Central Nervous System Infections in Immunocompromised Hosts
The pool of patients with underlying conditions associated with immune compromise is continuously expanding. Improved medical management of malignancies and chronic illnesses and the extensive use of immunosuppressive medications has led to a dramatic increase in the need to treat this patient population.
Immune dysfunction is characterized by the emergence of infections with opportunistic microorganisms that under normal conditions are less virulent and that exploit this breach in immunocompetence.
The unique characteristics of dysfunction in a specific arm of this multi-component immune system generates a unique pattern of susceptibility to a specific class of pathogens. Patients with defects in antibody or complement function more often have infections with pyogenic encapsulated bacteria, whereas those with deficient cell–mediated immune deficiency are more susceptible to fungal, viral, mycobacterial, and protozoal infections. This principle is clearly illustrated in primary immunodeficiency states that stem from genetic abnormalities selectively affecting specific arms of the immune system. For example, in chronic granulomatous disease and in Chédiak-Higashi syndrome, there is a selective abnormality of phagocytosis. The infectious agents affecting these patients differ from those seen in patients with another genetic disorder, severe combined immunodeficiency (SCID), in which T-lymphocyte abnormalities damage both the humoral and cell-mediated arms of the immune system.
In secondary immunodeficiency states, a primary illness or the treatment of an illness results in immunosuppression. This category includes human immunodeficiency virus (HIV) infection, cancer, and the use of corticosteroids or immunosuppressive medications to treat patients with conditions like collagen vascular diseases and the recipients of organ transplants. Again, the mechanism of immunosuppressive action of these drugs will affect the type of infections that can arise.1 In the growing group of patients with malignancies, there is usually interplay between several factors: the effects of the primary disease, myelosuppression from chemotherapy, and at times corticosteroid-induced immune dysfunction, each of them contributing to the overall immune dysfunction.
Central nervous system (CNS) infections in immunocompromised patients cause considerable morbidity and mortality. The CNS resides in a unique environment that affects the pathogenesis of infections. The brain is protected from infection by the calvaria and meninges, which serve as a mechanical barrier, and also by the chemical and mechanical filtering capabilities of the blood–brain barrier. However, the composition of the CSF makes it an excellent culture medium. In addition, the brain and subarachnoid space are considered immunologically sequestered because of the absence of lymphatics.2
The clinical manifestations of CNS infections in the immunocompromised host can reflect cerebral parenchymal and/or leptomeningeal involvement. With localized involvement in the form of solid mass lesions (abscesses, granulomas, or cysts) or more localized encephalitis, a clinical picture of focal neurologic deficits is expected to predominate. Brain abscesses in immunocompromised patients (as opposed to those in the general population) are caused more frequently by nonpyogenic microorganisms, such as fungi, protozoa, and mycobacteria. Meningeal or ependymal involvement will induce more generalized neurologic dysfunction, manifested by headache, photophobia, seizures, reduced level of consciousness, or other signs of elevated intracranial pressure (papilledema, sixth cranial nerve palsy).3 In addition to the characteristic infectious profile that emerges, immunosuppression can alter the host response to the offending agents, thus obscuring diagnostic clues. Investigation for the presence of infection should therefore be diligently pursued in the appropriate setting of progressive neurologic dysfunction.4
Principles of Treatment
As patterns of infection are relatively defined in many subgroups of the immunocompromised population, prophylactic measures play a major role in disease prevention. The treatment of invasive infections in immunocompromised hosts is primarily pharmacologic. Definitive culture is ideal, but this can be time- and resource-consuming. Considering the high morbidity and mortality rates in immunocompromised patients with infectious diseases and the dire consequences of delaying therapy, empiric treatment is frequently considered the standard of care.
