Chronic Meningitis

Joseph R. Zunt

Kelly J. Baldwin

INTRODUCTION

Chronic meningitis is commonly defined as inflammation of the meninges, most often accompanied by a pleocytosis of greater than 5 white blood cells per microliter in the cerebrospinal fluid (CSF), that has persisted for at least 1 month without spontaneous resolution. Clinical presentation often includes headache, nausea, vomiting, cranial neuropathies, symptoms of elevated intracranial pressure, or focal neurologic deficits (Table 64.1). The most common etiologies of chronic meningitis fall into three broad categories: infectious, autoimmune, and neoplastic. This chapter will focus on the most common infectious etiologies of chronic meningitis. Fungal, bacterial, and parasitic pathogens can invade the central nervous system and present clinically as chronic meningitis. Increasing use of immunosuppressant medications for autoimmune disease and posttransplantation immunosuppression, as well as predisposing conditions, such as impaired cellular and humoral immunity, have led to a larger population at risk for infectious causes of chronic meningitis.

Despite an increasing array of diagnostic assays, there remain a large proportion of patients with chronic meningitis who remain without a definitive pathogen identified. A thorough history and skillful physical examination is the key to guide further diagnostic testing (Table 64.2) and management (Table 64.3). When history, examination, CSF analysis, and imaging fail to yield an etiology, biopsy is required to establish a definitive diagnosis.

FUNGAL MENINGITIS

Fungi exist in two forms, molds and yeasts. Molds are the tubular form, consisting of hyphae that can be branched or contain a single filament. Yeasts are thick-walled, single-celled organisms that live inside cells. Dimorphic yeasts assume tubular forms at lower temperature but become encapsulated at temperatures above 35°C. Either fungal form can infect the nervous system, producing meningitis, vasculitis, abscess, granulomas, or encephalitis.

Fungi are universal saprophytic organisms found as spores in soil, on the skin of mammals and birds, and in bat or bird guano. They commonly enter the body through inhalation; direct invasion through the skin, mucus membranes, or sinuses; or via penetrating wounds. Although invasive fungal disease typically affects immunocompromised individuals, some organisms such as Coccidioides spp. and Cryptococcus spp. can also affect immunocompetent individuals. Fungal infections of the nervous system mainly occur in the presence of immunosuppression as a consequence of AIDS, cancer, hematologic malignancy, hereditary immune defects, organ or stem cell transplantation, or other conditions requiring therapeutic immunosuppression.

CRYPTOCOCCAL MENINGITIS

Epidemiology and Pathobiology

Cryptococcal meningitis is most often caused by the encapsulated yeast Cryptococcus neoformans, but other cryptococcal species, such as Cryptococcus gattii, are emerging as pathogens that affect immunocompetent individuals. With a worldwide distribution, C. neoformans is ubiquitous, found primarily in bird droppings, soil, and citrus peel. C. gattii is more commonly associated with the bark of several tree species. Infection usually occurs through inhalation of the organism, followed by a respiratory infection and dissemination. Cryptococcal meningitis is most common in people with impaired cell-mediated immunity, especially those with HIV infection, hematologic malignancies, solid organ transplant recipients, and patients on chronic corticosteroids or other immunosuppressive therapy. In patients immunocompromised due to HIV infection, cryptococcal meningitis is the most common systemic fungal infection and a frequent etiology of central nervous system (CNS) infection, with a prevalence varying from 10% in the United States to as high as 30% in sub-Saharan Africa.

Clinical Features

CRYPTOCOCCUS GATTII

This is a rare pathogen, with disease confined to tropical and subtropical climates, particularly the highly endemic regions of Australia and Papua New Guinea. In 2004, an outbreak of C. gattii infections was documented in the United States Pacific Northwest states of Oregon and Washington. A large retrospective review of the Pacific Northwest C. gattii infections revealed important clinical differences between C. gattii infections in the United States Pacific Northwest and historically endemic areas. Although C. gattii in historically endemic areas has been reported to infect primarily immunocompetent persons, causing meningoencephalitis, C. gattii infections in Oregon and Washington State occurred frequently in immunocompromised persons and presented most often as respiratory illness. Time from symptom onset to diagnosis of C. gattii infection was significantly longer among patients with pulmonary infections (50 days) than those with either CNS (24 days) or bloodstream infections (27 days). There were no differences in immune status between patients with bloodstream infections and either pulmonary or CNS infections.

