Chapter 82 Fungal, Rickettsial, and Parasitic Diseases of the Nervous System
Fungal Diseases
The importance of invasive fungal infections, including those of the central nervous system (CNS), has risen as the population of immunologically compromised patients, including preterm infants, has grown. Patients with congenital immunologicial deficiencies, aplastic anemia, or poorly controlled human immunodeficiency virus (HIV) infection are at risk for a wide variety of fungal infections because their illness prevents normal functioning of the immune system. Those patients receiving chemotherapy, hematopoetic stem-cell or solid organ transplants, or medications such as corticosteroids that blunt the normal immune systems, can also be highly susceptible. The normal host can also fall victim to invasive fungal infection, but does so less often and to a smaller spectrum of organisms [Chimelli and Mahler-Araujo, 1997].
Fungal diseases involving the brain are usually spread via the bloodstream after a systemic or pulmonary focus is established. Alternatively, pathogens invade the CNS via direct extension from adjacent sinuses, the cranial vault, orbits, or the spine. With exceptions, such as Candida spp. meningitis in premature neonates and Aspergillus spp. brain abscess in the highly compromised host, fungal infections of the CNS in children are rare. A review from a large university children’s hospital found that, in a 6-year period, only 2 percent of nearly 1500 positive cerebrospinal fluid (CSF) cultures recovered fungal isolates [Arisoy et al., 1994], mostly Candida spp.; nearly half came from low-birth-weight infants. Table 82-1 provides a more extensive list of risk factors, syndromes, and treatments for fungal infections of the nervous system. Since clinical manifestations of CNS fungal infections can be subtle and not specific to individual pathogens, errors and delays in diagnosis occur. Fungi may cause a variety of clinical syndromes, including meningitis, brain abscesses, granulomas, and invasion of the vasculature, further complicating clinical presentation and treatment [Salaki et al., 1984]. Prompt diagnosis and effective treatment often require a medical–surgical team approach.
Cryptococcosis
Epidemiology, Environmental Reservoir, and Pathogenesis
Cryptococcosis is globally distributed and is most commonly seen in patients with acquired immunodeficiency syndrome (AIDS) and in those receiving systemic corticosteroids; infection also occurs in those without apparent predisposition but at a lower frequency [Wendisch et al., 1996]. Although children are less frequently infected than adults, infants have contracted the disease [Hung et al., 1995; Littman and Walter, 1968; Wang et al., 1996], and vertical transmission has been reported from a mother with advanced AIDS [Sirinavin et al., 2004]. The mode of entry in humans is probably through inhalation or ingestion, and dissemination to the nervous system can follow. The most common cause of cryptococcal disease, Cryptococcus neoformans, is an encapsulated yeast found widely in the environment, particularly in bird feces and soil visited by birds (Figure 82-1). Cryptococcus gatti has been the cause of disease in animals and humans in British Columbia and the northwestern United States [Galanis et al., 2009], and appears to have a link to certain tree species in Australia and North America.
Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis
Cryptococcus most often causes a meningoencephalitis but can also cause brain abscess and cryptococcomas. Typical meningitis features, such as nausea, vomiting, headache, and fever, are often present. Caution is urged in ruling out the diagnosis based on history and physical examination alone because presenting symptoms may be nonspecific and a substantial number of patients are afebrile and lack meningeal signs [Sabetta and Andriole, 1985]. In AIDS patients, CNS cryptococcosis tends to be acute, with fever and headache in 70 percent; meningismus, photophobia, or mental status changes in 20–25 percent; and focal deficits in a small percentage [Daar and Meyer, 1992]. Despite this, a substantial minority of these patients may have initially normal CSF cell counts, glucose, and protein [Darras-Joly et al., 1996].
When C. neoformans causes mass lesions, it can result in papilledema, cranial neuropathies, and hemiparesis [Hung et al., 1995]. Brain abscess and cyptococcomas may begin with an indolent course, but hydrocephalus occurs and often necessitates shunting; if untreated, the mortality is high [Richardson et al., 1976]. Cryptococcus can be identified by culturing CSF on Sabouraud’s agar, but large-volume culture on more than one occasion may be needed. Latex agglutination detection of cryptococcal antigen is a rapid and useful adjunct test for both serum and CSF specimens. In the CSF, the antigen detection has an estimated sensitivity of 90 percent [Sabetta and Andriole, 1985]; both very high and very low antigen levels can give false-negative results. Since patients may have disseminated disease, C. neoformans can also frequently be cultured from urine or sputum, and the putative cause of CNS disease deduced. Cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans can reveal mass lesions and hydrocephalus.
Management
No pediatric-specific clinical treatment trials have been completed. The Infectious Disease Society of America (IDSA) recently published treatment guidelines and recommends an initial combination of amphotericin B and flucytosine for cryptococcal CNS disease in all age groups, regardless of HIV status [Perfect et al., 2010]. Oral fluconazole is recommended for both consolidation and long-term suppression therapy. All cases of CNS cryptococcal disease should be managed in consultation with an infectious disease specialist.
Coccidioidomycosis
Epidemiology, Microbiology, and Pathology
Coccidioidomycosis is caused by the fungus Coccidioides immitis, a dimorphic fungus that grows as either a mycelium or a unique structure called a spherule. Disease caused by C. immitis most commonly occurs in endemic areas of the southwestern United States, northern Mexico, and portions of Central and South America. The San Joaquin Valley in California is the most notorious endemic zone, giving rise to the term valley fever. Most infections occur during the dry season when spores are borne by dust. Most often, C. immitis infection is unnoticed or causes a self-limited respiratory tract infection; dissemination is uncommon, but the risk is higher in patients of Filipino, black, and Hispanic backgrounds [Einstein and Johnson, 1993], and in the setting of HIV infection, organ transplantation, or prolonged use of corticosteroids. Coccidioidomycosis is acquired by inhalation of spore-laden dust or transcutaneously after skin abrasion; it is not spread from person to person. Because most (60 percent) infections are asymptomatic or mildly symptomatic, reported cases represent only a small fraction of the total burden of disease. CNS infection in children is rarely reported.
