Magnetic resonance imaging in fungal infections of the brain.

ORIGINAL ARTICLE

Magnetic Resonance Imaging in Fungal Infections of the Brain Enrique Palacios, MD, FACR,* Rafael Rojas, MD,† Jason Rodulfa, MD,* and Eduardo González-Toledo, MD‡ Abstract: An invasive fungal infection is a rare disease that can occur in otherwise healthy individuals. Fungi themselves are universal, and they are overall harmless organisms that cause at most a self-limiting disease in the general population. Immunocompromised individuals, whether iatrogenically, genetically, or acquired, present a group who are especially susceptible to a life-threatening disease from a normally innocuous pathogen. Fungi are normally inhaled and are cleared by pulmonary defense mechanisms in immunocompetent hosts. Invasion begins when these mechanisms fail in depressed immunity. Through bypassing of the pulmonary immune system, fungi can spread hematogenously. Fungal infections of the central nervous system are the most common extrapulmonary manifestation after fungal inhalation. Other risk factors of fungemia include prolonged indwelling catheters, maxillofacial infections, uncontrolled diabetes mellitus, systemic antibiotics, implanted neurosurgical devices, and intravenous drug abuse. Thus, other than direct inoculation via surgical complications or open trauma, central nervous system fungal infections are almost never primary.

Pathogenesis in General Intracranial Infections Fungi damage to the brain is determined by its subtype. The smaller subtypes travel further peripherally after entering the cerebral vasculature, whereas the larger subtypes remain more proximally and affect larger caliber cerebral vasculature. Yeasts such as Candida and Cryptococcus are very small and, thus, are able to travel peripherally to seed the vessels of the meninges and subarachnoid space, resulting in inflammation.1 In fact, a retrospective study of patients with cancer who have positive cerebrospinal fluid (CSF) cultures found that 8% were of fungal origin.8 Large fungi, such as Aspergillus and Mucormycoses that grow as hyphae, form large colonies and are unable to navigate into the small peripheral vessels. They instead involve the larger cerebral vessels and cause disease in the parenchyma via angioinvasion, vasculitis, mycotic aneurysm formation, infarction, and even hemorrhage.1,9

Key Words: fungal infections, central nervous system, neuroimaging (Top Magn Reson Imaging 2014;23: 199–212)

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he incidence of invasive fungal diseases has been rising since the later part of the 20th century. This rise is postulated to originate from the combination of the increase in the overall prevalence of AIDS worldwide, the increase in organ transplantation, and improvements in both diagnostic imaging and laboratory detection techniques.1 The central nervous system (CNS) infection, overall, is still an uncommon manifestation of fungal dissemination.2 Clinical signs and symptoms may be nonspecific, laboratory cultures are oftentimes negative, and neuroimaging features can be nonspecific, as well.3–5 In fact, fungal CNS lesions are often mistaken on neuroimaging as tumors, pyogenic abscesses, or meningitis, such as a tuberculosis.5 Immunocompetent individuals might be susceptible to invasive fungal infections under certain circumstances, such as, near drowning, post–neurosurgical procedures, and severe trauma.2 It has been reported that, in HIV-negative CNS mycosis, 30% of the immunocompetent patients were farmers exposed to high amounts of aerosolized manure, pigeon excrement, and compost daily, whereas 28% were young men with no comorbidities.6 Blastomycosis has been shown to disseminate to the CNS after infection of immunocompetent individuals at a rate of 5%, compared with HIV patients who had a rate of CNS dissemination of 40%.7 Cryptococcus has been shown to affect intact immune systems up to 30% of the time.1 From the *Department of Radiology, Section of Neuroradiology, Tulane University School of Medicine, New Orleans, LA; †Department of Radiology, Section of Neuroradiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; and ‡Department of Radiology, Section of Neuroradiology, Louisiana State University Medical Center, Shreveport, LA. Reprints: Enrique Palacios, MD, FACR, 107 English Turn Dr, New Orleans, LA 70131 (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright © 2014 by Lippincott Williams & Wilkins

Intra-Axial Disease Intra-axial infections refer to parenchymal disease, which generally arises from large fungal agents with a size sufficient to affect large vessels; however, small fungi such as Cryptococcus may seldom be involved. They may manifest as granulomas, cerebritis, or abscess formation. Granulomas are most likely to be found in the frontal lobe or anterior cranial fossa. Cerebritis is the earliest manifestation of a cerebral infection with formation of a poorly defined area of coagulative necrosis that can progress into an abscess.