CRYPTOCOCCUS NEOFORMANS

The clinical manifestations of C. neoformans infection depends largely on the host immune status. Severity of infection varies from asymptomatic incidental pulmonary nodules to widely disseminated disease. HIV-infected patients with CD4+ counts of less than 50 cells/µL are especially vulnerable to disseminated infection and meningitis. Cryptococcal meningitis typically begins insidiously, with 75% of patients developing headache and fever over a 2- to 4-week period. As the infection evolves, 50% of people develop nausea, vomiting, and altered mental status. Visual symptoms and seizures are also common. Over half of immunocompromised patients develop intracranial hypertension; this is even more common in immunocompetent hosts. As increased intracranial pressure develops, patients become obtunded, and without intervention, herniation will follow.

TABLE 64.1 Neurologic and Systemic Symptoms and Imaging Characteristics of Chronic Infectious Meningitis

Condition	Neurologic Presentation	Systemic Symptoms	Neuroimaging
Cryptococcosis	Headache and fever (75%), nausea and vomiting (50%), altered mental status (50%), visual symptoms, seizures	Pulmonary, multiorgan involvement	Hydrocephalus, cerebral edema, leptomeningeal enhancement, and cryptococcomas
Coccidioidomycosis	Headache (75%); nausea and vomiting (40%); altered mental status (39%-73%); focal neurologic deficits, including ataxia, gait disturbance, diplopia, or facial palsies (33%-80%); and nuchal rigidity (20%)	Pulmonary, lymph nodes, skin	Hydrocephalus, meningeal enhancement, nodular enhancement, basilar meningitis, cerebral infarction
Blastomycosis	Focal neurologic deficits, seizures, and altered mental status Less common: fever, headache, and meningismus	Pulmonary, verrucous or fungating skin lesions, bones, joints, genitourinary system	Single or multiple abscesses, granuloma, meningeal enhancement, epidural extensions, and overlying osteomyelitis
Histoplasmosis	Headache and altered mental status	Acute pulmonary infection with fever, chills, and pulmonary opacities Multiorgan including bone marrow	Normal, granuloma, meningeal enhancement
Aspergillosis	Solitary mass lesion, cavernous sinus thrombosis, multiple intracranial abscesses, acute or chronic basilar meningitis, vasculitis, or myelitis	Pulmonary, sinusitis, multiorgan involvement	Multiple abscesses, meningeal enhancement, infarction, hemorrhage, sinusitis with extension
Tuberculosis	Headache, vomiting, meningeal signs, focal deficits, vision loss, cranial nerve palsies	Pulmonary, malaise, anorexia, fatigue, weight loss, fever, myalgia	Enhancement of the basilar meninges, thick exudates, obstructive hydrocephalus, miliary pattern, tuberculoma, and periventricular infarcts
Syphilis	Meningitis (headache, photophobia, nausea and vomiting, cranial nerve deficits), general paresis, psychiatric illness, cognitive decline, tabes dorsalis, or vascular disease	Genital ulcers, fever, lymphadenopathy, headache, malaise, myalgia, and a macular or pustular rash of the palms and soles Multiorgan involvement	Leptomeningeal enhancement, white matter disease in the brain and posterior columns, ischemic stroke
Borreliosis	Early: septic lymphocytic meningitis, cranial neuritis, or painful polyradiculitis Late: myelitis, encephalitis, and neurobehavioral changes	Rash, fever, diffuse aches and pains, headaches, malaise, fatigue, carditis	White matter edema with enhancement