The spectrum of neuropathologic change ranges from meningitis to meningoencephalitis and meningomyelitis with extensive parenchymal destruction, sometimes as a result of an associated endarteritis obliterans [Mischel and Vinters, 1995]. Parenchymal brain lesions are rare but may occur in the absence of meningitis [Banuelos et al., 1996].
Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis
Studies done on military recruits in the 1940s, using skin testing to diagnose acute infection, provided detailed data on infection in the normal host. Only 40 percent of these patients experienced acute respiratory symptoms [Smith et al., 1946], typically within 3 weeks after exposure and accompanied by fever, chills, night sweats, cough, anorexia, and weight loss. Dissemination of the infection from the pulmonary focus to distant sites usually occurs 1–6 months after primary infection in approximately 0.5 percent of cases; half of these are meningitis [Banuelos et al., 1996]. Other sites of dissemination include skin, lymph nodes, bones, and joints.
The clinical characteristics of coccidioidal meningitis are nonspecific and prompt diagnosis can be difficult [Caudill et al., 1970]. The most prevalent manifestations are headache, fever, malaise, and weight loss; meningismus may be absent [Saitoh et al., 2000]. Findings can include confusion, personality changes, focal neurological deficits, ataxia, obtundation, and coma. Brain and spinal cord abscesses can occur with or without concurrent meningitis [Banuelos et al., 1996]. Spinal cord symptoms may also occur in conjunction with coccidioidal osteomyelitis of the cervical vertebra [Jackson et al., 1964].
CSF abnormalities include mononuclear pleocytosis, increased protein content, increased chloride concentration, and normal or decreased glucose concentration. Diagnosis can be confirmed by either direct microscopy or culture of the CSF (Figure 82-2). Unfortunately, CSF cultures and microscopy are often negative in C. immitis meningitis, requiring indirect evidence of infection through serologic testing of serum and CSF. Complement fixation and precipitin tests are dependable and provide accurate diagnosis in more than 99 percent of patients with disseminated infection [Pappagianis, 1976]. Any discernible titer of complement fixation antibody in spinal fluid is considered diagnostic [Lyons and Andriole, 1986]. The coccidioidin skin test is not currently used for diagnosis of acute disease.
Imaging by CT or MRI scan may reveal widespread cisternal and cervical subarachnoid meningeal involvement in patients with coccidioidal meningitis [Wrobel et al., 1992], and may demonstrate the need for serial imaging to detect developing hydrocephalus.
Management
The 2008 IDSA guidelines for treatment of coccidioidal meningitis recommend fluconazole or itraconazole by mouth for all patients; intrathecal amphotericin was recommended by some clinicians but was graded C-III (poor evidence) by the IDSA [Ampel et al., 2009]. Fluconazole is well tolerated in both children and adults, and the oral form is highly bioavailable. Patients with C. immitis meningitis must be treated indefinitely with fluconazole to prevent relapse, and should be managed in conjunction with an infectious disease specialist.
North American Blastomycosis
Blastomycosis is caused by inhalation of airborne spores from Blastomycosis dermatitidis, a dimorphic fungus found in soil [Bradsher, 1996]. The endemic area includes the midwest, southeastern, and south central United States, and the Canadian provinces near the Great Lakes and St. Lawrence Seaway. The spectrum of clinical manifestations in adults includes pulmonary disease, acute and chronic skin disease, and disseminated disease involving the bones, the genitourinary tract, or the CNS; disseminated disease, and particularly CNS disease, is more common in those with compromised immune systems. Children are infrequently affected but suffer a similar spectrum of illness as adults [Schutze et al., 1996], and may be at increased risk if they play near beaver dams [Dismukes, 1986; Klein et al., 1986]. The three major CNS clinical manifestations are meningitis, intracranial mass, and spinal mass [Gonyea, 1978]. Patients with advanced HIV disease have accounted for an increase in cases compared with the past and are at greater risk for mortality [Witzig et al., 1994].
Diagnosis
In pulmonary disease, the organism can be identified on microscopy and culture of respiratory tract specimens. For CNS disease, ventricular and cisternal fluid may have a higher yield than lumbar CSF, which is rarely positive. Mass lesions are identified with neuroimaging [Ward et al., 1995]; microscopic study of biopsy material provides positive identification of the fungus. Skin tests and serologic tests are not helpful in the diagnosis of North American blastomycosis.
Management
Lipid formulations of amphotericin B for 4–6 weeks are recommended for moderate to severe disease [Chapman et al., 2008], followed by prolonged treatment with oral fluconazole, itraconazole, or voriconazole. Surgery may be indicated in patients with mass lesions, those with a need for a diagnostic biopsy, or those with osteomyelitis refractory to pharmacotherapy [Ward et al., 1995]. As with other CNS fungal diseases, co-management with an infectious disease specialist is recommended.
South American Blastomycosis
South American blastomycosis is caused by the fungus Paracoccidioides brasiliensis [Lutz, 1908]. The organism is a dimorphic fungal saprophyte found in soil and plants, which grows as a yeast at body temperature. Acquisition of disease is restricted to people living in latitudes between Mexico and Argentina, with most patients reported from Brazil. Most disease occurs in people older than the age of 30 years, with a striking male preponderance; among the rare childhood cases, the gender distribution is equal [Restrepo, 2000].
CNS involvement may follow disseminated infection; one review from Brazil found CNS involvement in 14 percent of symptomatic patients [de Almeida et al., 2004].
Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis
The most common findings in a series of 24 CNS cases included seizures, hemiparesis, cerebellar signs, and hydrocephalus [de Almeida et al., 2004]. CNS infection usually causes single or multiple mass lesions that appear hypodense and enhance on CT scan. The masses/abscesses may cause focal neurologic signs, increased intracranial pressure, and symptoms of meningeal inflammation.
The diagnosis of South American blastomycosis is suggested by simultaneous involvement of several organs or by characteristic oral and skin lesions in patients who reside in endemic areas. Microscopic study of scrapings from mucous lesions, sputum, gastric contents, lymph nodes, or surgical specimens is most helpful. The etiology of brain lesions must be deduced from culture results outside the CNS or via brain biopsy. CSF findings are typically normal, except for slightly elevated protein; CSF microscopy and culture are typically negative [de Almeida et al., 2004].
