Infections

Clinical Features

In the United States, the incidence of bacterial meningitis is approximately 1 to 10 cases per 100,000 population per year. The etiologic agents causing bacterial meningitis vary with the age of the affected patient, their immune status, and whether the infection is acquired in a community or nosocomial setting; accordingly, knowledge of common pathogens in various clinical settings is crucial in determining appropriate antibiotic therapy. The development of effective vaccines against Haemophilus influenzae type B, Streptococcus pneumoniae , and Neisseria meningitidis has resulted in a significant decline in the incidence of community-acquired bacterial meningitis, particularly in children. S. pneumoniae is the most common cause of community-acquired bacterial meningitis, accounting for over 50 % of cases. In neonates, group B Streptococcus and Escherichia coli are the predominant organisms; and in older children and adults, S. pneumoniae and N. meningitidis cause most cases. Listeria monocytogenes is most commonly found in the elderly and patients with immunodeficiency including people with alcoholism, patients with cancer, and those taking immunosuppressive medications.

Clinical features of meningitis include fever, headache, nausea, vomiting, confusion, and lethargy of acute onset, often associated with nuchal rigidity. The Kernig sign, or reflex contraction of the hamstring muscles when extending the leg after flexing the thigh on the body, and the Brudzinski sign, or flexion of both the knees and hips in response to passive flexion of the neck toward the chest, are common signs of meningeal irritation. CSF changes are often diagnostic and include cloudiness of the CSF, increased pressure, neutrophilic pleocytosis, a raised protein level, and a markedly reduced or absent glucose level. Gram stain is useful in demonstrating the causative organism. Neuroimaging is of little help in diagnosis but may show contrast enhancement of the subarachnoid space. Gram stains and CSF culture are used to identify the causative organism in most cases. Amplification of bacterial DNA by polymerase chain reaction (PCR) may be useful in select culture-negative cases.

Pathologic Features

Gross Findings

In patients who die of meningitis, the brain is surrounded by creamy yellow or green pus ( Fig. 7.1 ). Pus is first visible at the base of the brain and as thin creamy lines alongside meningeal vessels. These vessels are engorged and prominent. In fulminant cases, pus may also be noted within the ventricles (ventriculitis, Fig. 7.2 ). In those who survive, leptomeningeal fibrosis and consequent hydrocephalus may be evident.

Microscopic Findings

Microscopically, neutrophils fill the subarachnoid space and are characteristically easiest to find around blood vessels ( Fig. 7.3 ). They may infiltrate the walls of leptomeningeal veins and thereby lead to venous occlusion and hemorrhagic infarction of the underlying brain, which is often edematous. Gram stain may reveal the causative organism, although organisms are frequently not demonstrable in treated cases.

MENINGITIS—PATHOLOGIC FINDING

Gross Findings

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  The brain is surrounded by creamy yellow or green pus that is often basal and follows the distribution of meningeal blood vessels

Microscopic Findings

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  Neutrophils in the subarachnoid space

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  Leptomeningeal veins may be infiltrated

Differential Diagnosis

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  Leptomeningeal fibrosis

Prognosis and Therapy

Untreated bacterial meningitis is uniformly fatal. With treatment, case fatality rates vary with age, causative organism, and income status and range up to 40 %–50 %. Empiric antibiotic therapy should be based on the most common bacterial pathogens that cause disease according to the patient’s age group, clinical setting, epidemiology, and local antibiotic susceptibility patterns. Agents effective against most of the commonly encountered pathogens include ampicillin, broad-spectrum cephalosporins, and vancomycin. The use of adjunctive dexamethasone therapy has led to decreased rates of unfavorable outcomes and death. Vaccination of susceptible individuals is important in the prevention of meningitis.

Clinical Features

Brain abscesses may occur in any age group. Signs and symptoms in individual patients depend on the location of the lesion but most often include headache, nausea, emesis, alterations in consciousness, seizures, and motor weakness. Fever and evidence of a systemic or local source of infection may or may not be apparent.