Extra-Axial Disease Extra-axial disease generally refers to fungal meningitis. Small unicellular yeasts have the correct size to reach and to inflame the meninges. Most cases are caused by Cryptococcus, with Candida second in incidence. Fortunately, the number of fungal meningitides has been decreasing in Western states, thanks to the highly active antiretroviral therapy (HAART) and azoles; however, it still remains a significant problem in developing countries. Extra-axial disease is commonly an extension from fungal infection from the paranasal sinuses.1 This extension can occur through direct invasion into the adjacent orbits, cavernous sinus, and CNS, resulting in thrombosis, ischemia, proptosis, vascular invasion, and aggressive osseous destruction. The primary site of infection is usually the middle turbinates, with predilection for the ethmoid and sphenoid sinuses, usually unilateral. Central nervous system infection may also begin via vascular invasion, especially with the angioinvasive fungi of Aspergillus and the family of Mucorales.10

Vasculitis Certain fungi can gain access to the vasculature by using the enzyme elastase to weaken the elastin-rich arterial wall.11 Elastase-positive fungi display greater invasiveness. Elastin digestion incites an inflammatory reaction that results in a

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vasculitis. The inflammation creates in situ thrombosis, risking emboli of both thrombi and hyphae where infarction and hemorrhage may ensue.1 Vessel invasion from the parenchyma lesion or cavernous sinuses may also occur.10–12

Mycotic Aneurysms Mycotic aneurysms are aneurysms caused by an infectious process, most commonly by hematogenous spread. Fungal use of elastase to digest vessel walls may create wall weakness, leading to focal dilatation of the vessel wall and risk for parenchymal and/or subarachnoid hemorrhage. A pseudoaneurysm refers to a contained extravasation of a ruptured blood vessel.9,12 Mycotic aneurysms represent approximately 0.7% to 4% of all intracranial aneurysms.9,13 Most intracranial pseudoaneurysms are, in fact, bacterial in origin and currently arise from intravenous drug use, immunosuppression, or intravascular procedures. Before antibiotics, the most common cause was infectious endocarditis.9,13 Mycotic aneurysm, thus, is a misnomer , and a true mycotic aneurysm from fungi is extremely rare. In decreasing order, the most commonly affected vessels are the aorta, peripheral arteries, and the cerebral arteries.9,13 Intracranially, fungal causative agents include Aspergillus, Candida, Mucorales, and Coccidiodes, although Aspergillus was the most common; however, the most common overall are Staphylococcus and Streptococcus bacteria.9,13

Spinal Infections Fungal infections of the spine most often occur from hematogenous spread from infected devices such as intravascular lines or hardware implantation and, secondarily, from other infected organs. They can also occur more rarely as a complication in open spinal surgery. When the infection is hematogenous, it seeds the more vascularized areas of the vertebral column. The vertebral endplate is most likely seeded first, followed by the intervertebral disk and, in more severe cases, extension into the perispinal soft tissues.14

CLINICAL PRESENTATION IN GENERAL The variability on the level of immune responses means that CNS fungal infections clinically can present in subtle, non– specific ways. Intracranial infections can present with syndromes of meningitis, abscess, encephalitis, granulomas, or stroke.15 Chronic sinusitis or proptosis may be manifestations of rhinocerebral fungal disease.10 Spinal infections may be severe enough to produce a myelopathy. The broad clinical spectrum is caused by the various ways in which fungi affect both CNS tissue and vasculature and also by the lack of a proper immune response.12 Hematogenous spread can infect the brain and create diffuse or a localized inflammatory process causing focal neurological deficit. Culturing fungi from CSF can be difficult and oftentimes falsely negative for certain types of fungi.3 Cryptococcus and Histoplasma are the only 2 that have specific antigen testing from the CSF.4

MATERIALS, METHODS, AND RESULTS We reviewed the neuroimaging as well as the clinical presentations, management, and evolution of fungal infections in the CNS and spine in 24 patients during a 10-year period. These patients included 16 males and 8 females, ranging from 10 to 67 years of age. The patients selected were diagnosed with fungal infections on the basis of neuroimaging as well as biopsy, with cultures and at autopsy. All but 1patient were immunocompromised, 3 had chronic and uncontrolled diabetes mellitus, and 2 had malignancies.

