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NeuroAIDS
 
 
 
 

NeuroAIDS Vol. 4, No. 3, March 2001
>> NeuroAIDS

Meningitis in HIV-positive patients

William G. Powderly, MD, FRCPI1

1Professor of Medicine, Chief, Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8051, St. Louis, MO 63110

E-mail: wpowderl@imgate.wustl.edu

Keywords: meningitis, tuberculosis, cryptococcosis


Abstract
Meningitis in patients with HIV infection is almost always infectious in origin. Two opportunistic pathogens stand out as important problems in patients with AIDS - Cryptococcus neoformans and Mycobacterium tuberculosis, and together they account for about ¾ of the cases of meningitis. The rates of cryptococcal meningitis have been decreasing in the Western world with the introduction of effective suppressive therapy, especially fluconazole, and the introduction of effective treatment for HIV itself, with the consequent improvement in immune function. However, in developing countries, both tuberculosis and cryptococcosis remain among the most common and important causes of morbidity and mortality in patients with AIDS.

Introduction

The cardinal clinical consequence of progressive infection with HIV is the development of opportunistic infections (and to a lesser extent, malignancies) as a consequence of progressive loss of immune function. Although there are many potential pathogens that can complicate AIDS, in most circumstances only a very limited number affect the brain. Meningeal involvement can potentially complicate any opportunistic infection of the brain; meningitis may also complicate primary infection with HIV itself. However, two pathogens in particular, Cryptococcus neoformans and Mycobacterium tuberculosis must always be considered when evaluating meningitis in HIV-infected patients, because of the frequency of infection, and the potential morbidity they cause.


Fungal Meningitis

Infection with C. neoformans is the most common systemic fungal infection in patients infected with HIV and the most common cause of meningitis (1). About 5% of HIV-infected patients in the Western World develop disseminated cryptococcosis (2)(3)(4); the disease occurs in 20-30% of patients in other parts of the world such as in sub-Saharan Africa, and Thailand. C. neoformans is found worldwide as a soil organism; it is an encapsulated yeast measuring 4-6 um with a surrounding polysaccharide capsule ranging in size from 1 to over 30 um. Two varieties, distinguishable by serology, exist - C. neoformans var. neoformans (serotypes A and D) and C. neoformans var. gatti (serotypes B and C). Virtually all HIV-associated infection is caused by C. neoformans var. neoformans (5). It is unclear whether cryptococcal infection represents acute primary infection or reactivation of previously dormant disease.

It is postulated that initial infection occurs via inhalation of the basidiospores or unencapsulated forms leading to subsequent colonization of the airways and subsequent respiratory infection (6). Pulmonary macrophages are critically involved in control of the yeast (7), and complement mediated phagocytosis appears to be the primary initial defense against cryptococcal invasion (8). Other host-yeast interactions including CD4+ and CD8+ T-cells, as well as cytokines (such as gamma interferon, tumor necrosis factor alpha, IL-10 and 1l-12) also appear to be important (9)(10). In murine models, both CD4+ and CD8+ T-cells are required to inhibit cryptococcosis, and cytokines seem to be important in limiting dissemination (10). Thus, the defects in cell-mediated immunity characteristic of progressive HIV infection can be seen to readily increase the risk of disseminated cryptococcal infection.

The role of humoral immunity in control of cryptococcal infections is less certain. A recent case-control study (11) suggested an association between reduced expression of certain immunoglobulin subsets and cryptococcal meningitis in HIV-infected patients. In vitro studies of antibodies to the soluble capsular polysaccharide of C. neoformans reveal enhanced phagocytosis, increased fungicidal activity of leukocytes, and increased fungistatic activity of natural killer cells (12).

The most common presentation of cryptococcosis is a subacute meningitis or meningoencephalitis with fever, malaise and headache. Symptoms are usually present for 2-4 weeks before diagnosis. Classic meningeal symptoms and signs (such as neck stiffness or photophobia) occur in only about a quarter to a third of patients(13). Patients may present with encephalopathic symptoms such as lethargy, altered mentation, personality changes and memory loss. Analysis of the cerebrospinal fluid (CSF) usually shows a mildly elevated serum protein, normal or slightly low glucose, and a lymphocytic pleocytosis. A minimal inflammatory response characterized by less than 10 lymphocytes/mm3 CSF is seen in approximately 55% of cases (14). As many as ¼ of HIV-positive patients presenting with cryptococcal meningitis have normal CSF findings. Therefore, findings of an apparently normal CSF should not exclude the possibility of cryptococcal infection. India ink staining of the CSF will usually reveal the yeast. Cryptococcal antigen is almost invariably detectable in the CSF. The opening pressure in the CSF is elevated in a majority of patients.