Diagnosis

The diagnosis of cryptococcal meningitis should be considered in patients presenting with a subacute presentation of headache and fever, especially in the setting of HIV infection or immunosuppression. Computerized tomography (CT) and magnetic resonance imaging (MRI) are nonspecific for the diagnosis of cryptococcal meningitis but may reveal hydrocephalus, cerebral edema, leptomeningeal enhancement, or cryptococcomas. Classic MRI findings for fungal meningitis are shown in Figure 64.1. Lumbar puncture, the diagnostic procedure of choice, demonstrates an increased opening pressure, a mild mononuclear pleocytosis, increased protein, and low glucose concentrations. Patients with severe immunosuppression may lack this typical CSF appearance. The cryptococcal capsular polysaccharide antigen (CrAg) assay is both sensitive and specific for detecting C. neoformans in CSF samples and can be quantitated for prognostication. The CrAg titer is not reliable for determining response to therapy. Although a positive CrAg assay in serum cannot confirm the diagnosis of cryptococcal meningitis, a negative CrAg assay virtually excludes the diagnosis. Because the CrAg lateral flow assay (LFA) has nearly 100% sensitivity and specificity on CSF samples, it is considered the optimal point-of-care diagnostic assay for cryptococcal meningitis. In areas where CrAg is not available, direct CSF examination with India ink preparation is often used. Fungal culture for the organism is 90% sensitive and can also be useful for speciation, although it typically requires days for culture to grow. C. neoformans cultured from CSF, blood, or other sites produces white mucoid (depending on the capsule thickness) colonies, usually within 48 to 72 hours, on most bacterial and fungal media. Although C. neoformans grows at 37°C, a temperature of 30°C to 35°C is optimal.

TABLE 64.2 Cerebrospinal Fluid Characteristics and Serum Diagnostics for Chronic Infectious Meningitis

Condition	Microscopic Appearance	LP Opening Pressure	CSF WBC	CSF Differential	CSF Glucose	CSF Protein	CSF Diagnostics	Serum Diagnostics
Cryptococcosis	Encapsulated fungi; yeastlike cells with budding daughter cells; capsule visualized by India ink (halo effect)	High	High or normal	Mononuclear	Low	High	Fungal smear, fungal culture, India ink stain, CrAg lateral flow assay (LFA)	Blood culture
Coccidioidomycosis	Yeast form endosporulating spherules; branched septate hyphae with alternating arthroconidia	Normal	High	Early PMN, lymphocytic, eosinophilic (70%)	Low	High	Fungal culture, microscopy, complement fixation antibody assay, PCR	Microscopy from bronchoalveolar lavage (BAL) fluid, or other body fluid, or a positive culture from any location
Blastomycosis	Mycelium at room temperature; yeast phase at 37°C. Conidia, yeast cells with multinucleate broad budding.	High	High	Early PMN, lymphocytic	Low	High	Fungal culture, biopsy of involved tissue with micro	Direct visualization of the organism via microscopy
Histoplasmosis	Hyphae large macroconidia and smaller infectious microconidia. At temperatures <35°C yeast form. Hyphal elements possible.	Normal	High	Mononuclear	Low	High	Fungal smear and culture, antigen titers	Fungal culture from involved organ, antigen titers
Aspergillosis	Septate hyphae branched at 45-degree angles with conidiophores. Hyphae develop terminal buds forming small conidia.	Normal	High	Early neutrophil, lymphocytic	Low	High	Fungal culture, biopsy of affected tissue with micro, PCR	Galactomannan and beta-D-glucan. Microscopy, culture, or PCR from bronchoalveolar lavage or affected tissue.
Tuberculosis	Intracellular aerobic gram-positive acid-fast pleomorphic bacillus	High	High or normal	Mixed pleocytosis	Low	High	AFB smear and culture, PCR; GeneXpert, MODS	QuantiFERON, PPD, BAL for AFB smear and culture
Syphilis	Spirochetal bacterium	Normal	High or normal	Lymphocytic	Normal	High or normal	Darkfield microscopy, VDRL, PCR	RPR, VDRL, (FTA-ABS) and Treponema pallidum particle agglutination tests (MHA-TP)
Borreliosis	Spirochetal bacterium	Normal	High	Lymphocytic	Normal	High or normal	Darkfield microscopy, IgG and IgM antibody index, PCR	Two-tier testing (ELISA and IgM/IgG immunoblot)
LP, lumbar puncture; CSF, cerebrospinal fluid; WBC, white blood cell; CrAg, cryptococcal capsular polysaccharide antigen; PMN, polymorphonuclear; PCR, polymerase chain reaction; AFB, acid-fast bacillus; MODS, microscopic observation drug susceptibility; PPD, purified protein derivative; VDRL, Venereal Disease Research Laboratory; RPR, rapid plasma reagin; FTA-ABS, fluorescent treponemal antibody absorption; Ig, immunoglobulin; ELISA, enzyme-linked immunosorbent assay.