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DISCUSSION Neuroimaging Brain A lack of a proper immune response means that fungal infections will not be attacked in a predictable, consistent fashion among different individuals. Imaging features will thus be nonspecific.16 These are frequently misdiagnosed as brain tumors, tuberculous meningitis, or even pyogenic abscesses.12 Non– specific findings include imaging characteristics of an abscess, solid-enhancing lesion, hydrocephalus, mycotic aneurysms, meningeal enhancement, infarction, or edema, or hemorrhage.9,17 Disease may be easier to detect in immunocompetent hosts because of their ability to isolate pathogens and mount targeted immune responses.15 Three big categories of CNS fungal disease are intra-axial, extra-axial, and vasculitic types. Intra-axial parenchymal infections include cerebritis and abscesses. Early diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) features of cerebritis may show hyperintensity and hypointensity of the same region, respectively, indicating restricted diffusion. This is important because T1 postcontrast may not show enhancement and cerebritis on T2/fluid attenuated inversion recovery (FLAIR) may show as a cortical hyperintense area.18,19 Abscesses are ring-enhancing on T1 postcontrast with a centrally hyperintense region on T2. Abscess may also be non–ring-enhancing, which reflects the compromised immunity of the host being unable to isolate pathogen.1 Abscesses may be differentiated on the causal organism type. The fungal type can be differentiated from the non–fungal type by combining aspects of 3 modalities: magnetic resonance (MR), DWI, and Magnetic Resonance Spectroscopy (MRS). Lesions that behave as heterointense ring-enhancing lesion on T2 with non–enhancing irregular projections, irregular walls, and a low ADC have a high probability of being fungal abscesses. These projections are also isointense to hypointense on T1 as well as hypointense on T2 and do not enhance with contrast.20 Bacterial abscesses, meanwhile, are almost uniformly homogenous on DWI.21 Characteristics of Magnetic Resonance Spectroscopy (MRS) include multiple signals between 3.6 to 3.8 ppm assigned to Trehalose, a fungal wall disaccharide, and further increases probability of correct fungal diagnosis.5 It is postulated that bacterial and fungal abscesses are different morphologically because the center of bacterial type may be suppurative, whereas the fungal type is proteinaceous fluid with cellular infiltration.22 Fungal abscess may also be differentiated from the bacterial type on the basis of number and location. The fungal type is more likely multiple and can involve the basal ganglia, whereas the bacterial type is more likely to be singular with basal ganglia sparing.1 Extra-axial manifestations include meningitis and direct extension from sinuses. In fungal meningitis, the CSF may appear “dirty” on T1. Postcontrast T1 shows a thick enhancement of the basilar leptomeninges.19 Vascular disease can take the form of vasculitis or mycotic aneurysms. Vasculitis appears as hypointensity on T2 with restricted diffusion on DWI. If there is hemorrhage involved, hyperintensity and hypointensity will be seen on T1 and T2, respectively.1 Involvement of the skull base and base of the brain may be manifested by plaquelike dural thickening.19 Fungal mycotic aneurysms are more likely to affect the anterior circulation as opposed to the peripheral circulation.9,13 Bacterial mycotic aneurysms are multiple as well as spherical and involve peripheral cerebral vessels, whereas those of a fungal origin more likely infect long segments of proximal portions © 2014 Lippincott Williams & Wilkins



of large cerebral vessels and take on a fusiform shape.1,23 If the aneurysm is more centrally located, such as around the Circle of Willis, it may be difficult to distinguish from a congenital or berry aneurysm. It is important to assess for rapid morphological changes of the aneurysm as well as for any stenosis or occlusion because these point more toward infectious.9,13 Magnetic resonance and computed tomographic (CT) angiography have replaced conventional angiograms via arterial catheters to detect mycotic aneurysms. Multidetector CT angiography, in particular, is the current method of choice with its high sensitivity, rapid acquisition time, high resolution, and 3-dimensional reconstruction. Magnetic resonance, however, boasts a sensitivity of 95% to 100%, with disadvantages including susceptibility to motion artifact and possible intolerance. Development of techniques that enable comprehensive evaluation of the aorta as well as the cerebral and peripheral arteries for those patients unable to tolerate CT angiography is proving to be faster. Fat-suppressed T1 fast 2-dimensional spoiled gradient-echo pulse sequence provides the added advantage of assessing vessel walls and surrounding tissues.13 Computer-assisted diagnosis combined with MR angiography has also shown to increase both the sensitivity and specificity of pinpointing intracerebral aneurysms.24 This has implications to improve standard of care of the highly fatal mycotic aneurysms.

Spine Any regions in the spine and its contents can be involved by fungal processes.5 Candida, Aspergillus, Coccidioides, and Blastomycoces all can involve bony structures, whereas Cryptococcus can infect the spinal cord itself. Candida and Aspergillus show hypointensity on T1 with hyperintensity on T2 in the intervertebral disk space, whereas they may be hypointense on both T1 and T2 if they involve the vertebral body. Aspergillus can produce epidural abscesses. Coccidioides can be a multicentric disease of many different bones, with the vertebral column being the most common site of involvement. Magnetic resonance imaging requires whole-spine evaluation. Typical lesions are well demarcated without osseous deformity. The marrow may show heterogenous signaling. Interverbral disk can be involved, leading to nerve root impingement and cord compression.5 Spinal arachnoiditis can also be seen.25 Blastomycosis is very attracted to infecting bone, most commonly in the lower thoracic and lumbar spine. Imaging shows destruction of the vertebra as well as psoas muscle and epidural abscesses. The intervertebral disk space is not involved.5 Cryptococcus can show hyperintensity on T2 within the spinal cord with or without ring enhancement on T1 postcontrast.1 The vertebral body may also show lytic lesions with discrete margins. The intervertebral disk space is usually preserved.5

Other Clinical Considerations Ventriculostomy-Related Infection Ventriculostomy-related infection (VRI) is a rare but important cause of CNS fungal infections. Ventriculostomy catheters are useful in the setting of closed head injuries/hemorrhages or hydrocephalus for both CSF drainage and monitoring of intracranial pressure. However, these devices do pose an infection risk, which is mainly confined to the CSF and can ultimately lead to ventriculomeningitis. A review of 13 studies of VRI between 1984 and 2011 found that, of 339 total positive cultures, only 4 were fungal infections. Almost all other cases were caused by bacterial skin flora. However, CNS candidiasis is beginning to be recognized as an important complication of all neurosurgical procedures, especially because it is normal skin flora.26 Although rare, it is important to note that the best pharmacological treatment of VRI caused by fungi is neither © 2014 Lippincott Williams & Wilkins