With CNS involvement, the management of discrete CNS space-occupying lesions is directed by several principles:
The need to obtain tissue samples for prompt and definite diagnosis
Reduction of the size of the lesion to enhance treatment efficacy
When needed, alleviation of mass effect
Stereotactic or image-guided needle biopsy is a minimally invasive method of establishing a definite diagnosis and allows the institution of appropriate treatment. This surgical technique is especially well suited for deep-seated lesions, such as those in the brainstem or hypothalamus. An open surgical excision is an appropriate option for large, accessible lesions with multiple loculi that cause brain herniation and also for those that do not respond to aspiration.
This chapter focuses on CNS infections in immunocompromised patients from a neurosurgical perspective. First, the causative fungal, protozoal, bacterial, and viral microorganisms causing intraparenchymal masses or cerebritis are reviewed. A patient-oriented perspective follows, in which issues relevant to specific underlying causes of immunodeficiency (HIV infection and organ transplant) are addressed.
Fungal Infections
Fungi are ubiquitous in the environment and exist as yeast, molds, and dimorphic forms. Fungal exposure occurs mostly through inhalation, ingestion, or direct contact. Although invasive fungal infections do occur in immunocompetent patients (primary mycoses, mostly in endemic regions and by trauma-induced inoculations), they are far more prevalent and considerably more life-threatening in immunocompromised patients, and they occur predominantly when the underlying cause of immunodeficiency is cell-mediated immune dysfunction. Fungi can reach the CNS by hematogenous dissemination from the primary site of inoculation or by direct spread from a contiguous site of infection (nasal sinusitis, osteomyelitis, after surgical procedures, and following the introduction of foreign bodies like indwelling catheters). Clinical syndromes associated with CNS fungal infections depend on the pathologic reaction elicited by the fungus. The three cardinal manifestations of fungal infection are meningitis, the formation of mass lesions (abscesses or granulomas) in the brain, and brain infarction. Meningitis has been reported in almost two-thirds of subjects with CNS fungal infections and is caused mostly by small yeastlike forms (Candida and Cryptococcus). These organisms reach the arterioles and capillaries to produce subpial ischemic lesions. From there, spread to the subarachnoid space occurs, causing meningitis. In this setting, in addition to the signs of meningeal irritation, increased intracranial pressure can develop. Space-occupying lesions are predominantly caused by molds (filamentous fungi). When brain abscesses are formed, signs and symptoms of focal neurologic dysfunction will predominate. Rarely, fungal infections can lead to granuloma formation.5 Large hyphal forms, such as Aspergillus and Zygomycetes, can invade and obstruct large and intermediate-size arteries to cause brain infarction and strokelike symptoms.6,7 The incidence of CNS fungal infections seems to be underestimated because of their nonspecific clinical presentations and the insufficient diagnostic work-up that these patients sometimes undergo.8
Treatment
The treatment of invasive fungal infections is primarily pharmacologic. The extensive use of antifungal medications, either for treatment or for prophylaxis, has resulted in the emergence of new, previously less encountered causative agents. The resistance of these pathogens to conventional treatment poses new challenges. Thus, diagnosis by culture with identification of susceptibility patterns should be accomplished whenever possible.9 The approach to any space-occupying lesion is directed by the aforementioned principles of care.
Aspergillosis
Aspergillus, a mold with septate hyphae, is clinically the most important fungal pathogen. Of the more than 100 Aspergillus species that are known, the most virulent pathogen is A. fumigatus, although infections occur also with A. niger, A. flavus, and A. terreus.
Aerosolized spores usually gain entry to the CNS through the sinopulmonary system. Invasive aspergillosis develops mostly in hosts with neutrophil- or T-cell–mediated dysfunction, including bone marrow, stem cell, or solid organ transplant recipients; those treated with high-dose corticosteroids; and those with hematologic malignancies, liver disease, or sarcoid.9 Patients with HIV-associated aspergillosis typically have CD4+ cell counts below 100/µL and a history of other acquired immunodeficiency syndrome (AIDS)–defining opportunistic infections, and they typically are not receiving highly active antiretroviral therapy (HAART).