 

Figure 1 (Enlarge): India Ink stain of CSF showing encapsulated yeast

Infection with C. neoformans can involve sites other than the meninges. In patients with AIDS, dissemination is common and pulmonary presentations such as cough, dyspnea or abnormal chest radiographs may be the initial finding. Many patients have positive blood cultures. Skin involvement is common; several types of skin lesions have been described but the most common form is that resembling molluscum contagiosum.

 

Figure 2 (Enlarge): Cutaneous lesions of disseminated cryptococcosis

The latex agglutination test for cryptococcal polysaccharide antigen in the serum is highly sensitive and specific in the diagnosis of infection with C. neoformans and a positive serum cryptococcal antigen titer of greater than 1:8 is as presumptive evidence of cryptococcal infection. Such patients should be evaluated for possible meningeal involvement. Culture of C. neoformans from any body site should also be regarded as significant and is an indication for further evaluation and initiation of therapy.

 

Figure 3 (Enlarge): GMS stain of brain showing invasive cryptococcosis


Untreated, cryptococcal meningitis is fatal. In patients with AIDS, amphotericin B (0.7 mg/kg IV) given for 2 weeks followed by fluconazole 400 mg PO for a further 8 weeks is associated with the best outcome to date in prospective trials with a mortality of less than 10% and a mycologic response of approximately 70% (15)(16). This regimen is also reasonable for treatment of meningitis in other circumstances. Concomitant use of flucytosine, 100 mg/kg/day in four divided doses, with amphotericin B may be considered. Flucytosine does not improve immediate outcome, but may decrease the risk of relapse. The combination of fluconazole, 400-800 mg /day with flucytosine and liposomal formulations of amphotericin B are options for patients unable to tolerate the usual formulation of amphotericin B (16).

Clinical deterioration in patients with meningitis may be due to increased intracranial pressure, which may be diagnosed by a raised opening pressure of the CSF. A recent study in patients with AIDS showed a strong correlation between mortality in the first two weeks after diagnosis, and the baseline opening pressure (17). All patients with cryptococcal meningitis should have the opening pressure measured when a lumbar puncture is performed, and strong consideration should be given to reducing such pressure (by repeated lumbar punctures, a lumbar drain or a shunt) if the opening pressure is high (>25 cm of water).

Cryptococcal meningitis in AIDS requires lifelong suppressive therapy unless the immunosuppression is reversed (16)(18). Fluconazole, 200 mg daily, is the suppressive treatment of choice. Fluconazole, in dosages ranging from 400 mg weekly to 200 mg daily, and itraconazole, 100 mg twice daily, are very effective in preventing invasive cryptococcal infections, especially in HIV-positive patients with CD4 counts < 50-100 cells/mm3. (16)(19) However, because of the relative infrequency of invasive fungal infections, antifungal prophylaxis does not prolong life and is not routinely recommended.

Other fungi rarely involve the meninges. Histoplasma capsulatum meningitis can occasionally be an additional feature of disseminated histoplasmosis. Candida species may also rarely cause meningitis. Although mucosal candidiasis is very commonly a feature of HIV infection, systemic candidiasis is rare and usually is a very late complication of AIDS. Neutropenic patients and those using intravenous drugs are at greater risk for invasive candidiasis, including candida meningitis. The clinical features, and CSF findings are similar to cryptococcal infection.



Bacterial Infection (and other causes of meningitis)

Acute bacterial meningitis is an infrequent complication of HIV infection. HIV-positive patients are at considerable increased risk for pneumococcal infection (20). However, pneumonia is the most common manifestation of this predisposition, and although bacteremia is common, meningitis is not commonly seen in the developed world. In contrast, bacterial meningitis is much more common in HIV-infected patients in the developing world (1)(21). The limited available data suggests that HIV infected patients are also at slightly increased risk for invasive infections with Neisseria meningitidis compared to the general population; however meningococcal meningitis and septicemia remain infrequent. Neurosyphilis can also complicate HIV infection. Central nervous system involvement in syphilis may occur at any time after initial infection. In particular, syphilitic meningitis may be seen within the first few weeks of infection or as a primary presenting symptom. Meningeal and meningovascular involvement may be suggested by changes in mental status, auditory or other cranial nerve dysfunction, ocular abnormalities, signs of meningeal irritation (meningismus), or stroke. CSF findings consistent with neurosyphilis include elevated protein and elevated white blood cell count. A reactive VDRL test on CSF is very specific for neurosyphilis but quite insensitive, so clinical judgment must be used in making the diagnosis. Treatment of choice for neurosyphilis is intravenous administration of aqueous crystalline penicillin-G (12 to 24 million units) daily for 14 days. Ceftriaxone may be an alternative (22).

The most important bacterial cause of meningitis in patients with AIDS is tuberculosis (23). Worldwide, tuberculosis is the most common opportunistic complication of HIV infections and accounts for considerable morbidity. In the developed world, there is considerable overlap among groups at high risk for TB and HIV including those who are homeless, housed in institutions, injection drug users, or living in urban areas where TB rates are high. In urban areas where coinfection with TB and HIV is more common, there is also an increased risk of acquisition of multiple-drug-resistant TB (MDR TB), particularly among individuals previously treated with antimycobacterial drugs.