Radiographic Features

The radiographic appearance of brain abscesses is variable and evolves with time. Early cerebritis may be detected as an area of low attenuation on computed tomography (CT) or as an area of high signal intensity on T2-weighted magnetic resonance imaging (MRI). With time, a collagenous capsule that is dense on CT and of low signal on MRI becomes evident and is classically thinnest on the side nearest the lateral ventricle. A well-defined, ring-like pattern of enhancement appears after the administration of contrast material ( Fig. 7.4 ). Lesions are often multiple and are typically located at the gray-white matter junction in the distribution of the middle cerebral artery. Diffusion-weighted imaging (DWI) is the method of choice; almost all pyogenic abscesses show markedly hyperintense and homogeneous signal on DWI.

Pathologic Findings

• Gross Findings

Early abscesses are irregular areas of suppuration. With time, a capsule develops. Encapsulation begins as a rim of granulation tissue that ultimately evolves into a firm, fibrous capsule ( Fig. 7.5 ). Satellite lesions, or “daughter” abscesses, may develop, usually inwardly, and may rupture into the ventricular system.

• Microscopic Findings

Abscesses begin as foci of cerebritis, characterized by collections of neutrophils associated with necrosis and edema (early stage: days 1 to 3 [ Fig. 7.6A ]). Later, neutrophils are replaced by macrophages and lymphocytes (intermediate stage: days 4 to 9). In the final or capsular stage (day 10 onward), granulation tissue surrounds the area of inflammation ( Fig. 7.6B ) and eventually develops into a fibrous capsule. This capsule in turn is surrounded by gliotic, edematous brain tissue.

BRAIN ABSCESS—PATHOLOGIC FINDINGS

Gross Findings

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  Suppuration surrounded by a fibrous capsule

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  Satellite lesions

Microscopic Findings

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  Early stage: cerebritis with collections of neutrophils

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  Intermediate stage: macrophages and lymphocytes

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  Capsule stage: necrosis and inflammation surrounded by granulation tissue, a collagenous capsule, and gliosis

Differential Diagnosis

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  High-grade glial neoplasm

Prognosis and Therapy

Survival from a brain abscess is the rule in appropriately diagnosed and treated cases; the single most important contributing factor to mortality and permanent neurologic deficit is delay in diagnosis. Most cases are treated with antimicrobial therapy. Surgery to drain or remove the abscess and to identify the causative organism is necessary in some instances. Adjunctive glucocorticoid therapy to reduce cerebral edema and hyperbaric oxygen are used in some cases. Approximately 70 % of patients have minimal or no neurologic sequelae.

Clinical Features

Tuberculous meningitis is the most common form of tuberculosis of the CNS in the United States and other developed countries. It manifests as generalized complaints of headache, malaise, mental confusion, and vomiting. CSF findings include increased pressure, a pleocytosis made up of mononuclear cells or a combination of polymorphonuclear and mononuclear cells, moderately elevated protein levels, and a reduced or normal glucose content. There is often a history of or a concurrent positive tuberculin skin test or a history of exposure to TB. Active pulmonary TB is present on chest radiographs in 30 % to 50 % of cases.

Tuberculomas produce signs and symptoms of a mass. These lesions, which remain a common cause of intracranial masses in tropical countries, occur most often in the first three decades of life. There is often a history of exposure to the organism or recognized extracranial disease. The most common signs and symptoms include headache, seizures, papilledema, hemiplegia, and cerebellar dysfunction.

Spinal tuberculosis can result from foci of spinal cord myelitis/arachnoiditis or from vertebral body involvement (Pott disease). Patients typically present with some combination of signs of nerve root and cord compression.

Patients with tuberculosis and human immunodeficiency virus (HIV) infection may develop immune reconstitution inflammatory syndrome (see below).

Nontuberculous mycobacteria most commonly cause disseminated disease in immunocompromised individuals. The CNS may be affected, but this involvement is usually asymptomatic. When symptomatic CNS involvement does occur, the signs and symptoms are nonspecific and include a diffuse encephalopathy, seizures, headache, altered mentation or impaired cognition, nuchal rigidity, lethargy, cranial nerve palsies, and progressive neurologic deterioration.

Radiographic Features

In tuberculous meningitis, there may be radiologic enhancement at the base of the brain. Hydrocephalus is present in approximately 75 % of cases. A tuberculoma is a single or multilocular lesion with a peripheral rim of contrast enhancement and a hypodense, necrotic center. Spindle cell pseudotumors may rarely be seen in those with infections caused by atypical mycobacteria; these lesions produce hyperdense masses with surrounding edema on imaging studies.