Aspergillus is an angioinvasive mold, and CNS seeding typically occurs after hematogenous dissemination from a pulmonary site. Additionally, direct spread from the primary site of infection may occur: from the nasal sinuses to the adjacent frontal and temporal lobes, by extension of an ear infection, or by invasion of the thoracic vertebrae and eventually the spinal epidural space. CNS involvement is diagnosed in 10 to 20% of patients with systemic dissemination; however, it is discovered at autopsy in as many as 44 to 94% of cases.10
Cerebral aspergillosis frequently causes single or multiple brain abscesses and rarely granulomas. Aspergillus granulomas are characterized by abundant fibrosis, an ill-defined epithelioid granuloma, and many foreign body and Langhans-type giant cells. Uncommonly, basal meningitis, dural abscesses, mycotic aneurysms, and multifocal cerebritis can occur. Carotid artery invasion can cause cerebral ischemia or hemorrhagic infarction. Pulmonary infections extending to thoracic vertebrae and the epidural space are capable of causing spinal cord compression and myelitis.
The clinical presentation of Aspergillus infection is nonspecific. This type of infection should be suspected with the development of facial pain, fever, headache, altered mental status, seizures, or focal neurologic deficits, but severely immunocompromised patients are less likely to develop symptoms. Orbital infiltration is suspected with periorbital pain, proptosis, blurred vision, or diplopia. Strokelike syndromes can develop, especially if the internal carotid artery is involved.6 With case-fatality rates in CNS aspergillosis reported to be as high as 88%, the prompt diagnosis of invasive aspergillosis is crucial, but difficult.11
The radiologic appearance of cerebral aspergillosis is variable, showing regions of edema, hemorrhage, infarction (which can be poorly defined with minimal mass effect), or focal reticular or ring-enhancing mass lesions.12 Standard CSF analysis is generally nondiagnostic and cultures are almost always negative, but recently developed serologic methods hold promise for early diagnosis. These tests rely on the detection of cell wall components, galactomannan, and 1,3-β-D-glucan in serum or CSF. Galactomannan has an overall reported sensitivity of 71% and specificity of 89% for Aspergillus infections. Additionally, the usefulness of a variety of molecular polymerase chain reaction (PCR) tests is being investigated.13
Pharmacologic Treatment
The recommended treatment for invasive aspergillosis in patients without HIV infection is voriconazole. Amphotericin B deoxycholate and lipid-formulation amphotericin B are alternatives.9 Unfortunately, with the increasing use of voriconazole for prophylaxis, the empiric, preemptive, and targeted treatment of invasive aspergillosis has resulted in an increase in the incidence of voriconazole-resistant zygomycosis. More recently, a combination of therapeutic approaches has been explored.14,15
Zygomycosis
Zygomycetes are filamentous fungi with nonseptate branching hyphae. These microorganisms are ubiquitous saprophytes found in soil, plants, and decaying food. The three orders in this category are Mucorales (including the genera Mucor, Rhizopus, and Rhizomucor), Cunninghamella, and Absidia.6
Epidemiology and Clinical Manifestations
Mucormycosis is the second most common mycosis caused by molds and is especially known to infect patients with poorly controlled diabetes mellitus, although another population at high risk comprises patients with hematologic malignancies.16,17 Additionally, recipients of bone marrow transplants, patients with prolonged neutropenia or renal disease, and those receiving corticosteroid therapy are susceptible to infection. High glucose levels in patients with poorly controlled diabetes reduce the binding of iron to transferrin. The increased levels of free iron promote an accelerated growth of the fungus.