MRI in Fungal Infections of the Brain

completely understood nor determined. Fluconazole or voriconazole is hypothesized to work best because these achieve the highest CSF concentrations.27

Specific Pathogen Imaging Characteristics Cryptococcosis The small-sized encapsulated yeast Cryptococcus is the most common fungal pathogen that infects the brain and is also the most common cause of fungal meningitis in immunocompromised individuals.1,25 In fact, in several areas of Africa, it is the most common cause of meningitis and may be a common cause of parenchymal and vascular disease. The most common species causing disease is C. neoformans. It is treatable today with antifungals; if HIV is present, HAART. However, invasive disease is universally fatal without intervention. Cryptococcus is prolific in distribution and is characteristically found in avian excrement, soil, and certain tree bark. It is so prolific that nearly all adults in New York City test positive for anti–C. neoformans antigens.28 Infection occurs primarily through inhalation and hematogenous dissemination. The most susceptible individuals have impaired cellular immunity especially from HIV, but disease does occur significantly in immunocompetent hosts.25 Cryptococcus has unique invasive properties. It can hijack macrophages and use them as a “Trojan Horse” to bypass host immunity starting from the lungs and through the blood-brain barrier. It can also enter the brain through endocytosis via brain microvascular endothelial cells without disruption of the bloodbrain barrier.28 Cryptococcus also thrives in the CNS because it lacks means to attack the polysaccharide capsule, such as immunoglobulins.5 The role of inositol and its high levels in the brain also contribute to cryptococcal predilection for the CNS. Cryptococcus can use inositol as a sole carbon source, giving it a metabolic advantage. A certain transporter using inositol may also facilitate the crossing of the blood-brain carrier.28 Infection usually begins as meningitis that is most severe at the base of the brain,29 but specific presentations depends on the immune status of the host. Immunocompromised hosts may present with more subtle and gradually evolving symptoms, whereas immunocompetent hosts will more likely have classic signs and symptoms of meningitis as well as papilledema, hydrocephalus, seizures, focal neurological deficits, and cryptococcoma.25,30 Most patients have headache with fever that evolves more than 2 to 4 weeks, with other characteristics including altered mental status, nausea, vomiting, as well as changes in vision, focal neurological deficits, and seizures.25 Another characteristic sign is an afebrile unbearable headache.28 One third of patients can have kidney or skin involvement.30 Communicating hydrocephalus may ensue because of meningeal exudate or obstructive hydrocephalus from a granuloma formation around the choroid plexus.5,29 Ventriculitis can also be seen.15 Magnetic resonance on T1 postcontrast may show leptomeningeal enhancement most prominent at the base of the brain (Fig. 1).1,25 Cryptococcomas are chronic granulomas formed from parenchymal and vascular invasion of Cryptococcus and are commonly found in immunocompetent hosts.1,31 Cryptococcomas can appear hyperintense on T2 masses. They are mostly found in the basal ganglia (Fig. 2).1 Cryptococcomas may enhance on T1 postcontrast, but immunocompromised hosts can lack this feature because of inability to wall off the pathogen (Fig. 3). Effective HAART for HIV patients may induce immune-reconstitution syndrome whereby the host’s immunity suddenly mounts a response to the pathogen. Lesions can then ring-enhance after restoration of immunity.16 Granulomas found along the ependyma in the choroid plexus are characteristic of CNS Cryptococcus www.topicsinmri.com


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FIGURE 1. Cryptococcal meningitis. Post–contrast magnetic resonance images taken from a 37-year-old man with HIV: axial (A) and sagittal (B), revealing cerebellar leptomeningeal contrast enhancement.

(Fig. 4). The spinal cord may also be infected and show similar granuloma-type features that may or may not enhance on T1 postcontrast.1 Cryptococcus has a predilection for the CSF-filled perivascular, or Virchow-Robin, spaces in the subcortical region. Virchow-Robin spaces become dilated because of mucoid gelatinous material from the capsule of the pathogen. Magnetic resonance is the best modality for imaging the “soap-bubble” pattern seen in the basal ganglia, periventricular areas, thalamus, and midbrain (Figs. 5, 6).31 These perivascular dilations forming gelatinous pseudocysts are findings highly consistent with neurocryptococcosis and, on DWI, may show restricted diffusion in these lesions, usually bilateral and symmetrical.1,29 (Fig. 7).

Mucormycoses Mucormycosis refers to a spectrum of diseases manifestations caused by fungi from the order Mucorales (Mucor), which are large filamentous fungi similar to Aspergillus but instead have hyphae that grow at right angles. The most commonly isolated organisms are Rhizopus, Rhizomucor, and Absidia. They can affect the nares, CNS, lungs, gastrointestinal tract, or subcutaneous tissues.32 The hallmark of mucormycosis is an overwhelming angioinvasion leading to vessel thrombosis and eventual tissue necrosis, which manifests as a black eschar formation in later states. This virulence factor means that Mucor easily spreads hematogenously from the primary site.33 Like Aspergillus, Mucor uses elastase to facilitate angioinvasion.34 Mucormycosis most commonly manifests as rhinocerebral disease