Pathologic Features

Gross Findings

Tuberculous meningitis is characterized by a thick, gray exudate that typically involves the base of the brain but subsequently extends to the Sylvian fissures and envelopes the spinal cord ( Fig. 7.7A ). Small nodules or tubercles may be identified in this exudate.

Tuberculomas are round or oval masses. They have necrotic, firm centers and are creamy in color ( Fig. 7.7B ). The surrounding rim is gray and gelatinous, and there is much less swelling than around cerebral abscesses.

MYCOBACTERIAL INFECTIONS—PATHOLOGIC FEATURES

Gross Findings

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  TB meningitis: thick, gray exudate that typically involves the base of the brain

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  Tuberculoma: round or oval mass with a necrotic, firm center; creamy in color

Microscopic Findings

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  TB meningitis: lymphocytes, plasma cells, and tubercles with necrotic centers surrounded by epithelioid histiocytes and lymphocytes; obliterative endarteritis

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  Tuberculoma: necrotizing granulomatous inflammation surrounded by gliotic brain tissue

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  Acid-fast organisms difficult to identify

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  Nontuberculous mycobacteria: poorly formed granulomas, perivascular lymphocytes and macrophages with acid-fast organisms, spindle cell pseudotumors

Ancillary Studies

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  PCR to identify mycobacterial DNA

Differential Diagnosis

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  Fungal infections

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  Sarcoidosis

Microscopic Findings

In TB meningitis, one sees lymphocytes, other mononuclear inflammatory cells, and tubercles/granulomas composed of a central area of necrosis surrounded by epithelioid cells and lymphocytes. Langhans giant cells may also be seen but are typically sparse. Meningeal blood vessels may be involved with resulting fibrinoid necrosis and thrombosis. So-called endarteritis obliterans, characterized by thickening of the vascular intima by collagenous fibrosis, may be present. The diagnosis is definitively established by identifying acid-fast organisms with either a Ziehl-Neelsen stain ( Fig. 7.8 ) or an auramine-rhodamine fluorescent technique. Organisms are often difficult to identify, especially if treatment has been initiated; therefore a negative acid-fast stain does not completely exclude the diagnosis.

Tuberculomas are also characterized by necrotizing granulomatous inflammation. Typically, they consist of a caseous center surrounded by epithelioid histiocytes, giant cells, and lymphocytes ( Fig. 7.9 ). The surrounding brain tissue is gliotic. Again, organisms may be difficult to identify.

Nontuberculous mycobacteria may also produce granulomatous inflammation, but the granulomas are typically poorly formed. Perivascular infiltrates composed of lymphocytes and macrophages, some of which contain acid-fast organisms ( Fig. 7.10 ), may be seen in symptomatic patients. Rarely, spindle cell pseudotumors, which are identical to those seen in other organ systems in immunocompromised patients, may be present. They are composed of spindle cells arranged in fascicles associated with lymphocytes, plasma cells, and occasional neutrophils. Acid-fast bacilli may be seen within the spindle cells.

Prognosis and Therapy

Disseminated TB is often fatal unless treated early. A combination of antimycobacterial agents, including isoniazid, rifampin, pyrazinamide, and ethambutol, is used to minimize the possibility of antibiotic resistance, which has become an increasingly common problem. Adjunctive corticosteroid therapy is recommended for all patients with CNS disease. Prophylactic treatment of those infected with M. tuberculosis but free of disease is useful in preventing CNS disease. An attenuated vaccine developed from a strain of M. bovis by Calmette and Guérin (the BCG vaccine) is used in some groups but may cause infection, particularly in immunosuppressed patients.

Clinical Features

Although rare, there has been a resurgence of syphilis in low- and middle-income countries and in certain populations, including those with HIV coinfection, in developed countries. In patients in whom tertiary syphilis develops, asymptomatic neurosyphilis is common. The clinical findings in symptomatic patients are extremely variable, and neurosyphilis has been termed “the great imitator” of other diseases because the clinical presentation is often atypical and misleading. Those with HIV infection are more likely to progress to symptomatic neurosyphilis and to have an accelerated course. Ocular manifestations may also be more common in this patient population.

Patients with meningovascular neurosyphilis present with signs of chronic meningitis. If the vascular component of the disease is severe, infarcts may develop. Extension of the inflammatory process into cranial and spinal nerves and blood vessels may produce optic atrophy or cranial nerve palsies. If the meningeal exudate organizes, symptoms of obstructive hydrocephalus may develop.

