Tuberculosis and Fungal, Parasitic, and Other Infections

Main Text

Preamble

In this chapter, we continue the delineation of acquired infections that we began in Chapter 12 with pyogenic and viral CNS infections.

We first turn our attention to mycobacterial infections, focusing primarily on tuberculosis (TB) followed by a brief discussion of fungal and parasitic infections. We close the chapter with a brief consideration of miscellaneous and emerging CNS infections to remind us that the “hot zone” is right outside our windows, no matter where we live!

Mycobacterial Infections

Preamble

Mycobacteria are small, rod-shaped, acid-fast bacilli that are divided into three main groups, each with a different signature disease: (1) Mycobacterium tuberculosis (TB), (2) nontuberculous mycobacteria (“atypical” mycobacterial spectrum infections), and (3) Mycobacterium leprae (leprosy). M. tuberculosis causes > 98% of CNS TB and is therefore the major focus of our discussion.

Tuberculosis

Etiology

Most TB is caused by M. tuberculosis. Human-to-human transmission is typical. Animal-to-human transmission via Mycobacterium bovis, a common pathogen in the past, is now rarely encountered. Neurotuberculosis is secondary to hematogenous spread from extracranial infection, most frequently in the lungs.

Pathology

CNS TB has several distinct pathologic manifestations. Acute/subacute TB meningitis (TBM) constitutes 70-80% of cases. An inflammatory reaction (“exudate”) with a variable admixture of exudative, proliferative, and necrotizing components in subarachnoid cisterns is typical finding (13-1)(13-2).

The second most common manifestation of neurotuberculosis is a focal parenchymal infection with central caseating necrosis (TB granuloma or tuberculoma) (13-3). True CNS abscesses are rare. TB pseudoabscess is found in 20% of TB patients coinfected with HIV.

Location

TBM has a striking predilection for the basal cisterns, although exudates in superficial convexity sulci do occur (13-2). Most tuberculomas occur in cerebral hemispheres, especially frontal and parietal lobes and basal ganglia.

Size and Number

Tuberculomas vary in size. The majority are small (< 2.5 cm), and the “miliary” nodules are often just a few millimeters in diameter. “Giant” tuberculomas can reach 4-6 cm.

Tuberculomas also vary in number, ranging from a solitary lesion to innumerable small “miliary” lesions.

Gross Pathology

TBM is a dense exudate that coats the brain surfaces and cranial nerves (CNs) (13-1). The suprasellar/chiasmatic region, ambient cisterns, and interpeduncular fossa are most commonly involved (13-2). Tuberculomas with “caseating” necrosis have a creamy (cheese-like) necrotic center surrounded by a grayish granulomatous rim (13-3).

Clinical Issues

Demographics

CNS TB occurs in both immunocompetent and immunocompromised patients. Among people with latent TB infection, HIV is the strongest known risk factor for progression to active TB. In TB and HIV/AIDS co-infection, each disease greatly amplifies the lethality of the other.

CNS TB occurs at all ages, but 60-70% of cases occur during the first two decades. There is no sex predilection.

Presentation

The most common manifestation of active CNS TB is meningitis (TBM). Presentation varies from fever and headache with mild meningismus to confusion, lethargy, seizures, and coma. Symptoms of increased intracranial pressure and cranial neuropathies are common.

Focal neurologic deficits may occur;one of the most common “brain tumors” in endemic countries is tuberculoma, which accounts for 10-30% of all CNS mass lesions.

Natural History and Treatment

Prognosis depends on the patient’s immune status as well as treatment. Untreated TB can be fatal in 4-8 weeks. Even with treatment, 1/3 of patients deteriorate within six weeks. Overall mortality is 25-30% and is even higher in drug-resistant TB. TB is also the leading cause of communicable disease-related deaths in people with HIV.

Multidrug-resistant TB (MDR TB)is resistant to at least two of the first-line anti-TB drugs (isoniazid and rifampin). Extensively drug-resistant TB (XDR TB)is defined as TB that is resistant to first-line drugs, any fluoroquinolone, and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin).

Common complications of CNS TB include hydrocephalus (70%) and stroke (up to 40%).