with the organism entering the CNS through the paranasal sinuses. Through the nasal route, evolution into rhino-orbito-cerebral disease can easily happen. Common presentations include headache, sinusitis, fever, facial pain and numbness, unilateral periorbital cellulitis, proptosis, as well as chemosis. When cranial neuropathy occurs, cavernous sinus thrombosis must be suspected.33 Hematogenous dissemination from a primary site most commonly invades the CNS, and patients present with sudden neurological deficits or a coma because of cerebral infarction and/or abscess. Mortality from this complication approaches 100%, yet diagnosis can be exceedingly difficult because of the extreme illness of the patient combined with persistently negative blood cultures.33 There are many risk factors for the different types of diseases Mucor can cause. Mucor thrives in acidic and hyperglycemic environments, which is also an environment that inhibits antibiotic properties of host defense cells such as phagocytes.32 Thus, uncontrolled diabetes mellitus is the most common risk factor, especially for CNS mucormycosis, with more than half of patients also presenting with diabetic ketoacidosis.35 Because rhinocerebral mucormycosis is so tightly associated with diabetes mellitus, any diabetic patient with sinusitis or facial/eye pain should be worked up for mucormycosis.34 An iron-rich state is a risk factor for disseminated disease. Patients in renal failure requiring dialysis who are treated with deferoxamine are susceptible because these fungi use the iron-rich deferoxamine to sequester previously unaccessible iron. Acidosis also seems to increase free iron levels, further explaining how patients with ketoacidosis are at risk. Mucor also is becoming a large

FIGURE 2. Cryptococcosis in the basal ganglia. Magnetic resonance images taken from a 56-year-old immunocompromised woman: axial (A) and coronal T2-weighted (B) images showing punctate abnormalities in the basal ganglia, representing inflammatory dilatation of the perivascular spaces. C, Axial postcontrast image revealing ill-defined enhancement in the basal ganglia.

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FIGURE 3. Cryptococcosis. Magnetic resonance images taken from a 38-year-old immunocompromised man: A, Axial non–contrast image. B and C, Axial and coronal post–contrast images, respectively, revealing multiple small enhancing nodules in the basal ganglia bilaterally within the perivascular spaces.

nosocomial problem, especially with its ubiquity and life support systems.33 Isolated CNS Mucor infection is almost always caused by intravenous drug use.35 Spinal mucormycosis has been reported as a complication of leukemia treatment.16 Other risk factors include the following: neutropenia for pulmonary and disseminated mucormycosis, malnutrition for gastrointestinal disorders, trauma, as well as infection in the subcutaneous injection site. With the increasing incidence of diabetes mellitus, organ transplants, cancer, and an increased survival of debilitated patients, the rates for mucormycosis have recently been on the rise.33,36 Imaging characteristically shows sino-orbital and vascular disease. The ethmoid sinus is most frequently involved, with eventual progression into the valveless venous system of the cavernous sinus, orbit, or brain parenchyma. The paranasal sinuses show nonspecific nodular mucosal thickening, commonly without air-fluid levels (Fig. 8). Optic nerve infarction can be assessed with DWI imaging, which shows subtle restricted diffusion in the optic nerve that increases in diffusion restriction as the disease progresses. This is correlated with hypointensity of

the same nerve on ADC map, FLAIR, and T2WI, which may be less revealing.34 Diagnosis by imaging can be very difficult and must be combined with clinical presentation, particularly when the patient has severely decompensated with vascular injury from vascular invasion (Figs. 9–11). Laboratory studies also are difficult because Mucor is rarely isolated from blood or CSF, and there are no reliable serologic tests for this ubiquitous organism, thus culturing of the site is unreliable because the organism can be killed during preparation. Diagnosis ultimately depends on tissue biopsy. A high index of suspicion for rhinocerebral mucormycosis warrants empiric antifungals until results are finalized.33

Aspergillosis Central nervous system aspergillosis is a rapidly progressing and devastating disease with a mortality rate between 85% and 100%. Primary infection most commonly occurs in the paranasal sinuses and lungs but can occur in the ears or secondary to trauma, or neurosurgical devices.37 Common clinical

FIGURE 4. Cryptococcosis. Magnetic resonance images taken from a 37-year-old man with HIV: axial (A) and sagittal (B) post–contrast images revealing a cryptococcoma in the left basal ganglia and subependymal wall. C, Associated with posterior fossa meningitis, manifested with leptomeningeal contrast enhancement. (Same case as that in Fig. 1). © 2014 Lippincott Williams & Wilkins

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FIGURE 5. Cryptococcosis. Post–contrast magnetic resonance images taken from a 60-year-old immunocompromised woman: axial (A) and coronal (B) images revealing nodular non–enhancing lesions in the basal ganglia. These lesions are within dilated perivascular spaces in the basal ganglia, the so-called gelatinous cysts.