Management
Inadequate clinical trials have been completed to allow evidence-based treatment recommendations for CNS paracoccidioidal infection. Brazilian guidelines on treatment [Shikanai et al., 2006] are available in Portuguese and recommend that CNS infection be treated with trimethoprim-sulfamethoxazole at a high dose for at least 2 years; amphotericin B can be used for shorter periods. Voriconazole has been used for mild to moderate paracoccidioidomycosis but its role in CNS disease is unclear [de Almeida et al., 2004; Queiroz-Telles et al., 2007; Araujo et al., 1978].
Histoplasmosis
Epidemiology, Microbiology, and Pathology
Histoplasmosis is globally distributed; the Mississippi River basin, Mexico, and Central and South America are all endemic areas [Loosli, 1957]. In these regions, as many as 80 percent of children manifest positive histoplasmosis skin test results by age 5 years [Rogers, 1967]. In most cases, infection is self-limited, but an estimated 10 percent of those infected with Histoplasma capsulatum develop pulmonary symptoms to a degree prompting medical evaluation; those younger than the age of 2 years, the elderly, and those with immunocompromising conditions are more likely to be symptomatic. Overall, males are more likely to have symptomatic pulmonary disease, whereas the disseminated form of the disease affects males and females equally. Only a small subset of individuals with primary histoplasmosis develop disseminated disease, and an even smaller group develop a CNS infection. A review of 235 cases of histoplasmosis reported between 1952 and 1960 revealed that, of the one-third of the patients who had disseminated disease, one-quarter exhibited CNS impairment [Cooper and Goldstein, 1963]. In contrast, CNS disease was not found in a review of 57 histoplasmosis patients, including 23 with disseminated disease, at a pediatric oncology center in an endemic area [Adderson, 2004].
Histoplasma capsulatum is found in the Americas, and Histoplasma duboisii is found in Africa. This dimorphic fungus grows as a yeast at body temperature, whereas mycelia form at room temperature. The mycelia phase contains macroconidia (8–15 mm) and microconidia (2–5 mm); the latter may be essential for human infectivity because they are small enough to reach the alveoli. The organism is found in soil; dampness and nutrients from bird and bat droppings encourage growth in aviaries, chicken coops, mines, caves, and open fields [Ajello and Zeidberg, 1951]. During dry spells, the organism may become airborne and the spores inhaled. No evidence of person-to-person or animal-to-human transmission exists.
Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis
Most children with respiratory infection are asymptomatic or experience little difficulty [Ibach et al., 1954]. Fever, chills, and a productive cough can occur, and initial chest radiographs may document a nodular or diffuse infiltrate. Years later, chest radiographs demonstrate characteristic calcification in the central lymph nodes and peripheral lung fields. If untreated, the infection lasts 2–12 weeks.
Progressive disseminated histoplasmosis is rare in healthy children. Signs and symptoms associated with CNS involvement in children include intracranial hypertension, memory impairment, confusion, seizures, and urinary incontinence [Machado et al., 1993]. Reported CNS complications in children include hydrocephalus [Enarson et al., 1978], meningitis [Couch et al., 1978], ataxia, seizures, and cranial nerve palsy [Rivera et al., 1992]. Approximately 5 percent of adult patients with disseminated histoplasmosis will have CNS involvement [Borges et al., 1997], with a median time to diagnosis of 36 months [Machado et al., 1993].
The histoplasmin skin test converts to positive during the course of the acute infection, but this test is not used diagnostically. A 4-fold rise in complement fixation titers between acute and convalescent specimens or a single elevated titer in the correct clinical setting is diagnostic. A rise in complement fixation titers after treatment suggests relapse. The organism can be directly detected through culture of CSF, blood, and bone marrow, and through biopsy of liver, bone marrow, and lymph nodes. Histoplasma antigen can be detected in serum or urine [Wheat et al., 1986] and in some CSF specimens of patients with chronic Histoplasma meningitis, but its use for CNS disease is unreliable [Wheat et al., 1989].
All patients with disseminated histoplasmosis should be evaluated for adrenal insufficiency. In one series, half of the patients, regardless of treatment, had adrenal insufficiency, which was the most common cause of death [Sarosi et al., 1971]. Because Histoplasma can remain quiescent in the lungs or the adrenal glands for more than 40 years before dissemination, it needs to be considered in unexplained neurologic disease, particularly in people who lived in endemic areas as children [Tan et al., 1992].
Management
CNS infection in children should be treated sequentially with amphotericin B, followed by itraconazole, according to the 2007 IDSA guidelines [Wheat et al., 2007]. The prognosis of Histoplasma CNS infections is guarded: 20–40 percent of patients die, despite treatment, and relapse among survivors is common [Wheat et al., 2000].
Nocardia
Nocardia spp., Gram-positive, branching, filamentous bacteria, are ubiquitous in the environment; Nocardia asteroides, Nocardia farcinica, and Nocardia brasiliensis are the species most often responsible for clinical disease. Although this is a bacterial infection, it is included in this section because diagnosis may need to be sought specifically, and may require techniques different from those used to identify typical causes of bacterial CNS infection [Threlkeld and Hooper, 1997]. Nocardial disease during childhood is relatively uncommon but needs to be considered in immunologically compromised hosts and those with chronic lung disease. CNS infection may be isolated or found at the same time as pulmonary or disseminated infection [Beaman and Beaman, 1994]. In those with disseminated infection, CNS involvement should be viewed with concern because it is associated with mortality rates of 80 percent [Beaman and Beaman, 1994; Threlkeld and Hooper, 1997]. When CNS disease is the only manifestation of nocardiosis, it suggests that an inapparent pulmonary disease has resolved. Risk factors for pediatric CNS infections include malignancy, chronic granulomatous disease, lupus, HIV infection, organ transplantation, and surgery [Marlowe et al., 2000].
Brain abscess is the most frequently reported CNS manifestation of nocardial infection, but meningitis can occur, typically after rupture of an abscess and, more rarely, as the primary presentation [Al Soub et al., 2007]. Nocardia brain abscess presents with signs and symptoms typical for this syndrome, including fever, headache, seizure, and focal neurologic findings. Meningitis is often reported as having a subacute or chronic course [Bross and Gordon, 1991].