Imaging

CT Findings

TB Meningitis

Nonspecific hydrocephalus is the most frequent finding on NECT. “Blurred” ventricular margins indicate extracellular fluid accumulation in the subependymal white matter. As the disease progresses, iso- to mildly hyperdense basilar and sulcal exudates replace and efface the normal hypodense CSF (13-5A). CECT usually shows intense enhancement of the basilar meninges and subarachnoid spaces (13-5B).

Tuberculoma

NECT scans show one or more iso- to slightly hyperdense round, lobulated, or crenated masses with variable perilesional edema. Calcification can be seen in healed granulomas (13-4). CECT scans demonstrate punctate, solid, or ring-like enhancement.

MR Findings

TB Meningitis

Basilar exudates are isointense with brain on T1WI, giving the appearance of “dirty” CSF. FLAIR scans show increased signal intensity in the sulci and cisterns (13-6A). Marked linear or nodular meningeal enhancement is seen on T1 C+ FS sequences (13-5D)(13-6). Tuberculous exudates may extend into the brain parenchyma along the perivascular spaces, causing a meningoencephalitis.

Vascular complications occur in 20-50% of cases. The “flow voids” of major arteries may appear irregular or reduced. Penetrating artery infarcts with enhancement and restricted diffusion are common.

CN involvement is seen in 17-40% of cases. The optic nerve and CNs III, IV, and VII are most commonly affected (13-5C). The affected CNs appear thickened and enhance intensely on postcontrast images (13-5C).

Tuberculoma

Most TB granulomas are solid caseating, necrotizing lesions that appear hypo- or isointense with brain on T1WI (13-7A) and hypointense on T2WI (13-7B)(13-8A). Liquefied areas may be T2 hyperintense with a hypointense rim and resemble abscess.

Enhancement is variable, ranging from small punctate foci to multiple rim-enhancing lesions. Mild to moderate, round or lobulated ring-like enhancement around a nonenhancing center is the most typical pattern (13-8C).

MRS can be very helpful in characterizing tuberculomas and distinguishing them from neoplasm or pyogenic abscess. A large lipid peak with absence of other metabolites, such as amino acids and succinate, is seen in 85-90% of cases.

PET/CT

FDG PET/CT has the unique ability to identify a subset of patients declared cured based on the current standard of care but who still harbor live bacilli capable of causing relapse after therapy is discontinued.

Differential Diagnosis

The major differential diagnosis of TBM is pyogenic or carcinomatous meningitis, as their imaging findings can be indistinguishable. Carcinomatous meningitis is usually seen in older patients with a known systemic or primary CNS neoplasm.

Neurosarcoidosis can also mimic TBM. Infiltration of the pituitary gland, infundibulum, and hypothalamus is common.

The major differential diagnosis of multiple parenchymal tuberculomas is neurocysticercosis (NCC). NCC usually shows multiple lesions in different stages of evolution. Tuberculomas can also resemble pyogenic abscesses or neoplasms. Abscesses restrict on DWI. Tuberculomas have a large lipid peak on MRS and lack the elevated Cho typical of neoplasm.

Nontuberculous Mycobacterial Infections

Nontuberculous mycobacteria (NTM) are ubiquitous organisms that are widely distributed in water and soil. Human disease is usually caused by environmental exposure, not human-to-human contact.

The most common manifestation of NTM in the head and neck is cervical lymphadenitis, typically occurring in children younger than five years old and immunocompromised patients. CNS involvement is rare. When it occurs, it is usually a manifestation of an immune reconstitution inflammatory syndrome (IRIS).

Fungal Infections

Preamble

Fungi are ubiquitous organisms with worldwide distribution. Most CNS fungal infections are opportunistic, acquired by inhaling fungal spores in contaminated dust and soil. Initial pulmonary infection is followed by hematogenous dissemination.

Terminology

CNS fungal infections are also called cerebral mycosis. A focal “fungus ball” is also called a mycetoma or fungal granuloma.