The major mode of infection is by inhalation. Mucor organisms then lodge in the lungs or sinuses to establish the primary site of infection. Among intravenous drug users, hematogenous transmission can occur. The clinical spectrum of CNS involvement can be part of a fulminant, disseminated disease or occur as an isolated cerebral or rhinocerebral mucormycosis. Rhinocerebral mucormycosis most often develops by direct spread from the paranasal sinuses to adjacent structures, which include the palate, face, and orbit. Cerebral infection often occurs after direct extension from the ethmoid sinus through the meninges or via a perineural route. Mucormycosis, like aspergillosis, has a tendency to invade blood vessels and cause tissue necrosis or serve as a vehicle for further propagation of the infection.18
Patients with rhinocerebral mucormycosis present with headache or facial pain that is often localized to the frontal or retro-orbital regions. A dark sinus discharge occurs, and necrotic tissue can be seen as a black eschar. Intracranial involvement can lead to cranial nerve palsies, acute motor or sensory deficits from infarction caused by major arterial thrombosis, lethargy and seizures.19 Orbital cellulitis, together with proptosis, ophthalmoplegia, and visual impairment, signifies intraorbital or cavernous sinus involvement and represents a medical emergency.6
Diagnosis
CSF analysis results are usually nonspecific. The growth of Zygomycetes organisms in blood cultures or tissue exudate is rare. Core tissue samples are preferable but nondiagnostic in 40% of the cases. Computed tomography (CT) and especially magnetic resonance (MR) imaging of the brain are quite sensitive for the diagnosis of mucormycosis. The MR signal intensity of Mucor species lesions tends to be isointense or hypointense on all sequences. After the administration of gadolinium, the lesions have variable enhancement patterns ranging from homogeneous to heterogeneous or have no enhancement. MR imaging can also clearly demonstrate cavernous sinus and dural involvement.20,21
MR spectroscopy shows markedly elevated lactate, depleted N-acetyl aspartate, and metabolite resonance attributable to succinate and acetate, which is essentially the same as that of pyogenic bacterial abscess without the commonly seen elevations of amino acids valine, leucine, and isoleucine.22
Treatment
Disseminated mucormycosis with CNS involvement has a 98% mortality rate. For localized cerebral or rhinocerebral disease, the mortality can reach 62%. Appropriate drug therapy together with aggressive surgical débridement of tissue and treatment of underlying risk factors provides the best chance for a good outcome.16,17
Primary (Endemic) Mycoses
These fungi are endemic in certain geographic locations and affect primarily immunocompetent individuals. In individuals with immunosuppression, the disease has a very high probability of becoming disseminated from the primary site, which is usually the respiratory system, to reach the CNS and cause severe debilitation. Additionally, under these conditions, clinically evident disease can reflect reactivation of a dormant past infection. Aside from meningitis, which is the most common presentation, brain abscesses and granulomas can appear, causing mass effect and localized signs.6,9
Coccidioidomycosis
There are two species of the dimorphic fungus Coccidioides. C. immitis is endemic in California, and C. posadasii is endemic in northern Mexico, the southwestern United States (California and Arizona), Central America, and South America. The two species cause clinically indistinguishable disease. They are abundant in soil, and primary pulmonary infection results primarily after outdoor exposure. In immunocompetent hosts, the infection can be clinically silent. When it is evident, signs and symptoms suggest mild respiratory involvement. On the other hand, in immunocompromised patients with deficient cellular immunity, the rate of disseminated disease is as high as 22%.
Disseminated disease mostly involves the skin, joints, bones, and spleen, but approximately 50% of patients will have meningeal involvement. In some cases, subclinical, chronic meningitis will develop, only to become manifest clinically after a delayed period of weeks to months.
With meningitis, headache, fever, nausea and vomiting, nuchal rigidity, seizures, and papilledema can be present. Hydrocephalus will develop in approximately 50% of patients. CNS infection can progress infrequently to the development of a compressive space-occupying lesion, such as brain abscess or granuloma.