Diagnosis of Nocardia brain abscess may require a drainage procedure to obtain an adequate specimen for prolonged laboratory incubation to ensure growth on culture. A nocardial etiology of brain abscess or culture-negative meningitis is strongly suggested by concurrent isolation of this organism from a pulmonary site [Bross and Gordon, 1991].
Treatment of nocardial CNS infection requires multiple agents for prolonged periods. Susceptibility testing done at a reference laboratory can help guide initial therapy and provide options, if intolerance to initial therapy develops. Most Nocardia spp. are susceptible to trimethoprim-sulfamethoxazole, but treatment of CNS infection typically requires parenteral therapy with amikacin plus imipenem or ceftriaxone, with or without trimethoprim-sulfamethoxazole [Gilbert et al., 2004]. A review of antibiotic treatment for nocardial infections has been published [Threlkeld and Hooper, 1997]; most patients require at least 6 months of therapy, and the compromised host requires longer. Treatment composition and duration are based on expert opinion, since no controlled trials have been completed. Serial neuroimaging studies during treatment may be helpful in monitoring resolution of the abscesses [Kirmani et al., 1978]. In selected patients, surgical extirpation of multiple abscesses can be successfully accomplished [Rosenblum and Rosegay, 1979].
Actinomycosis
Epidemiology, Microbiology, and Pathology
Actinomyces spp. are anaerobic or microaerophilic, Gram-positive, non-spore forming, branching bacilli that normally colonize the mouth, intestine, and female genital tract. Invasive disease, usually caused by Actinomyces israelii, is most common in those of ages 10–60 years, with males more frequently affected than females. CNS disease in young children has not been reported [Olah et al., 2004], but risk factors for CNS disease in older children and adults include untreated focal infections, immunosuppression, and congenital heart disease with right-to-left shunts [Olah et al., 2004]. Although CNS disease is rare, it can occur either after direct extension from a contiguous focus or by hematogenous spread from another site.
Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis
Actinomycosis is a chronic, slow-growing, inflammatory mass, most frequently affecting the lungs, cervicofacial region, abdomen, and pelvis (in association with intrauterine devices) [Vinard et al., 1992; Winking et al., 1996]. The mass has a tough, fibrous capsule, does not respect tissue planes, and develops sinus tracts. Concurrent chronic infections and other debilitating conditions predispose patients to dissemination.
A review of 181 cases of actinomycosis revealed that less than 2 percent of patients had cerebral involvement, as manifested by abscess (solitary or multiple) and, less commonly, meningitis [Brown, 1973; Fetter et al., 1967; Winking et al., 1996]. Abscesses have been reported in the cerebrum, cerebellum, optic chiasm, parasellar region, and subdural space [Bebrova et al., 1994; Brown, 1973]. Osteomyelitis of the spine may be the origin of spinal cord abscess and compression [Fetter et al., 1967]. Neuroimaging demonstrates abscess easily, but microbiologic diagnosis of CNS disease can be challenging because the organism may be difficult to recover on culture if preceding antibiotics have been given. In addition, infections involving Actinomyces spp. are often polymicrobial, sometimes clouding the role of individual species. The etiology of CNS disease may be inferred if Actinomyces spp. are isolated at another site, particularly the lung.
Management
Recommendations for treatment of actinomycosis at any site are based on experience and in vitro susceptibility testing, rather than clinical trials. Standard recommended treatment for CNS disease is penicillin for at least 6 months. Recently, successful shorter courses of treatment with drugs other than penicillin, such as ceftriaxone and cefotaxime, for CNS disease have been reported [Olah et al., 2004; Sudhakar and Ross, 2004]. Surgical drainage of the abscess frequently is indicated [Jamjoom et al., 1994; Winking et al., 1996] and will speed definitive diagnosis of CNS disease.
Aspergillosis
Epidemiology, Microbiology, and Pathology
Like many fungal pathogens, Aspergillus spp. (Figure 82-3) initially gain entrance to the lung by inhalation. The name of this fungus was established because of the similarity of its fruiting head to the aspergillum, a perforated globe used to sprinkle holy water during religious ceremonies. Disseminated disease and CNS infection are nearly always accompanied by a serious underlying condition.
Aspergillosis of the CNS was rare until the population of immunocompromised hosts increased during the past two decades [Carpentier et al., 1996; Sparano et al., 1992; Torre Cisneros et al., 1993; Wright et al., 1993]. Among compromised hosts, the highest frequency of invasive aspergillosis is in heart and lung transplant recipients (19–26 percent), followed by those with chronic granulomatous disease (24–40 percent), acute leukemia (5–24 percent), bone marrow or hematopoietic stem cell recipients (0.5–9 percent), AIDS (0–12 percent), and solid organ transplant recipients (0.5–10 percent) [Denning, 1998]. CNS disease complicates 10–20 percent of invasive disease and is nearly universally accompanied by concurrent infection at other sites, typically the lung.
Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis
Other less common manifestations include meningitis, meningoencephalitis, hemorrhagic or ischemic necrosis, solitary granulomas, and invasive fungal arteritis [Torre Cisneros et al., 1993]. Highly immunocompromised patients may have altered mental status and seizures, whereas more competent hosts may have headache and focal complaints. In one series, the most frequent neurologic symptoms included altered mental status (86 percent), seizures (41 percent), and focal neurologic deficits (32 percent) [Torre Cisneros et al., 1993]. Neuroimaging may reveal sinus invasion, enhancing or nonenhancing hypodense brain lesions indicative of abscess [Sparano et al., 1992], or prominent ischemic lesions in the basal ganglia [Miaux et al., 1995]; concurrent chest radiography or CT scan usually shows multiple nodular lesions.
Definitive diagnosis of invasive Aspergillus is made by smear and culture of biopsy material. A presumptive diagnosis of CNS infection can be made if Aspergillus is identified from another site at the same time that neuroimaging shows multiple mass lesions. Serum galactomannan testing for invasive aspergillosis is available [Herbrecht et al., 2002] and provides a noninvasive alternative to support the diagnosis; however, published cutoffs of sensitivity and specificity are variable [Marr et al., 2004].