Paretic neurosyphilis occurs when brain tissue is invaded by the treponemal organisms. In this form of the disease, which has been termed “general paresis of the insane,” an insidious, progressive loss of mental and physical functions develops, with mood alterations terminating in severe dementia. Argyll Robertson pupils, which show accommodation but do not react to light, are seen in this form of tertiary neurosyphilis.

Tabes dorsalis results from damage to the sensory nerves in the dorsal roots of the spinal cord. Sensory disturbances, including “lightning pains” and loss of deep tendon reflexes, are typical findings. Impaired joint position sense with ataxia and loss of pain sensation leading to skin and joint damage (Charcot joints) are also observed.

The diagnosis of neurosyphilis is based on serum and CSF serologic tests. These are classified as non-treponemal (Venereal Disease Research Laboratory [VDRL] or rapid plasma reagin) or treponemal (fluorescent treponemal-antibody absorption [FTA-ABS]) tests. The sensitivity and specificity of these tests are variable and depend on the choice of control material, the prevalence and stage of syphilis, and the accuracy of the diagnoses used for reference. The diagnosis of symptomatic neurosyphilis may be made if a serum FTA-ABS test is reactive (reflecting previous syphilis) and a CSF VDRL test is reactive (indicating neurosyphilis). Testing for HIV infection is recommended in all patients with syphilis. Serial examination of the CSF white cell count is often used to determine the adequacy of treatment. Stigmata of congenital syphilis include interstitial keratitis, chorioretinitis, and deafness. In congenitally infected children, all the aforementioned neurosyphilitic syndromes may eventually develop.

Pathologic Features

Gross Findings

Thickened, fibrotic meninges are characteristic of meningovascular neurosyphilis. When the infection is confined to the cervical region, the term “pachymeningitis cervicalis hypertrophica” has been applied. Syphilitic gummas, which vary from 0.1 to 4 cm in diameter, may occur in the meninges, where they are usually attached to the dura and the underlying brain, in which they become embedded. Gummas are generally round, reddish tan to gray, and firm and rubbery with a central area of necrosis.

The brains of patients suffering from paretic neurosyphilis are shrunken and firm and covered by thick, opaque leptomeninges. The atrophy is most marked frontally ( Fig. 7.11 ), and the ventricles are typically greatly enlarged. The ependyma may have a fine ground-glass appearance because of extensive granular ependymitis.

In long-standing tabes dorsalis, degeneration of the posterior columns leads to an excavated dorsal surface of the spinal cord. The posterior nerve roots are gray and shrunken.

Microscopic Findings

In meningovascular neurosyphilis, an admixture of lymphocytes and plasma cells is present in association with fibrosis. The vascular component, termed “Heubner arteritis,” is a form of endarteritis obliterans with crescentic, collagenous thickening of the vascular intima. Lymphocytes and plasma cells are present in the adventitia, cuffing the vasa vasorum, and may penetrate the media. Gummas, if present, consist of a central area of necrosis surrounded by epithelioid histiocytes, multinucleated foreign body-type giant cells, lymphocytes, plasma cells, and focal fibrosis.

The cerebral cortex in paretic neurosyphilis is atrophic and lacks a normal laminar architectural pattern. There is loss of neurons with proliferation of astrocytes and microglial cells. The microglial cells are hypertrophied and elongated and often contain abundant iron, which may be highlighted with a Perls stain. The cerebral cortex has been described as having a windswept or bush fire appearance. There may be perivascular lymphocytes and plasma cells, and treponemal organisms may occasionally be observed with special stains (modified Steiner or Warthin-Starry silver stains).

Tabes dorsalis is characterized by a loss of myelinated axons in the dorsal nerve roots and pallor and atrophy in the dorsal columns ( Fig. 7.12 ). Typically, no significant inflammatory infiltrate is found, and organisms are not identifiable.

