures, (b) meningoencephalitis, or (c) single or multiple mass lesions. The diagnosis may be established by noting a fourfold rise in Toxoplasma titer on a serologic test, such as the indirect fluorescent antibody titer, or by detecting IgM antibody with an enzyme-linked immunosorbent assay (ELISA). IgM antibody usually disappears in a few months, whereas IgG antibody persists for life. Toxoplasmosis can also be diagnosed with polymerase chain reaction testing of blood or CSF. Finally, a clue to histoplasmosis, coccidioidomycosis, or Strongyloides infection may be a history of residence in an endemic area. (N.M.G.)
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A neurologic disorder was associated with the use of OKT3 monoclonal antibody. Symptoms resolved within 2 to 5 days of onset without residual defects.
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A rare cause of encephalitis in usually normal hosts. Diagnosis was difficult because the blood cultures were positive in only 61% of cases and the CSF in 41%.
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In patients with disseminated toxoplasmosis, Toxoplasma tachyzoites can be seen by using a Wright’s stain on the peripheral blood buffy coat smear.
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Diagnosis is usually made by using polymerase chain reaction on CSF, whereas viral cultures are often negative.
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Meningitis is an infrequent complication of disseminated candidiasis.
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Most cases occurred in the setting of disseminated disease. Amphotericin B was not effective.
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The cell count was abnormal in 97% of patients, protein was elevated in 90%, CSF pressure was increased in 64%, and low sugar was found in 55%.
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An extensive review. In patients with lymphoma, the three most frequent causes of CNS infection were Cryptococcus, Listeria, and pneumococci.
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A decline in the incidence of cryptococcal meningitis and an increase in Listeria meningitis are reported.
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Soil exposure may be a risk factor. Thirty percent of patients had lesions on computed tomography of the head.
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In liver transplant recipients, Aspergillus is the most common cause of brain abscess, which is usually fatal.
Denning DW, et al. NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy for invasive aspergillosis. Am J Med 1994;97:135–144.
Itraconazole is an alternative drug for invasive aspergillosis, with a response rate of 39%.
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Disseminated disease with pulmonary and neurologic involvement can develop in immunosuppressed patients. (See also Meyer RD, et al. An orthotopic heart transplant recipient with subacute meningitis. Rev Infect Dis 1991;13:513.)
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A discussion of risk factors associated with the failure of antifungal therapy or relapse. A CSF cryptococcal antigen titer of 1:32 or higher is a poor prognostic sign.
Drancourt M, et al. Brain abscess due to Gordona terrae in an immunocompromised child: case report and review of infections caused by G. terrae. Clin Infect Dis 1994;19:258–262.
A gram-positive coccobacillus is a rare cause of a brain abscess.
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The differential diagnosis is reviewed.
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A cause was identified in only 23% of cases, with transverse myelitis and malignancy being the most frequent.
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Contrast enhancement may not occur in the compromised host. The etiology could not be predicted by the CT findings.
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A sputum culture for Nocardia may reflect colonization.
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Meningitis may occur with only minimal signs and symptoms.
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Results of the latex agglutination test for cryptococcal antigen may be positive in patients with negative India ink preparations.
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An unexplained CNS infarct resulting in a focal seizure may be a clue to Aspergillus infection of the CNS in a high-risk patient.
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Magnetic resonance imaging is the diagnostic method of choice and will show areas of increased signal, indicative of demyelination, in the white matter.
Griffin JW, et al. Lymphomatous leptomeningitis. Am J Med 1971;51:200.
Cytologic study of the CSF may reveal the cause of cranial nerve palsies, headache, and papilledema in a patient with lymphoma.
Hall WA. Neurosurgical infections in the compromised host. Neurosurg Clin North Am 1992;3:435.
Hall WA, et al. Central nervous system infections in heart and heart-lung transplant recipients. Arch Neurol 1989;46:173.
Meningitis was caused by Listeria and Cryptococcus; Aspergillus, Nocardia, and Candida were involved in patients with a brain abscess.
Heegaard ED, Peterslund NA, Hornsleth A. Parvovirus B19 infection associated with encephalitis in a patient suffering from malignant lymphoma. Scand J Infect Dis 1995;27:631–633.
A rare cause of encephalitis.
Hooper DC, Pruitt AA, Rubin RH. Central nervous system infection in the chronically immunosuppressed. Medicine (Baltimore) 1982;61:166.
Review. The most common presenting features were fever (78%) and headache (58%). Meningismus was present in only about 25% of patients.
Jabbour N, et al. Cryptococcal meningitis after liver transplantation. Transplantation 1996;61:146–149.
In liver transplant recipients, headache, fever, and mental status changes occurred most often; meningismus was found in only 30%.
Louria DB, et al. Listeriosis complicating malignant disease. Ann Intern Med 1967;67:261.
The most common manifestation is bacteremia or meningitis, or both.
Lukes SA, et al. Bacterial infections of the CNS in neutropenic patients. Neurology 1984;34:269.
Mental status changes (93%) and fever (95%) are common. Seizures were noted in 40% of patients. Platelet transfusions should be given to patients with thrombocytopenia before a lumbar puncture.