Management
Cerebral aspergillosis has a very poor prognosis, particularly in the immunocompromised host. Surgical drainage and removal of abscesses and granulomas are often performed for diagnostic and therapeutic reasons, but may not improve outcome [Casey et al., 1994; Haran and Chandy, 1993]. Case reports and one retrospective review suggest that a subset of patients will respond and some may be cured [Damaj et al., 2004; de Lastours et al., 2003; Schwartz and Thiel, 2004, 2009]. The 2009 IDSA guidelines for Aspergillus spp. infection of the CNS recommend voriconazole as the primary medical therapy, with itraconazole, posaconazole, and liposomal formulations of amphotericin B as alternatives in cases of intolerance. Appropriate surgical debridement of CNS and other sites, and minimization of immunosuppresion are also recommended, while the use of corticosteroids is discouraged.
Candidiasis
Candida spp. are the most common invasive fungal infections in infants and children [Arisoy et al., 1994]. Cerebral candidiasis is a rare sequela of disseminated disease in debilitated patients. Risk factors include prematurity, long-term receipt of broad-spectrum antibiotics, total parenteral nutrition, central venous catheterization, immunosuppression, immunodeficiency (congenital or acquired), chronic renal disease, diabetes, neutropenia, and ventriculoperitoneal shunts [Arisoy et al., 1994; Chiou et al., 1994; McAbee et al., 1995]. In a review from a large pediatric referral hospital, 12 percent of disseminated Candida infections affected the brain [Zaoutis et al., 2004]. Historically, Candida albicans has been the most common species identified in CNS disease, but many others, including Candida tropicalis, Candida glabrata, and Candida parapsilosis, are also frequently reported.
Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis
Meningitis is the most common manifestation of candidal CNS disease, but abscesses and granulomas occur independently and in combination with meningitis (Figure 82-4). When brain abscesses occur, they are typically multiple in number, illustrating the consequence of hematogenous dissemination [Incesu et al., 1994]. Intracerebral abscess after Candida septicemia is illustrated in Figure 82-4B. The clinical presentation of meningitis may be subtle in children because many patients have serious underlying illness and may have other concurrent infections. Mass lesions can cause hemiparesis, cranial nerve palsies, or signs of hydrocephalus [Coker and Beltran, 1988]. Fungal arterial and venous involvement can cause serious complications, as can the development of intracranial mycotic aneurysms [Goldman et al., 1979].
Diagnosis can be promptly confirmed by identification of the organism in spinal fluid or infected neural tissue [McGinnis, 1983]. Pleocytosis or reduced CSF glucose occurs in only about half of the patients who are culture-positive [Hughes, 1992].
Management
There are no comparative trials to permit definitive antifungal recommendations. Prompt speciation and susceptibility testing help optimize antifungal therapy. Recent IDSA guidelines for adults for C. albicans infection in the CNS recommend a liposomal formulation of amphotericin, with or without 5-flucytosine followed by fluconazole [Pappas et al., 2009]. Standard amphotericin deoxycholate may be acceptable in some young children, particularly neonates who are not routinely treated with 5-flucytosine. Consultation with an infectious disease specialist, regarding diagnosis, treatment, and follow-up, is recommended.
Zygomycosis
Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis
This invasive infection rarely, if ever, occurs in the normal host. Medical risk factors include diabetes mellitus, intravenous drug use, solid organ or bone marrow transplantation, and other immunocompromising conditions [Hussain et al., 1995]. Fever, facial and ocular pain, or CNS symptoms may herald the onset, and a black eschar-like plaque may be seen if sought in the oro- or nasopharynx. Etiology of CNS disease seen in MRI or CT imaging can be inferred from biopsy of nasopharyngeal or sinus specimens. Hyphae can be seen with conventional and special stains of biopsy material and are distinguished by their lack of septae, 90-degree branching, and breadth (10–20 μM).
Management
The prognosis for zygomycosis of the CNS is usually poor; however, several case reports describe survival in well-controlled diabetic patients treated with surgical debridement plus local and systemic administration of amphotericin B [Hamilton et al., 2003; Moll et al., 1994; Sandler et al., 1971]. Unfortunately, these organisms tend to infect and obstruct cranial blood vessels, and thus hamper drug delivery to affected tissue. General principles of management include correcting diabetic ketoacidosis if present, minimizing immunosuppressive therapy, and removing infected tissue surgically, often through extensive debridement, in addition to antifungal therapy [Cuadrado et al., 1988; Galetta et al., 1990; Hussain et al., 1995]. The most commonly recommended antifungal agents for zygomycosis are lipid-formulation amphotericin products at high doses. Although voriconazole is not active against zygmycosis, posaconazole is a potential alternative for initial or step-down therapy [van Burik et al., 2006]. Some authors have advocated less radical surgery combined with systemic and local (via Ommaya reservoir) amphotericin, augmented by hyperbaric oxygen therapy [Hamilton et al., 2003]. All cases should be managed by a joint medical-surgical team.
Scedosporium spp. Infection
Two species of Scedosporium environmental molds, prolificans and apiospermum (sexual state known as Pseudallescheria boydii), can cause a wide variety of human disease, including CNS infection [Cortez et al., 2008]. Risk groups include compromised hosts and survivors of near-drowning in polluted water. In a comprehensive review of 38 CNS cases, the youngest patient was 24 months old [Nesky et al., 2000].
Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis
Scedosporium spp. can cause skin, lung, bone, joint, ocular, bloodstream and CNS infections. Brain abscess is the typical CNS manifestation and can be solitary or multiple; meningitis occurs but is less common [Rosen et al., 1965; Bell and Myers, 1978; Cortez et al., 2008]. Definitive diagnosis is through brain biopsy, although culture of the organism from a nonsterile site can support the diagnosis. There are no available noninvasive or antigen detection tests. On microscopy, this organism can be confused with Aspergillus or Fusarium spp., but it is easily distinguished once cultured.