NEUROSYPHILIS—PATHOLOGIC FEATURES

Gross Findings

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  Meningovascular neurosyphilis: thick, opaque meninges and gummas

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  Paretic neurosyphilis: atrophy, meningeal fibrosis, large ventricles, granular ependymitis

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  Tabes dorsalis: excavated dorsal spinal cord, atrophic and gray dorsal nerve roots

Microscopic Findings

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  Meningovascular neurosyphilis: lymphocytes and plasma cells, obliterative endarteritis, necrotizing granulomatous inflammation in gummas

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  Paretic neurosyphilis: loss of cerebral laminar architecture with neuronal loss and proliferation of astrocytes and microglial cells; organisms may be identified

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  Tabes dorsalis: loss of myelinated axons in nerve roots with pallor and atrophy of the dorsal columns; no organisms

Differential Diagnosis

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  Tuberculosis and other causes of granulomatous inflammation

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  Tabes dorsalis: subacute, combined degeneration, vacuolar myelopathy, tropical spastic paraparesis

Prognosis and Therapy

Treatment of neurosyphilis is largely preventive; the disease should be treated in its primary stage. Undetected cases often respond to parenteral penicillin.

Clinical Features

The most common manifestation of Lyme disease is the characteristic cutaneous lesion known as erythema migrans, which typically arises at the site of the tick bite. This is often followed by arthritis affecting large joints. Nervous system manifestations include lymphocytic meningitis, cranial neuropathy, or radiculoneuropathy. In many cases facial nerve palsy is present. Clinical symptoms of meningitis are highly variable and may be indistinguishable from viral meningitis. So-called Lyme encephalopathy, characterized by mild memory and cognitive impairment, is thought to be a nonspecific correlate of chronic inflammation. The CSF typically shows a lymphocytic pleocytosis and protein elevation with increased CSF-to-serum antibody ratios.

Prognosis and Therapy

Oral treatment with doxycycline is effective in the majority of patients.

Pathologic Features

Histologic findings include small collections of macrophages that are often perivascular in location ( Fig. 7.13 ). A lymphoplasmacytic infiltrate and gliosis are also present. The macrophages are lipid laden and filled with sickle-shaped organisms that are PAS-, Gram-, and methenamine silver–positive.

Differential Diagnosis

The diagnosis of Whipple disease is not usually difficult if the entity is considered. The differential diagnosis includes infection with organisms of the M. avium complex, which are also present within macrophages in a perivascular location and are PAS- and Gram-positive.

Clinical Features

CNS involvement occurs in less than 5 % of Actinomyces infections. Intracranial infections occur after direct trauma, cervicofacial actinomycosis, or hematogenous spread from a systemic infection or as the result of local spread from an ear-nose-throat infection. Risk factors include chronic sinusitis/mastoiditis/gingivitis and dental procedures, congenital heart disease, infected intrauterine devices, and alcoholism. Patients have symptoms of either a space-occupying lesion (abscess) or meningitis.

Pathologic Features

Actinomycosis of the CNS typically results in abscess formation. The lesions show central necrosis with an inflammatory infiltrate composed predominantly of neutrophils. Colonies of branching organisms form the characteristic sulfur granules ( Fig. 7.14 ). These granules in turn are surrounded by chronic inflammation and granulation tissue. The filamentous organisms are Gram-positive and can be highlighted with methenamine silver stains. 16S rRNA sequencing/next-generation sequencing in addition to culture of abscess material may be more sensitive in identifying the causative organism than culture alone.

ACTINOMYCOSIS—FACT SHEET

Definition

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  An infection caused by anaerobic Actinomyces species

Clinical Features

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  CNS infection is acquired via spread from elsewhere in the body

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  Space-occupying lesions or meningitis

Prognosis and Treatment

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  Treatment consists of surgical drainage and antibiotics

ACTINOMYCOSIS—PATHOLOGIC FEATURES

Gross Findings

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  Abscesses

Microscopic Findings

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  Abscess formation

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  Sulfur granules

Differential Diagnosis

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  Nocardiosis (acid-fast)

Prognosis and Therapy

Optimal management consists of combined adequate surgical drainage and prolonged antibiotic therapy.

Clinical Features

Disease of the CNS caused by Nocardia is generally thought to occur via hematogenous dissemination from an infection in the lungs. Predisposing factors include deficiencies in cell-mediated immunity such as corticosteroid use, organ transplantation, and underlying autoimmune disease. Patients typically present with a subacute onset of signs and symptoms, including head or neck pain, nausea and vomiting, or altered mental status. CSF findings include a neutrophilic pleocytosis with decreased glucose levels.

Pathologic Features

Nocardia may produce either abscesses ( Fig. 7.15 ), meningitis, or both. The abscesses are typically similar to those found in other bacterial infections, although a granulomatous reaction can sometimes be seen. The organisms appear as thin, branching filaments and may be identified with a tissue Gram stain, silver stains, or modified acid-fast stains ( Fig. 7.16 ).