presentations include fever, altered mental status, headaches, seizures, and meningitis. The vascular system tends to be involved and can be manifested by vasculitis, infarctions, as well as intraparenchymal and subarachnoid hemorrhages.37,38 Aspergillus, a large filamentous fungus, is a ubiquitous soil organism easily cleared by the immunocompetent and has historically infected individuals who have had chronic exposure, thus giving rise to the pathology of “farmer's lung.”38 Today, the most prevalent risk factors for CNS aspergillosis include immunosuppression, hematological malignancies, diabetes mellitus, and a prior CNS pathology. Diabetes mellitus is proposed to depress phagocyte activity that is crucial for Aspergillus clearance.37 The use of corticosteroids may not only depress immune cells but may also promote fungal germination.12 Underlying CNS pathology may point to possible disruption of the bloodbrain barrier, thus providing easier access to the CNS. Occasionally, there are immunocompetent patients with no apparent risk

factors who are affected by CNS aspergillosis. In this regard, it is proposed that certain immune receptor deficiencies may have predisposed those individuals to a CNS fungal infection.37 The increased use of prophylactics for fungal infections has led to improved length of survival in transplant patients; however, it is important to understand the relationship between the type of prophylactic therapy to be used and the predominant type of fungal infection, such as Candida, a true yeast versus Aspergillus, a true mold.39 After inhalation of aerosolized spores called conidia, Aspergillus may affect the host in 3 ways: allergic aspergillosis, aspergilloma, or invasive aspergillosis. The allergic form is characterized by sinonasal mucosal hypertrophy as well as inflammation and is treated with surgical debridement and corticosteroids. An aspergilloma is a concentrated ball of Aspergillus, necrotic material, and granulation tissue, most often in a preexisting lung lesion. They may stay dormant without systemic invasion. Invasive

FIGURE 6. Cryptococcosis. Non–contrast MR examination: axial FLAIR (A) and proton density (B, C) showing numerous periventricular subependymal cystic or nodular lesions, the so-called gelatinous cysts. Associated periventricular edema is also present.

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FIGURE 7. Cryptococcosis. Images taken from a 58-year-old immunocompromised woman with poorly controlled diabetes mellitus: MR axial images. A, Diffusion-weighted image demonstrating multiple small areas of diffusion restriction in the basal ganglia and white matter. B, T2-weighted image showing hyperintensities in the basal ganglia that enhance after administration of contrast in C.

aspergillosis arises from hematogenous or direct spread from a primary site of infection, most commonly the lungs and rhinosinuses.11,12

Invasive Aspergillus can be disseminated or can be an extension from the sinonasal area (Fig. 13), yet CSF and blood studies are usually negative, thus necessitating the need for

FIGURE 8. Rhinocerebral mucormycosis. Images taken from a 38-year-old man with uncontrolled diabetes mellitus, headaches, diplopia, acute cavernous sinus syndrome, and trigeminal sensory loss: CT coronal (A) as well as MR axial and coronal T2-weighted images (B, C, D, and E) involving the left ethmoid sinus extending into the left orbit and cavernous sinus. F, Magnetic resonance axial post–contrast image revealed an enhancing inflammatory process.


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FIGURE 9. Rhinocerebral mucormycosis. Cerebellar infarction on the left, secondary to angioinvasion. Computed tomographic non–contrast axial image (A), diffusion-weighted image (B), FLAIR image (C), and digital angiogram (D) anterior projection revealing acute occlusion of the left vertebral artery (same case as that in as Fig. 8 ).

diagnostic imaging to confirm diagnosis.12 Aspergillus is angioinvasive because of its ability to produce elastase. Larger cerebral vessels are more likely to be involved as a cause large infarctions; however, small vessels can be involved as well (Fig. 14).1,12 Primary pulmonary dissemination may lead to meningitis, basal skull inflammatory processes, and multiple bilateral lesions in the basal ganglia, brain stem, and brain parenchyma.12 Cerebritis may finally occur via necrotizing factors to neural and glial cells with progression of the infection possibly leading to abscess formation.6 On MR, an Aspergillus abscess may easily resemble a pyogenic abscess and thus must be correlated clinically.40 Characteristics on T1 include circular forms with hypointense centers surrounded by a hyperintensity that subsequently ring-enhances on contrast administration40 (Fig. 15). The hypointense center may reflect hemosiderin-laden macrophages among a hemorrhage, with hyphae located on the periphery. Importantly, however, Aspergillus abscesses may not enhance on contrast because of the failure of host immunity to isolate pathogen.1 T2 may show hypointensity to isointensity in these lesions because of paramagnetic elements such as manganese, iron, and magnesium.11 Diffusion-weighted imaging and ADC show hyperintensity and

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hypointensity, respectively, indicating restricted diffusion.40 There may also be multiple ring-enhancing foci that extend from the brain stem and basal ganglia up to the parenchyma because this organism easily spreads hematogenously.40 Surgical treatment is especially important in CNS aspergilosis treatment. Mortality can improve from 60.4% to 100% down to 25% to 28.6% when neurosurgery and medical treatment are implemented compared with simply medical treatment alone. In fact, surgical resection or aspiration with aggressive medical therapy can be curative of an aspergilloma hemorrhages.37,38

Coccidioidomycosis Cocccidioidomycosis is caused by Coccidioides immitis, yet another dimorphic fungus. This type is also geographically distributed. Endemic areas are the southwestern United States, Mexico, as well as Central and South America.1 Infection occurs through inhalation and causes “valley fever” in some immunocompetent hosts, which is a self-limiting respiratory disease. Because of the arid endemic habitats of Coccidioides, dust storms can aerosolize heavy amounts of the fungus and can cause more severe disease. Hematogenous disseminated disease is found © 2014 Lippincott Williams & Wilkins