Diagnosis and Treatment
Although CSF analysis will show nonspecific biochemical changes compatible with meningitis and lymphocytic pleocytosis, the presence of eosinophilia is highly suggestive of Coccidioides infection. Cultures will be positive in approximately 50% of cases. The diagnosis can be made by examining skin biopsies or by serologic tests. In the past, intrathecal amphotericin B was used. Amphotericin B has been replaced by fluconazole as the drug of choice. Those responding to therapy remain on lifelong treatment because of the high relapse rate.9
Histoplasmosis
Histoplasma capsulatum, a dimorphic fungus, is the only species of the genus Histoplasma. H. capsulatum var. capsulatum is associated with North American histoplasmosis. The organism is found in bird droppings and bat guano, and in the United States it is endemic in the states bordering the Ohio and lower Mississippi River valleys. Primary infection involves the respiratory system. Although disseminated histoplasmosis is rare, it develops after infection in as many as 80% of immunocompromised patients. Most reports are from patients with HIV infection and lymphoma. CNS involvement occurs in 5 to 20% of those with disseminated disease but can occur in isolation. The clinical spectrum of disease is chronic meningitis with the development of hydrocephalus, or less commonly focal parenchymal mass lesions or strokes due to emboli.
Diagnosis and Treatment
With the exception of patients with HIV infection, serologic antibody tests in immunocompromised patients are of little value. The diagnosis can be made by detecting the antigen in serum, urine, or CSF samples. Additionally, the fungus can be cultured from sputum or blood. The treatment of choice for CNS histoplasmosis is amphotericin B.9
Blastomycosis
The dimorphic fungus Blastomyces is endemic in the southeastern and central southern United States, the Great Lakes region of Canada and the bordering Midwestern states, and an area along the Saint Lawrence River in New York and Canada. The lungs are the primary site from which disseminated disease can evolve. In 6 to 35% of those with disseminated disease, there is CNS involvement. In immunocompromised patients, the risk for CNS spread is considerably higher. CNS seeding can result in either meningitis or brain mass lesions (including abscesses). Additionally, spinal epidural abscesses can develop by direct extension from infected vertebrae.
Diagnosis and Treatment
Serology is usually noninformative, but the fungus can be isolated directly from infected tissue specimens or from CSF samples if a lesion is based in the dura. Amphotericin B is the drug of choice for treatment.9 Effective surgical resection has been reported in small series.
Candidiasis
Candida species (primarily C. albicans) are opportunistic yeasts. They are a major cause of bloodstream infections, especially in surgical and critical care hospital settings. Immunodeficiency, especially phagocyte dysfunction, predisposes patients to both systemic candidiasis and CNS involvement.16 Candida CNS infections are reported in 18 to 25% of those with disseminated disease and are likely underdiagnosed. Infection can develop in patients with diabetes or cancer, organ transplant recipients, those receiving cytotoxic or prolonged corticosteroid therapies, and patients who have undergone invasive procedures. From an immunologic perspective, patients with HIV infection are not at higher risk for infection because their defective cellular immunity is due to T-lymphocyte dysfunction.
CNS involvement usually manifests as multiple microabscesses measuring less than 1 mm in diameter. These occur primarily within the supratentorial cortex and less often in the basal ganglia and white matter.23 Less commonly, meningitis (> 20%) and rarely macroabscesses can develop.24 Vascular complications (infarction, mycotic aneurysms, and subarachnoid hemorrhage) have also been documented.
Microabscess formation usually presents as a diffuse, vague encephalopathy. These lesions are below CT resolution but can be visualized on MR imaging.25 Meningitis usually presents with a subacute onset of headache and fever, confusion, and altered sensorium but can be fulminant and result in hydrocephalus. Macroabscesses will present with localizing signs and seizures.