TABLE 64.3 Treatment of Chronic Infectious Meningitis

Condition	Treatment	Alternatives and Other Considerations
Cryptococcosis	Amphotericin B (AmB) 0.7-1 mg/kg/day IV plus flucytosine 100 mg/kg/day × 14 days then fluconazole 400 mg PO daily × 8 wk then fluconazole 200 mg daily lifelong	Repeat LP to keep opening pressures in normal range; CSF shunting when needed.
Coccidioidomycosis	Induction therapy with oral fluconazole 400-800 mg/day, followed by 200-400 mg/day indefinitely	Itraconazole 400-600 mg/day or amphotericin B 0.5-0.7 mg/kg/day. Intrathecal amphotericin B in addition to an azole. Shunting for hydrocephalus when needed.
Blastomycosis	Liposomal amphotericin B, 5 mg/kg/day for 4-6 wk, followed by an oral azole. Possible options for azole therapy include fluconazole (800 mg/day), itraconazole (200 mg two or three times per day), or voriconazole (200-400 mg twice per day) for at least 12 months and until resolution of CSF abnormalities.	Surgical drainage of any epidural abscess
Histoplasmosis	Liposomal amphotericin B (5.0 mg/kg daily for a total of 175 mg/kg given over 4-6 wk). Fluconazole (800 mg/day) should be continued for 9-12 mo.	Chronic fluconazole maintenance therapy (800 mg/day) in relapsing patients. Intrathecal amphotericin B.
Aspergillosis	Voriconazole 6 mg/kg IV twice a day on day 1 followed by 4 mg/kg IV twice daily. Followed by maintenance therapy of voriconazole 200 mg every 12 h.	Voriconazole plus caspofungin for invasive disease
Tuberculosis	Intensive four-drug regimen × 2 mo then continuation two-drug regimen × 10 mo based on resistance patterns	Choice of treatment should be directed by resistance patterns. Steroids should be considered for meningitis.
Syphilis	Aqueous penicillin G 18-24 million U/day administered as 3-4 million units IV every 4 h or as continuous infusion for 10-14 days	Procaine penicillin 2.4 million units IM daily with probenecid 500 mg orally four times daily for 10-14 days
Borreliosis	Ceftriaxone 2 g IV daily for 14 days	IV cefotaxime or IV penicillin G. Oral doxycycline.
IV, intravenous; PO, by mouth; LP, lumbar puncture; CSF, cerebrospinal fluid; IM, intramuscular.

Treatment

A combination of antifungal medication and aggressive management of hydrocephalus is integral to the successful treatment of patients with cryptococcal meningitis. Amphotericin B (AmB) plus flucytosine, as compared with AmB alone, is associated with improved survival of patients with cryptococcal meningitis. Elevated intracranial pressure (ICP) can be managed through a variety of treatments. Patients should initially undergo daily lumbar punctures to reduce opening pressure until normal opening pressure is consistently maintained; some patients may require multiple daily lumbar punctures. For patients requiring frequent lumbar punctures, placement of a lumbar drain or ventriculostomy can provide a temporary means for controlling ICP. Ventriculoperitoneal shunt can be considered for patients with persistently elevated ICP. A recent retrospective study of elevated ICP in patients with cryptococcal meningitis determined by aggressive management of ICP during the initial 5 days of illness was associated with lower mortality than initial antifungal management alone.

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