FIGURE 10. Rhinocerebral mucormycosis. Subsequent hemorrhagic infarction in the left frontal lobe reflecting angioinvasion. A, Computed tomographic axial non–contrast image. B, Digital angiogram, anterior projection of the left internal carotid artery revealing stenosis of the left middle cerebral and anterior cerebral arteries. (Same case as that in Fig. 8).

in the immunocompromised, those of African or Asian descent, and pregnant women. Dissemination may travel to bone, soft tissues, lymph nodes, skin, and cerebral vasculature.25 The most common manifestation is basilar meningitis, with the most common presenting symptom being headache. Other symptoms include facial palsies, ataxia, diplopia, nausea and vomiting, as well as altered mental status. Complications from meningitis include communicating hydrocephalus, cerebral infarction, and mycotic aneurysms with rupture.5,9,25 Granulomas and abscesses can also form.1,5 Magnetic resonance characteristically shows hyperintensity on both T1 and T2 in the basilar cisterns as well as diffuse leptomeningeal enhancement in these same regions on T1 postcontrast including the Sylvian fissures and pericallosal regions (Fig. 16).1 Leptomeningeal enhancement can also extend to the spinal cord. Other areas with schemic changes seen as hyperintensity on T2 may also be seen in associated areas of meningitis and can be secondary to vasculitis.5 Abscesses are typically demonstrated as ring-enhanced lesions).1 Patients with

intraparenchymal coccidioidomycosis demonstrated on magnetic resonance imaging have a very poor prognosis.25

Candidasis Candidiasis is an invasive fungal disease most commonly caused by Candida albicans, small intracellular yeast found as normal flora of the skin, oral cavity, intestines, and other mucous membranes.26 Central nervous system candidiasis occurs from hematogenous dissemination. Dissemination can result if there is an imbalance between Candida and other normal flora.1 As a result, they can overgrow as a result of systemic antibiotics but also from immunosuppression, diabetes mellitus, or hematologic malignancies.31 Other risk factors include prolonged indwelling catheters, total parenteral nutrition, trauma/burns, neurosurgery, and intravenous drug use.5,26 Vaginally delivered premature infants may also develop CNS candidiasis because, during pregnancy, vaginal flora overgrowth predisposes Candida inoculation of the infant during passage through the birth canal. This is

FIGURE 11. Rhinocerebral mucormycosis. Images taken from a 38-year-old man with uncontrolled diabetes mellitus. Magnetic resonance images of the paranasal sinuses axial (A), coronal (B), and sagittal (C) sections respectively, demonstrating extensive enhancing inflammatory process involving the paranasal sinuses with severe retro-orbital and cavernous sinus extension more pronounced on the left. © 2014 Lippincott Williams & Wilkins

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FIGURE 12. Rhinocerebral mucormycosis. Digital angiogram. A, Anterior projection of the left internal carotid artery demonstrates stenosis of the cavernous portion with pseudoaneurysm formation. B, Occlusion test showing adequate cross flow through the anterior communicating artery. Endovascular occlusion of the pseudoaneurysm was performed (not shown). (Same case as that in Fig. 11).

especially true if there are any birth defects exposing the CNS, such as a meningomyelocele.26 As the fourth leading cause of blood infection in hospitals, CNS candidiasis has been found to be the cause of 50% of death due to candidiasis in general. Candida invades via large vessels, but because of its small size as yeast, it most frequently causes focal necrosis of microvessels. This leads to multiple microabscesses at the gray-white junction, basal ganglia, brain stem, and cerebellum (Fig. 17).5,22 Meningitis and macroabscesses also occur but less frequently. Vascular involvement may lead to basal ganglia infarction and mycotic aneurysms.1 Central nervous system candidiasis predominantly presents as diffuse encephalopathy.22 Imaging may show hypointense lesions on T2, which may be caused by hemorrhage.1 Microabscesses may also be visualized as small ringenhancing lesions. Initial imaging may also reveal restricted

diffusion with multiple punctate hyperintense areas on DWI in these microabscess lesions.22

Nocardia Nocardiosis is an opportunistic, localized, or disseminated granulomatous infection caused by an aerobic actinomycete most commonly found in soil, decomposing vegetation, and other organic matter as well as in fresh and salt water.41 Infection most commonly occurs through the respiratory tract. Manifestations of the disease can range from cutaneous infection caused by traumatic inoculation of the organism in a normal host to severe hematogenous spread to pulmonary or CNS disease in an immunocompromised host.42 Nocardia brain abscess is a rare CNS infection that carries a high mortality rate reaching as high as 34% (Fig. 18), which

FIGURE 13. Acute invasive sinonasal aspergillosis. Images taken from a 9-year-old immunocompromised female patient with chronic leukemia: CT coronal (A) and MR (B-F) images revealing extensive sinonasal inflammatory process on the left with severe left orbital extension with some meningeal involvement on the left.