Diagnosis
Because CSF serology and cultures are unreliable, the diagnosis is often made indirectly, by funduscopic examination, blood cultures, and infrequently by samples from other tissues. CSF 1,3-β-D-glucan has better sensitivity than serum assays, ranging from 70 to 90%. PCR tests are being introduced but are of limited use because of a lack of availability and clinical validation and their high cost.15
Nocardiosis
Nocardia, an aerobic actinomyces, is a gram-positive branching rod found in soil, decaying vegetables, and aquatic media. N. asteroides, which causes human disease, has been redefined to include a complex of four members: N. asteroides sensu stricto, N. farcinica, N. nova, and N. transvalensis. Of those, N. nova and N. farcinica are the most virulent. Nocardia does not normally colonize human tissue and is considered an opportunistic microorganism, particularly in patients with cell-mediated immune dysfunction. Nocardia has the capacity to evade clearance by the immune system by several mechanisms that disrupt phagocytic activity, and about one-third of infected individuals have an intact immune system.26 Organ transplant recipients constitute around 20% of patients with Nocardia infection, with an incidence of 0.1 to 3.5%. Steroid-sparing regimens have reduced the risk in this population.27 The prevalence of nocardiosis in HIV-positive patients is low (0.2 to 2.0%), and nocardiosis appears mostly in severely immunocompromised (CD4+ cell count < 35/µL) patients. However, in cases of invasive nocardiosis, patients with HIV infection comprise a major risk group. HIV patients can benefit from the administration of trimethoprim-sulfamethoxazole prophylaxis against Pneumocystis jiroveci pneumonia, which is also effective against Nocardia infections.28,29 Because of the enlarging pool of susceptible patients, the incidence of nocardiosis is increasing, so that nocardiosis is now viewed as an emerging infectious disease.30
The most common site of primary infection is pulmonary (approximately 40% of patients), but nocardiosis can be transmitted transcutaneously via penetrating trauma, animal scratches, or bites and can also be spread iatrogenically. Nocardia frequently erodes into blood vessels and thus has the potential for hematogenous spread. Although any organ can be involved, the incidence of CNS nocardiosis is disproportionately high during dissemination (44%) or as an isolated primary site of infection (38%). The hallmark of CNS involvement is brain abscess formation without a predilection for any specific cerebral region ( Fig. 18.1 ). Although constitutional symptoms can be found, the presentation can be solely that of a space-occupying lesion causing mass effect. A clinical presentation of subacute or chronic meningitis is infrequent.
Diagnosis
CNS nocardiosis should be suspected in any immunocompromised patient whose clinical and radiologic presentation is compatible with a brain mass and concurrent pulmonary involvement. Additionally, a proven cutaneous or pulmonary nocardiosis infection in an immunocompromised patient, even without the suspicion of CNS involvement, warrants brain MR imaging to rule out occult CNS disease. The definitive diagnosis of nocardiosis requires identification of the pathogen in a collected specimen. Delay in diagnosis is common because of the nonspecific clinical presentation and difficulties in obtaining adequate specimens. Growing the bacteria is difficult, and blood cultures are rarely diagnostic. PCR provides rapid results and is highly sensitive and specific, but its availability is limited and its cost is high.
Treatment
Because the sensitivity of isolated strains to antibiotics is highly variable, defining patterns of susceptibility is mandatory in each case. While these results are awaited, combination therapy is frequently used for the empiric treatment of nocardiosis. Trimethoprim-sulfamethoxazole and ceftriaxone are used primarily,27 often with great success. The treatment of brain abscesses generally follows the guidelines set before for the treatment of infectious space-occupying lesions.31
Parasitic Infections
Many parasitic infections, including malaria, schistosomiasis, microsporidiosis, leishmaniasis, and trypanosomiasis, can involve the CNS in both immunocompetent and immunocompromised patients.32 In addition, some parasites, such as Strongyloides stercoralis, can rarely cause CNS infection in immunocompromised hosts. We discuss the more common opportunistic pathogens that selectively affect immunocompromised patients.