NOCARDIOSIS—PATHOLOGIC FEATURES

Gross Findings

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  Abscesses, meningitis, or both

Microscopic Findings

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  Neutrophilic response most common

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  Granulomatous inflammation sometimes occurs

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  Organisms are acid-fast, branching filaments

Differential Diagnosis

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  Other causes of pyogenic abscesses

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  Actinomycosis

Prognosis and Therapy

The diagnosis of nocardiosis is often delayed, which results in suboptimal treatment in some cases. Mortality with this infection ranges from 25 % to 75 %. A variety of antibacterial agents, including the sulfonamides, are effective in the treatment of this organism.

Clinical Features

Cryptococcosis occurs in all races and is more common in males. It sometimes develops spontaneously in previously healthy individuals; however, in up to 85 % of cases it is associated with debilitating illnesses. Predisposing conditions include lymphoproliferative disorders, corticosteroid therapy, organ transplantation, rheumatologic disease treated with monoclonal antibodies, and HIV infection. Patients present with headache, fever, cranial neuropathies, altered mentation, lethargy, memory loss, and signs of meningeal irritation. Restoration of pathogen-specific immunity in transplant patients or those with HIV infection can result in the immune reconstitution inflammatory syndrome (IRIS); clinical features of cryptococcal IRIS are similar to those of active cryptococcal infection. Imaging studies are often normal due to a sparse inflammatory infiltrate but may reveal diffuse meningeal enhancement as well as multiple punctuate lesions, which often involve the basal ganglia. CSF stains may demonstrate the organisms, or cryptococcal polysaccharide capsular antigen may be detected in CSF and/or blood.

Pathologic Features

Gross Findings

In most cases the leptomeninges are thickened and opaque, particularly over the base of the brain and cerebellum. Hydrocephalus may be present in chronic cases. Parenchymal lesions resemble soap bubbles ( Fig. 7.19 ); this appearance is related to exuberant capsular material produced by the proliferating organisms. Lesions are most commonly seen in the basal ganglia and thalamus. Rarely, masses of fungi aggregate in an inflammatory lesion, a finding referred to as a cryptococcoma.

Microscopic Findings

The inflammatory infiltrate in cryptococcosis is typically scant. Granulomatous inflammation may be seen in some cases. The organisms may form small colonies, usually around blood vessels. They stain faintly with H&E but can be highlighted with PAS, mucicarmine, Alcian blue, or methenamine silver stains ( Fig. 7.20 ). Small buds may be attached to the main body by a short neck.

CRYPTOCOCCOSIS—PATHOLOGIC FEATURES

Gross Findings

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  Thickening and opacification of the leptomeninges

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  Soap bubble lesions in the basal ganglia

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  Cryptococcoma

Microscopic Findings

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  Scant inflammatory infiltrate

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  Narrow-based budding yeasts

Differential Diagnosis

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  Blastomycosis

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  Corpora amylacea

Prognosis and Therapy

Cryptococcosis typically runs a steadily progressive course ranging from a few weeks to 6 months. Periods of relapse and remission are common in untreated individuals. Flucytosine in combination with amphotericin B deoxycholate is currently the first-line treatment of severe cryptococcal disease. In HIV-associated infections, anti-retroviral therapy (ART) has a major impact on long-term prognosis; however, there may be an increased risk of IRIS among HIV-infected patients initiated on ART early after the diagnosis of an opportunistic infection.

Clinical Features

Involvement of the CNS is mainly observed in patients who develop disseminated candidiasis. Hematogenous dissemination is promoted by a variety of conditions including neutropenia, diabetes, and AIDS; it is also seen in patients with extensive wounds (burns and operations) as well as premature infants, those recovering from transplantation, or in patients who have undergone catheterization. Meningoencephalitis is the most common clinical manifestation of neurocandidiasis; other clinical presentations include endophthalmitis, multiple cerebral abscesses, vasculitis, intraventricular fungus balls, hydrocephalus, calcifications, and cranial neuropathies.

Pathologic Features

Gross Findings

The brain is often grossly normal. Microabscesses may be present and are most commonly seen in the distribution of the anterior and middle cerebral arteries.