Management
The principles of therapy are similar to that for aspergillosis and zygomycosis, and include surgical resection of accessible brain abscesses, reduction or reversal of immunosuppression, and the use of antifungal agents. Unfortunately, these organisms are notoriously resistant to most agents, and most patients with CNS disease succumb. Recently, however, in vitro data and a small number of clinical reports support the efficacy of voriconazole, possibly in combination with other agents [Cortez et al., 2008; Nesky et al., 2000; Poza et al., 2000; Gosbell et al., 2003; Howden et al., 2003].
Rickettsial Diseases
Rickettsiae are pleomorphic coccobacilli that are obligate intracellular bacteria whose arthropod vectors include ticks, mites, fleas, or lice [Kim and Durack, 1997]. Rickettsial diseases include the spotted fevers, typhus fevers, scrub typhus, Q fever, and ehrlichioses [Marrie and Raoult, 1992; Pai et al., 1997]. Rickettsial infections often have an accompanying skin eruption. Coxiella burnetii, the rickettsia causing Q fever, differs from the other organisms because it does not require a vector and rarely causes a skin rash.
CNS involvement can occur in all forms of rickettsial infections [Marrie and Raoult, 1992]. Pathologic changes may be extensive and, in some infections, systemic and cerebral vasculitis may be prominent. The clinical and pathologic response of the CNS to different infections caused by Rickettsia spp. is generally similar and differs only in severity [Harrell, 1953; Woodward and Osterman, 1984]. Headache is often the earliest and most frequent symptom in all rickettsial infections [Harrell, 1953].
Recommended treatment of rickettsial diseases in almost all clinical situations includes tetracyclines. Most broad-spectrum antibiotics, such as penicillins, cephalosporins, and penems, are ineffective. Doxycycline is considered the drug of choice in almost all clinical situations for both pediatric and adult patients [Dalton et al., 1995; Kirkland et al., 1995]. The dosage is 100 mg twice per day for adults, and the pediatric dose is 4 mg/kg/day, divided twice daily, intravenously or orally, for 10–14 days [Schutze and Jacobs, 1997]. Because tetracyclines are contraindicated during pregnancy, chloramphenicol is used as an alternate drug in this patient population; however, this drug has questionable efficacy for patients with ehrlichiosis and Q fever [Markley et al., 1998]. Empiric treatment with doxycycline should be initiated early in the course if clinical and epidemiologic findings are suggestive of a rickettsial infection because delays in treatment can lead to adverse outcomes. Tetracycline use in pediatric patients is often discouraged because of the potential association with tooth discoloration. For suspected cases of rickettsial illnesses, however, it is important to use a tetracycline. Tetracycline tooth staining is dose-related and studies have found that perceptible tooth staining does not occur until multiple courses have been used [Grossman et al., 1971; Lochary et al., 1998].
Table 82-2 lists rickettsial diseases, organisms, vectors, reservoirs, and geographic distribution. Rocky Mountain spotted fever is the prototypic condition for these infections.
Rocky Mountain Spotted Fever
Rocky Mountain spotted fever (RMSF) is caused by Rickettsia rickettsii and is the most common fatal tick-borne illness in the United States [CDC, 2004]. Early missionaries and settlers discerned the association of tick bites with the disease and called the disease tick fever [Aikawa, 1966]. Howard Ricketts identified the etiologic organism in 1906 and established the tick as the vector in transmitting the organism to humans.
The disease is prevalent in wide geographic areas. RMSF has been reported throughout the United States, with the exception of Hawaii and Vermont [Walker, 1995]. The states with the highest incidence of RMSF are Oklahoma and North Carolina [CDC, 2008a]. In the United States, the number of RMSF cases has increased in recent years, with over 2000 cases a year reported in 2006 and 2007 – the highest recorded levels in more than 80 years [Walker et al., 2008; CDC, 2008b]. Outside the United States, the re-emergence of the disease has been described in several countries of Central and South America [Heldrich, 1987; Hidalgo et al., 2007; Nava et al., 2008]. In the Northern Hemisphere, the incidence of the disease is greatest from April to September, when tick bites are most likely to occur. The American dog tick (Dermacentor variabilis) is the primary vector responsible for the transmission of R. rickettsii along the southern Atlantic coast and the southeastern and south-central United States. In the western region of the United States, the vector is usually the wood tick (Dermacentor andersoni; Figure 82-5). Given the habitat preferences of the vector, rural and suburban populations are more likely to be infected than urban residents.
Children have a higher risk of infection (half of the cases are younger than 19 years of age [Kamper, 1991]) because they are exposed to tick bites during outdoor play. RMSF should be considered in the differential diagnosis of anyone with compatible clinical features and exposure to a grassy or wooded area where ticks may be present [Walker, 1995]. Dogs may carry ticks into households and yards, and are a risk factor for infection [Paddock et al., 2002; Walker, 1995]. The absence of a reported tick bite history should not dissuade a clinician from suspecting RMSF. In a recent study of 92 children with RMSF, only 49 percent recalled a recent tick bite [Buckingham et al., 2007].
The incubation period ranges from 2 to 14 days (mean 7 days) after a tick bite [Thorner et al., 1998]. Transmission of rickettsiae occurs as a tick feeds on the blood of its host. After entering the body, rickettsiae multiply and disrupt the endothelial cells of capillaries and arterioles. Vasculitis is the pathologic hallmark of RMSF, and many of the clinical features are a result of vascular inflammation. In RMSF, the rickettsiae may also infect the smooth muscle cells of the tunica media. Loss of integrity of the small vessels in the brain results in hemorrhage into the subarachnoid space. Subsequent meningeal irritation and an accompanying perivascular mononuclear infiltrate develop. The brain parenchyma is studded with areas of microscopic infarctions. In the healing phase, a proliferative fibroblastic and gliotic response is evident; the ensuing focal nodules develop more often in white matter in spotted fever and more often in gray matter in typhus.