Toxoplasmosis
Toxoplasma gondii is an obligatory intracellular protozoan. This parasite is able to develop in a variety of vertebrate hosts, but its definitive host is the house cat and other members of the family Felidae. Infection in humans occurs after the ingestion of cysts contained in uncooked meat or after exposure to oocytes shed in cat feces. Serologic markers reveal a variable geographic prevalence of toxoplasmosis. In Europe, 50 to 90% of the healthy adult population is seropositive, whereas the rate is estimated to be 15 to 35% in the United States.33
In immunocompetent adults and children past the neonatal period, the infection is usually asymptomatic. In a small percentage of patients, the clinical picture resembles that of infectious mononucleosis. Hematogenous spread from the intestine can seed any nucleated cell but most commonly affects the lungs, lymphoid system, heart, and CNS. Multiplication of the parasite within invaded cells leads to cellular disruption and death. Focal areas of necrosis and cyst formation result.32
Most cases of clinically apparent toxoplasmosis in immunocompromised patients are the result of reactivation of a previously acquired latent infection. The vast majority of cases of cerebral toxoplasmosis have been documented in AIDS patients, in whom it is the most frequent opportunistic brain infection, occurring in approximately 20 to 30% of individuals.34 Toxoplasmosis is the leading cause of a mass lesion in AIDS patients. However, patients with malignancies may also develop cerebral toxoplasmosis, in particular those who undergo an allogeneic stem cell transplant (SCT) or a T-cell–depleting treatment regimen containing alemtuzumab or fludarabine. In addition to fungal infection, cerebral toxoplasmosis has become one of the leading causes of cerebral abscesses in patients after allogeneic SCT.35,36 In solid organ transplant recipients, a primary infection can develop if a donor organ containing encysted T. gondii is transplanted into a seronegative recipient. Seronegative patients receiving cardiac or renal allografts from seropositive donors are at the highest risk for toxoplasmosis.37,38
In the CNS, toxoplasmosis produces multiple necrotic brain abscesses that develop at the corticomedullary junction and in the basal ganglia. These lesions manifest clinically as seizures and localized signs of a mass lesion, such as focal neurologic deficits and cranial nerve palsies. Lesions are solitary in approximately 30% of patients. Systemic manifestations include hepatosplenomegaly, pneumonitis, myositis, myocarditis, and skin rash.
Diagnosis
The diagnosis is based on the demonstration of the pathogen (tachyzoites or cysts) in tissue sections or by CSF staining. MR imaging typically shows multiple ring-enhancing or smaller nodular lesions surrounded by cerebral edema. Less commonly, MR imaging demonstrates signs of meningoencephalitis. Although these MR imaging findings are nonspecific, the extent of CNS involvement is well demonstrated. A small eccentric nodule (eccentric target sign) in the enhancing ring is suggestive of toxoplasmosis, although the sensitivity of this finding is less than 30%. Rarely, the lesions can be hemorrhagic ( Fig. 18.2 ). In immunosuppressed patients without HIV infection, the degree of perilesional enhancement has been found to be inversely related to the extent of immunosuppression. The radiologic differential diagnosis for toxoplasmosis in the CNS includes CNS lymphoma (typically subependymal lesions that lack the eccentric target sign), metastatic disease, and other nonpyogenic infections.3
The definitive diagnosis of toxoplasmosis can be established by identifying tachyzoites in tissue samples. Serologic investigations of the CSF may be useful, particularly for immunoglobulin G by enzyme-linked immunosorbent assay (ELISA). Immunoglobulin M antibody detection has a negligible value in the diagnosis of neurotoxoplasmosis because most cases are not newly acquired. The detection of specific DNA by PCR in the CSF, claimed to have high sensitivity and specificity, has produced inconsistent results and thus cannot be relied on for making the diagnosis. The presence of multiple ring-enhancing lesions in the basal ganglia or cerebrum on neuroimaging, in the presence of anti-Toxoplasma immunoglobulin G antibodies, is suggestive of CNS toxoplasmosis and is sufficient to start empiric pharmacologic treatment.32
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