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FIGURE 14. Aspergillosis. Pathological specimen in an immunocompromised individual with chronic hematologic malignancy showing a pseudoaneurysm in the left cavernous sinus associated with large cerebral infarctions in the left temporal lobe and bilateral basal ganglia.

is considered the highest among brain abscesses caused by microorganisms.43 Central nervous system infection may have no signs or symptoms or may present with focal neurological deficits, seizures, and coma. Nocardia asteroides is the most common species that infects humans. An increasing number of cases are being reported in immunocompetent individuals without predisposing factors.44 Although up to two thirds of Nocardia species infections occur in immunocompetent individuals, more than half the patients with CNS disease are immunocompromised.45

Blastomycosis Blastomycosis is an uncommon cause of fungal CNS disease, caused by Blastomyces dermatitidis. This is a type of dimorphic fungi, which means that it has a filamentous form at 25°C and a yeast form at 35°C.4 It is found in the geographical areas around the Mississippi and Ohio River Valley regions of North America. Infection occurs predominantly via inhalation. The lung is the most common organ involved and it is a chronic disease, frequently asymptomatic or it may mimic tuberculosis.46 Extrapulmonary dissemination most frequently invades the skin, bones, and genitourinary system. Blastomycosis involving the CNS is an uncommon complication but can be fatal when the CNS is involved. It usually presents with non–specific neurological symptoms, with headache as the most common presentation and,


less frequently, focal neurological deficits, altered mental status, vision changes, or seizures.47 Meningitis is the most frequent manifestation; however, intracerebral granulomas, spinal epidural abscesses, as well as osteomyelitis have been reported.46 Blastomycosis, interestingly, does not favor immunocompromised hosts over immunocompetent hosts.5 Magnetic resonance imaging most frequently shows leptomeningeal enhancement, which can be diffuse, basilar, and nodular.46,47 When abscesses occur, they may enhance on T1 postcontrast and, overall, are indistinguishable from the bacterial type.5,46 Granulomas may be hyperintense on T2 along with T1 enhancement with postcontrast.5 Magnetic resonance imaging is more sensitive than CT in CNS blastomycosis, particularly in demonstrating the coexistence of meningitis and intraparenchymal mass lesions.47

Histoplasmosis Histoplasmosis is caused by Histoplasma capsulatum, which is another example of a dimorphic fungus. It is endemic to the Mississippi and Ohio River valleys but is also found in Mexico, South America, Southeast Asia, and sub-Saharan Africa. It originates from bird or bat droppings. It is commonly found in bat-inhabited caves, chicken coops, and soils enriched with these kinds of excrement.1,26 Infection as well occurs through inhalation and may simply be a mild respiratory disease in the immunocompetent individual. Immunocompromised individuals are at risk for this disseminated disease, especially those with AIDS living in endemic areas.1 Magnetic resonance most commonly shows meningeal enhancement. Granulomas are the second most common finding showing hypointensity on T1 and T2 because of paramagnetic substances. Abscesses and cerebritis may occur as well.1,5

CONCLUSIONS Fungal infections of the CNS are devastating complications of seemingly innocuous organisms. As described in this chapter, the clinical presentations and MR findings easily overlap with each other and with other distinct pathological entities. Here, we attempted to describe the different patterns of each fungal organism and to stress the need to correlate the imaging findings with the clinical manifestations because there is significant lack of specificity, both clinically and on imaging. However, neuroimaging with CT and MR should be considered an

FIGURE 15. Aspergillus brain abscess. Images taken from a 36-year-old woman. Magnetic resonance axial images: T2-weighted (A) and T1-weighted (B) post–contrast images revealing a small abscess in the left occipitoparietal area. Minimal meningeal enhancement is noted in the basal cisterns from meningitis. © 2014 Lippincott Williams & Wilkins

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FIGURE 16. Coccidioidomycosis. Magnetic resonance images taken from a 46-year-old immunocompetent man from an endemic area of the southwestern part of the United States: axial FLAIR (A), axial (B), coronal (C), and sagittal (D) images postcontrast revealing diffused inflammatory meningeal enhancement of the basal cisterns, including the posterior fossa.

FIGURE 17. Candidiasis brain abscesses. Images taken from a 67-year-old immunosuppressed man with a hematologic malignancy. A, Computed tomographic axial post–contrast image revealing numerous enhancing microabscesses. B, Magnetic resonance sagittal T2 image showing hyperintensities in the supratentorial and infratentorial spaces representing microabscesses. C, Coronal post–contrast image showing the numerous enhancing microabscesses.

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FIGURE 18. Nocardia brain abscess. Magnetic resonance images taken from a 67-year-old immunocompetent woman: coronal FLAIR (A), coronal (B) and sagittal (C) T2 images, as well as sagittal (D) post–contrast images revealed an intraparenchymal abscess in the left parietal region with associated edema, hemorrhagic component, and minimal peripheral enhancement.

excellent adjunct to the clinical presentation providing the clinician with anatomical information that allows a prompt diagnosis to obtain improved patient outcomes. The increasing incidence of disseminated fungal diseases affecting the CNS highlights the need to learn more about decreasing risk factors, providing effective management and therapy as well as using advanced neuroimaging modalities to aid in diagnosis.

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