Clinical Characteristics, Clinical Laboratory Tests, and Diagnosis
Symptoms of RMSF vary in severity from mild to severe; the course may rapidly lead to death. RMSF is characterized by the classic triad of fever, headache, and rash in the setting of a recent tick bite. Most patients with RMSF, however, do not present with the classic triad. Initial symptoms are nonspecific and include fever, malaise, lethargy, and headache. The headache is usually intense and refractory to most analgesics. Progressive restlessness, irritability, confusion, and delirium may also occur. By day 5 of the illness, 85 percent of patients develop a rash. The rash often begins with a maculopapular appearance and becomes more defined as petechiae as the rash evolves. The rash often begins around the ankles or wrists and then spreads to other parts of the body (Figure 82-6). Acute renal failure, coagulopathy, and cerebral edema are well-recognized complications. Edema, usually periorbital at first and then generalized, is characteristic of and may suggest the diagnosis. Hepatosplenomegaly accompanied by liver dysfunction, including coagulation defects, may confound the diagnostic process. In fulminating disease, shock, coma, and general or focal neurologic impairment, including vertigo, seizures, hemiparesis, and ataxia, may dominate the clinical manifestations [Marrie and Raoult, 1992]. Skin necrosis and gangrene can be a late complication (Figure 82-7). RMSF may manifest as a skeletal muscle disease. Acute temporary hearing impairment has been described, but permanent auditory disruption is uncommon [Kelsey, 1979]. Ophthalmic features in all rickettsial disorders are virtually identical [Raab et al., 1969; Smith and Burton, 1977], and may include photophobia, conjunctivitis, petechiae on the bulbar conjunctiva, exudates and retinal venous engorgement, papilledema, and ocular palsies.
Fig. 82-6 Petechial rash of Rocky Mountain spotted fever involving the ankle.
(Courtesy of Dr. Daniel J Sexton.)
Fig. 82-7 Necrosis and gangrene of digits is a late complication of Rocky Mountain spotted fever.
(Courtesy Dr. Daniel J Sexton.)
The differential diagnosis of RMSF includes meningococcemia, enteroviral infection, scarlet fever, toxic shock syndrome, Kawasaki disease, Epstein–Barr virus, syphilis, typhoid, rat-bite fever, and other tick-borne diseases. Muscle biopsy reveals perivascular infiltrates of chronic inflammatory cells and focal chronic interstitial myositis [Krober, 1978]. Other organs, including kidneys, heart, lungs, spleen, and epididymis, may also be affected [Green et al., 1978]. Muscle weakness may be overwhelming; therefore, Guillain–Barré syndrome, viral myositis, and collagen disease may be erroneously diagnosed (although a case of Guillain–Barré syndrome associated with RMSF has been documented [Toerner et al., 1996]).
Laboratory abnormalities are common in severe disease and often include hyponatremia and thrombocytopenia. Spinal fluid may indicate a lymphocytic pleocytosis and the protein is elevated in about 30–50 percent of patients [Kim and Durack, 1997]. The cellular response in CSF may suggest bacterial meningitis, and the dermal petechiae may mimic those in meningococcemia. MRI of the brain reveals increased signal intensity in the distribution of perivascular spaces, which resolves in relation to clinical improvement [Baganz et al., 1995]. Postmortem examination of RMSF cases has demonstrated that rickettsial vasculitis can result in focal neurologic damage in the brain and spinal cord, as well as myocarditis and vasculitis in the lungs, kidney, and spleen [Walker and Mattern, 1980].
The most widely used and best serologic test for RMSF is the indirect fluorescent antibody assay, which is available through commercial laboratories and most state health departments [Lochary et al., 1998; Sexton and Kaye, 2002]. Immunofluorescent antibody for immunoglobulin M or immunoglobulin G antibodies can be used to make a presumptive diagnosis of acute infection, although these antibodies are often undetectable in the early phase of the illness. Confirmatory indirect fluorescent antibody testing requires demonstration of a 4-fold or greater rise in immunoglobulin G or immunoglobulin M antibody titer between paired serum specimens, and is generally considered as a retrospective diagnosis [Thorner et al., 1998]. Direct immunofluorescence antibody or immunohistochemical staining of skin biopsies is 70–90 percent sensitive for patients with a rash. For patients without a rash, diagnosis by direct immunofluorescence antibody can be problematic. Polymerase chain reaction testing for R. rickettsii DNA can be applied to serum, whole blood, or tissue specimens, but is generally available only at specialized research laboratories, and the sensitivity of the assay is directly related to the severity of the illness [Sexton et al., 1994].
Management
Early therapy with doxycycline for at least 7 days is recommended. The case fatality is 2–10 percent in treated patients and may be as high as 30 percent in untreated patients [Dalton et al., 1995]. Serologic confirmation may be delayed for 2–3 weeks; therefore, therapy should be administered when the diagnosis is suspected, based on clinical and epidemiologic findings. A history of tick bite is a useful epidemiologic clue in making a presumptive diagnosis. With early treatment, the prognosis for full recovery from RMSF is excellent. Neurologic sequelae may occur when therapy is postponed [Miller and Price, 1972]; mild intellectual impairment has been described [Wright, 1972].
Typhus Fever Group
The typhus fever group consists of epidemic (louse-borne typhus), Brill–Zinsser disease, and murine (flea-borne) typhus. Louse-borne typhus fever, caused by Rickettsia prowazekii, is distributed worldwide. Epidemics of typhus fever occur by transmission from human to louse to human, typically after skin is rubbed that is contaminated with infective louse feces. Epidemics of typhus fever are often associated with war, movements of large numbers of people, and squalid living conditions [Zinsser, 1935]. Systemic and neurologic symptoms are similar to RMSF (see above). A severe headache is almost always present. More severe CNS features, such as neck stiffness, seizures, delirium, and coma, can also occur. Treatment (e.g., with doxycycline) is the same as that used for the spotted fever group of infections.
Brill–Zinsser disease is a relapsing form of louse-borne typhus that may occur years to decades after the primary attack [Feigin et al., 1992]. Presumably, the rickettsiae remain dormant in the reticuloendothelial system until a subsequent reactivation occurs. Symptoms are similar to the primary attack, although generally milder, and doxycycline is the recommended therapy.