The clinical manifestations of TB depend in part on the degree of immunosuppression in the patient. When the patients are still relatively immunocompetent, with CD4 lymphocyte counts > 200 cell/mm3 , pulmonary disease is most common. However, disseminated infection is more likely to ensue with more advanced immunodeficiency. The sites most frequently involved are the central nervous system (tuberculous meningitis), the reticuloendothelial system (lymph nodes, spleen, liver, bone marrow), or bone (vertebral bodies). However, virtually any other organ can be infected during hematogenous dissemination. Tuberculous meningitis may present clinically with fever, headache, mental-status changes, or focal neurologic deficits. Analysis of the cerebrospinal fluid usually shows an elevated serum protein, low glucose, and a lymphocytic pleocytosis. Identification of the organism in the CSF is unusual although cultures are typically positive within 2-3 weeks. Blood cultures may also be positive, especially in the setting of disseminated infection. CT or MRI scans of patients with tuberculous meningitis may show parenchymal mass lesions (tuberculomas); there are conflicting data on the prevalence of tuberculomas and other pathological changes that represent an inflammatory response in HIV-infected patients (24)(25).

Untreated, tuberculous meningitis progresses relentlessly and is uniformly fatal. Treatment of tuberculosis requires use of an adequate number of active antituberculous drugs for a prolonged duration. Treatment should be guided by antimycobacterial drug-susceptibility testing. Initial isolates and isolates recovered from those who relapse or for whom therapy fails should be tested for susceptibility to antituberculous drugs. In HIV-positive patients, issues of therapy are also complicated by the potential requirement for antiretroviral therapy. Many of the more potent antiviral agents, such as the protease inhibitors and non-nucleoside reverse transcriptase inhibitors have significant interactions with rifamycins, which are critically important in the treatment of tuberculosis (26). Concomitant usage of potent antiretroviral therapy and anti-tuberculous therapy requires expert management and should follow published guidelines (26) (27).

Management of tuberculosis is further complicated by the emergence of resistance to treatment as a significant factor. In 1998, 8% of TB isolates recovered from patients in the United States were resistant to at least isoniazid, and 1.1% were resistant to at least isoniazid and rifampin (28). Development of resistance has been associated with poor adherence to therapy, failure to recognize drug resistance leading to a delay in initiation of appropriate treatment, and the use of ineffective treatment regimens.

Initial therapy for uncomplicated TB in whom potent antiretroviral therapy is not started should include at least four drugs: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin (23)(29). Tuberculous meningitis should be treated for at least 12 months. The role of concomitant corticosteroids is uncertain (30). Although some studies suggest that steroids may reduce acute mortality, especially in children, there are limited data available on their use in HIV-infected patients.

Unusual clinical manifestations have also been described in patients receiving potent antiretroviral therapy. In the first few months after starting antiretroviral therapy, patients may experience apparent worsening of their tuberculosis with increased fever, pleural effusions, enlarging lymph nodes (especially mediastinal). In patients with meningitis, cerebritis and space-occupying lesions on scans has also been described. This paradoxical worsening is probably immune-mediated, does not imply failure of anti-TB treatment, and may respond to corticosteroids.

Other causes of meningitis

Opportunistic viral meningitis is rare. In contrast, meningitis can be a presentation of acute infection with HIV itself (31). The clinical manifestations of symptomatic primary HIV infection are myriad and most often include the acute onset of fever, generalized lymphadenopathy, pharyngitis, erythematous maculopapular rash. Headache is common and probably represents meningeal involvement in many cases. However it is rarely severe enough to prompt evaluation that includes a lumbar puncture. Aseptic meningitis with a lymphocytic pleocytosis is most commonly seen when CSF is analyzed. More severe neurologic manifestations including encephalitis, the Guillain-Barré syndrome, facial palsy, cauda equina syndrome, brachial neuritis, and peripheral neuropathy may occur, demonstrating the neurotropism of HIV. These manifestations usually recover completely as the acute syndrome resolves.

One final consideration in meningitis in patients with HIV infection is that it might be drug induced. Several cases of aseptic meningitis due to trimethoprim/sulfamethoxazole have been described (32). The presentation is one of acute meningitis with lymphocytic pleocytosis on CSF analysis. Resolution is prompt when the drug is stopped.



Conclusions

Meningitis in patients with HIV disease is most frequently due to opportunistic infections. Thus, predictions center on the likelihood of controlling opportunistic infection. The best way to prevent opportunistic infections is to give effective antiretroviral therapy - the future epidemiology of opportunistic infections is inextricably linked with the effectiveness of future antiretroviral treatment (33).


References


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