Meyer RD, et al. Aspergillosis complicating neoplastic disease. Am J Med 1973;54:6.
The characteristic clinical features are fever and pulmonary infiltrates, with no response to antimicrobials; CNS findings are usually caused by multiple brain abscesses.
Murray JF, et al. The changing spectrum of nocardiosis. Am Rev Respir Dis 1961;83:315.
Nocardia is a branching, filamentous, gram-positive, weakly acid-fast organism that causes necrosis and abscess formation but not granulomas.
Narayan O, et al. Etiology of progressive multifocal leukoencephalopathy. Identification of papovavirus. N Engl J Med 1973;289:1278.
This subacute demyelinating disease occurs in the compromised host, especially in patients with lymphoma.
Pagano L, et al. Localization of aspergillosis to the central nervous system among patients with acute leukemia: report of 14 cases. Clin Infect Dis 1996;23:628–630.
Primary focus of infection is the lungs. Death occurred usually within 5 days of onset of neurologic symptoms.
Palmer DL, Harvey RL, Wheeler JK. Diagnostic and therapeutic considerations in Nocardia asteroides infection. Medicine (Baltimore) 1974;53:391.
The lungs are the most frequent primary site (in 73%), with the nervous system the most commonly involved secondary site (23%).
Perfect JR. Fungal meningitis. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the central nervous system. New York: Lippincott–Raven Publishers, 1997:721–739.
Review. Fungal meningitis must also be considered in a patient with chronic meningitis.
Pruitt AA. Central nervous system infections in cancer patients. Neurol Clin 1991;9:867.
Rodriguez JC, et al. Evaluation of different techniques in the diagnosis of Toxoplasma encephalitis. J Med Microbiol 1997;46:597–601.
Polymerase chain reaction on CSF had a sensitivity of 81% in the diagnosis of Toxoplasma encephalitis in untreated patients and of only 20% in treated patients.
Ruskin J, Remington JS. Toxoplasmosis in the compromised host. Ann Intern Med 1976;84:193.
A review. Neurologic manifestations predominate in more than half the patients.
Salaki JS, Louria DB, Chmel H. Fungal and yeast infections of the central nervous system: a clinical review. Medicine (Baltimore) 1984;63:108.
Schuchat A, Swaminathan B, Broome CV. Epidemiology of human listeriosis. Clin Microbiol Rev 1991;4:169.
Food-borne sources may be responsible for outbreaks.
Skogberg K, et al. Clinical presentation and outcome of listeriosis in patients with and without immunosuppressive therapy. Clin Infect Dis 1992;14:815.
Bacteremia and meningitis were the two most common clinical forms of the disease. Mortality was 32% in patients with any underlying illness.
Stamm AM, et al. Listeriosis in renal transplant recipients: report of an outbreak and review of 102 cases. Rev Infect Dis 1982;4:665.
Onset often occurs shortly after transplantation.
Stone MM, et al. Brief report: meningitis due to iatrogenic BCG infection in two immunocompromised children. N Engl J Med 1995;333:561–563.
A rare cause of meningitis—the accidental intrathecal inoculation of bacillus Calmette-Guérin.
Strayer DR, Bender RA. Eosinophilic meningitis complicating Hodgkin’s disease. Cancer 1977;40:406.
A case report and differential diagnosis.
Tabacof J, et al. Strongyloides hyperinfection in two patients with lymphoma, purulent meningitis, and sepsis. Cancer 1991;68:1821.
Strongyloides can be the underlying cause of a gram-negative bacteremia or CNS infection in a patient with lymphoma.
Thaelkeld SC, Hooper DC. Update on management of patients with Nocardia infections. In: Remington JS, Swartz MN, eds. Current clinical topics in infectious diseases. Boston: Blackwell Science, 1997:1–23.
Review. For disseminated infection, treat for 6 months to 1 year.
Tunkel AR, Scheld WM. Central nervous system infection in the immunocompromised host. In: Rubin RH, Young S, eds. Clinical approach to infection in the compromised host, 3rd ed. New York: Plenum Publishing, 1994:163–210.
Comprehensive review.
Van der Horst CM, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med 1997;337:15–21.
Use of higher-dose amphotericin B (0.7mg/kg daily) plus flucytosine was associated with an improved outcome compared with lower-dose amphotericin B (0.4mg/kg daily).
White M, et al. Cryptococcal meningitis: outcome in patients with AIDS and patients with neoplastic disease. J Infect Dis 1992;165:960.
In this small study, the outcome of cryptococcal meningitis in patients with AIDS was better than in those with underlying neoplastic disease.
Wilfert CM, et al. Persistent and fatal central nervous system echovirus infections in patients with agammaglobulinemia. N Engl J Med 1977;296:1486.
Enteroviral infections can be fatal in immunodeficient persons.
Wilson JP, et al. Nocardial infections in renal transplant recipients. Medicine (Baltimore) 1989;68:38.
Review. CNS involvement was noted in 16% of patients.
Winston DJ, Emmanouilides C, Busuttil RW. Infections in liver transplant recipients. Clin Infect Dis 1995;21:1077–1091.
Aspergillus is the most frequent cause of infection of the central nervous system in liver transplant recipients. Bacterial meningitis is rare, but consider Listeria.


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