Murine, or flea-borne typhus, caused by Rickettsia typhi, is one of the most prevalent rickettsial diseases found in humans throughout the world [Azad, 1990]. Before World War II, murine typhus was widespread in the United States, and approximately 42,000 cases were reported between 1931 and 1946 [Azad, 1990; Pratt, 1958]. During the Vietnam War, murine typhus [Miller and Beeson, 1946] was one of the most common causes of acute febrile illness in American military personnel [Berman and Kundin, 1973]. Currently, endemic foci often exist around port cities and adjacent coastal areas [Azad, 1990; Civen and Ngo, 2008]. R. typhi is transmitted from rat to rat by the rat flea. In addition to rats, many animals, such as other rodents, skunks, opossums, shrews, and cats, can serve as hosts for R. typhi and arthropod vectors. Rickettsia felis causes a recently described rickettsial infection with similar clinical manifestations. The life cycle of R. felis is through opossums, cats, and cat fleas; infection has been identified in southern California and Texas [Civen and Ngo, 2008]. Human infection occurs after exposure of abraded or flea-bitten skin to infective flea feces [Feigin et al., 1992]. Unlike many other arthropod-borne infections, murine typhus can be acquired in households because the transmission cycle includes commensal rats and fleas [Azad, 1990]. Symptoms of murine typhus are similar to but generally milder than those occurring in RMSF. R. typhi infections are likely underdiagnosed because the clinical and laboratory features are similar to viral infections. The illness is often characterized by fever (frequently prolonged), headache, myalgia, and sometimes a maculopapular or petechial rash [Gelston and Jones, 1977]. Lymphadenopathy was reported as a common manifestation in a study in children [Bitsori et al., 2002]. When present, the rash often occurs on the trunk. The infection may resemble Kawasaki’s disease [Bitsori et al., 2002]. There is considerable variability in the frequency of reports of neurologic manifestations of murine typhus, ranging from 2 to 20 percent of cases [Allen and Saitz, 1945; Bitsori et al., 2002]. Meningitis and encephalitis are occasionally reported [Bitsori et al., 2002; Galanakis et al., 2002; Gelston and Jones, 1977]. Less commonly, focal symptoms, such as papilledema, focal seizure, and hemiparesis, have also been described [Masalha et al., 1998]. Sensorineural hearing loss has been reported during the convalescent phase of the illness [Tsiachris et al., 2008]. Diagnostic evaluation and treatment are similar to other diseases of the typhus group.
Scrub Typhus
Scrub typhus, caused by Orientia tsutsugamushi, is a systemic illness that causes a generalized vasculitis [Pai et al., 1997]. O. tsutsugamushi was formerly a member of the spotted fever group of Rickettsia spp., but was placed in its own genus based on molecular phylogenetic studies [Tamura et al., 1995]. Trombiculid (chigger) mites serve as reservoirs and vectors of this disease, and human infection occurs after a chigger bite in endemic areas, primarily in the southwest Pacific and Southeast Asia [Feigin et al., 1992]. An eschar, a characteristic feature of the disease, is seen in 60–80 percent of cases [Jelinek and Loscher, 2001] (Figure 82-8). Fever, headache, and rash are also common clinical manifestations. Complications include renal failure, pneumonitis, acute respiratory distress syndrome, and myocarditis. CNS complications include meningitis or meningoencephalitis. Case series have reported varying occurrence/frequencies of meningoencephalitis ranging from 3 to 20 percent [Fang et al., 1997; Pai et al., 1997; Huang et al., 2009]. Other less commonly reported neurologic complications include acute disseminated encephalomyelitis (ADEM), Guillain–Barré syndrome, brachial plexus neuropathy, and acute sensorineural hearing loss [Chen et al., 2006; Lee et al., 2009; Ting et al., 1992; Kang et al., 2009]. Approximately 50 percent of patients will have a mild CSF monocytic pleocytosis or an increase in protein concentration [Pai et al., 1997]. Doxycycline is considered the most effective treatment.
Q Fever
Q fever, caused by Coxiella burnetii, is a worldwide zoonosis. Infection in humans occurs from inhalation of the organism in areas where infected livestock are kept and, on occasion, from ingestion of contaminated dairy products. Occasional outbreaks in research laboratories that use sheep or cattle have also been reported [Feigin et al., 1992]. Prominent symptoms include fever, headache, and pneumonia. A rash rarely, if ever, occurs. Cases of encephalitis have been reported to accompany Q fever and may occur late in the course [Maurin and Raoult, 1999]. Other reported neurologic manifestations have been described, and these include pseudotumor cerebri syndrome, myelitis, meningitis, hemiparesis, aphasia, ataxia, seizures, tinnitus, cranial nerve palsies, and behavioral abnormalities [Ravid et al., 2008; Bernit et al., 2002; Glaser et al., 2010]. The reported frequencies of neurologic symptoms associated with Q fever vary considerably, ranging from 2 to 22 percent [Clark et al., 1951; Bernit et al., 2002].
Other Rickettsiae
Several new rickettsiae have been described since the early 1990s: Rickettsia japonica in Japan and Korea, Rickettsia honei in Australia and Southeast Asia, Rickettsia africae in Africa and the French West Indies, the Rickettsia mongolotimonae strain in Asia, Europe, and Africa, Rickettsia slovaca in Europe, Rickettsia aeschlimannii in Africa and Europe, Rickettsia heilongjanghensis in Asia, and Rickettsia parkeri in the United States [Raoult, 2004; Walker, 2007]. The extent of neurologic involvement with these emerging infections is unknown.
Ehrlichiosis
Emerging infections, akin to those caused by other rickettsial agents, have been increasingly reported in recent years [Walker et al., 1996].
The term ehrlichiosis was initially used to describe veterinary infections with Rickettsia-like bacteria that infected leukocytes. Human infection with Ehrlichia in the United States was first identified in a 51-year-old male with a history of a tick bite, fever, leukopenia, thrombocytopenia, and elevated liver enzymes [Maeda et al., 1987]. The patient was originally diagnosed with RMSF (see above). Cytoplasmic inclusions were observed in peripheral lymphocytes, and the patient was subsequently diagnosed with an Ehrlichia infection (E. chaffeensis) species. Since then, two additional Ehrlichia species have been recognized: Ehrlichia ewingii and Anaplasma (formerly Ehrlichia) phagocytophilum.
Ehrlichia are obligate intracellular bacteria and belong to the family Rickettsiaceae. All Ehrlichia are transmitted by ticks, and the interval from tick exposure to onset of illness is between 2 and 21 days [Harkess, 1991]. E. chaffeensis