Microscopic Findings

Histologically, candidiasis is characterized by small foci of cerebritis ( Fig. 7.21 ). Granulomatous inflammation may be seen in some cases. Both yeast forms and pseudohyphae may be present and are faintly basophilic in H&E-stained sections. The organisms stain intensely with both PAS and methenamine silver ( Fig. 7.22 ). Vascular complications, including infarcts, mycotic aneurysms, and subarachnoid hemorrhage, occur in a significant number of patients.

CANDIDIASIS—PATHOLOGIC FEATURES

Gross Findings

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  Microabscesses in the distribution of the anterior and middle cerebral arteries

Microscopic Findings

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  Small foci of cerebritis

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  Yeast forms and pseudohyphae

Differential Diagnosis

• n

  Other yeasts

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  Hyphal organisms

Prognosis and Therapy

Mortality ranges up to 90% in patients with CNS involvement. Treatment of CNS candidiasis is with amphotericin B and 5-fluorocytosine.

Clinical Features

CNS aspergillosis typically occurs in the setting of corticosteroid therapy and in neutropenic patients, particularly those with hematologic malignancies. It can also occur in immunocompetent patients and those with milder forms of immunosuppression, such as diabetes mellitus. Focal neurologic deficits are common. Other frequently encountered signs and symptoms include fever, headache, and seizures. Clinical features are usually dramatic and tend to progress rapidly. Imaging studies are nonspecific. Galactomannan and 1,3-β-d-glucan may be found in the serum or CSF. PCR performed on CSF and serum may provide a diagnosis in some cases.

Pathologic Features

Gross Findings

Multiple lesions are usually present and most often involve areas supplied by the anterior and middle cerebral arteries. Because the fungus is highly angiotropic, foci of hemorrhagic necrosis are common ( Fig. 7.23 ).

Microscopic Findings

The inflammatory response depends in part on the immune status of the patient, and both neutrophilic and granulomatous inflammatory infiltrates may be seen. Blood vessels are typically involved and show thrombosis and invasion of their walls by fungi. The organisms are septate hyphae that branch at acute angles ( Fig. 7.24 ). Fruiting bodies ( Fig. 7.25 ), which are typically only seen in cultures, may rarely be seen in tissue sections if the organisms have been exposed to air.

ASPERGILLOSIS—PATHOLOGIC FEATURES

Gross Findings

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  Multiple lesions

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  Foci of hemorrhagic necrosis

Microscopic Findings

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  Neutrophilic and/or granulomatous inflammation

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  Vascular invasion and thrombosis

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  Septate hyphae that branch at acute angles

Differential Diagnosis

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  Mucormycosis

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  Other mycoses caused by septate hyphal organisms

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  Large, myelinated axons or cortical blood vessels

Prognosis and Therapy

CNS involvement is associated with a high mortality rate, particularly in immunosuppressed patients. Treatment with voriconazole improves patient survival. Combined medical and neurosurgical treatment should be considered in these patients.

Clinical Features

Rhinocerebral mucormycosis is classically seen in the setting of diabetic ketoacidosis. Signs and symptoms often result from involvement of the orbit and include unilateral ophthalmoplegia, proptosis, edema of the eyelid, corneal edema, and blindness. Hematogenous dissemination to the CNS occurs in patients who are intravenous drug abusers and those who are immunosuppressed. Iron overload is also a known risk factor.

Pathologic Features

Gross Findings

Rhinocerebral mucormycosis is characterized grossly by necrotic, hemorrhagic lesions that most commonly involve the base of the frontal lobes. When CNS involvement results from hematogenous dissemination, hemorrhagic lesions are often present in the deep gray nuclei ( Fig. 7.26 ).

Microscopic Findings

Zygomycetes organisms typically elicit a minimal inflammatory response that is predominantly neutrophilic. These fungi, like Aspergillus species, are highly angiotropic and are often identified within the walls of blood vessels. They appear as broad, nonseptate, irregular (ribbon-like) hyphae that branch at right angles ( Fig. 7.27 ).

MUCORMYCOSIS—PATHOLOGIC FEATURES

Gross Findings

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  Hemorrhagic lesions involving the base of the frontal lobes

Microscopic Findings

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  Minimal inflammatory infiltrate, mostly neutrophils

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  Vascular invasion and thrombosis

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  Irregular, broad, nonseptate hyphae that branch at right angles

Differential Diagnosis

• n

  Aspergillosis