Etiology

Fungal Pathogens

The specific agents vary with immune status. Candidiasis, mucormycosis, and cryptococcal infections are usually opportunistic infections. They occur in patients with predisposing factors, such as diabetes, hematologic malignancies, and immunosuppression. Coccidioidomycosis and aspergillosis affect both immunocompetent (often older adults) and immunocompromised patients.

Aside from Candida albicans (a normal constituent of human gut flora), cryptococcal meningitis is the leading cause of CNS fungal infections in humans.

Environmental Exposure

Coccidioidomycosis occurs in areas with low rainfall and high summer temperatures (e.g., Mexico, southwestern United States, some parts of South America), whereas histoplasmosis and blastomycosis occur in watershed areas with moist air and damp, rotting wood (e.g., Africa, around major lakes and river valleys in North America).

Systemic and CNS Infections

Hematogenous spread from the lungs to the CNS is the most common route of infection, and cryptococcal meningitis is the most common fungal disease of the CNS.

Fungal sinonasal infections may invade the skull base and cavernous sinus directly. Sinonasal disease with intracranial extension (rhinocerebral disease) is the most common pattern of Aspergillus and Mucor CNS infection.

Disseminated fungal disease usually occurs only in immunocompromised patients.

Pathology

CNS mycoses have four basic pathologic manifestations: Diffuse meningeal disease, solitary or multiple focal parenchymal lesions (13-15), disseminated nonfocal parenchymal disease (rare), and focal dura-based masses (rarest).

The most common gross finding is basilar meningitis with congested meninges (13-13). Parenchymal fungal infections can be either focal or disseminated. Fungal abscesses are encapsulated lesions with a soft tan or thick mucoid-appearing center, an irregular reddish margin, and surrounding edema. Disseminated disease is less common and causes a fungal cerebritis with diffusely swollen brain.

Hemorrhagic infarcts (13-9), typically in the basal ganglia or at the gray matter-white matter junction, are common with angioinvasive fungi (13-10). On rare occasions, fungal infections can produce dura-based masses that closely resemble meningioma.

Clinical Issues

Epidemiology

Once uncommon, CNS infections have been rising as the number of immunocompromised patients increases worldwide. Epidemiology varies with the specific fungus. Many infections are both common and asymptomatic (e.g., ~ 25% of the entire population in the USA and Canada are infected with Histoplasma).

Candidiasis is the most common nosocomial fungal infection worldwide. Aspergillosis accounts for 20-30% of fungal brain abscesses and is the most common cerebral complication following bone marrow transplantation. Mucor is ubiquitous but generally infects only immunocompromised patients.

Demographics and Presentation

Immunocompetent patients have a bimodal age distribution with fungal infections disproportionately represented in children and older individuals. There is a slight male predominance. Immunocompromised patients of all ages and both sexes are at risk.

Nonspecific symptoms, such as weight loss, fever, malaise, and fatigue, are common. Many patients initially have symptoms of pulmonary infection. CNS involvement is presaged by headache, meningismus, mental status changes, &/or seizure.

Imaging

General Features

Findings vary with the patient’s immune status. Well-formed fungal abscesses are seen in immunocompetent patients. Imaging early in the course of a rapidly progressive infection in an immunocompromised patient may show diffuse cerebral edema more characteristic of encephalitis than fungal abscess.

CT Findings

Findings on NECT include hypodense parenchymal lesions (13-12A) caused by focal granulomas or ischemia. Hydrocephalus is common in patients with fungal meningitis. Patients with coccidioidal meningitis may demonstrate thickened, mildly hyperdense basal meninges.

Disseminated parenchymal infection causes diffuse cerebral edema. Multifocal parenchymal hemorrhages are common in patients with angioinvasive fungal species (13-11).

Diffuse meningeal disease demonstrates pia-subarachnoid space enhancement on CECT. Multiple punctate or ring-enhancing parenchymal lesions are typical findings of parenchymal mycetomas.

Mycetoma in the paranasal sinuses is usually seen as a single opacified hyperdense sinus that contains fine round to linear calcifications. Fungal sinusitis occasionally becomes invasive, crossing the mucosa to involve blood vessels, bone, orbit, cavernous sinuses, and intracranial cavities (13-19A). Focal or widespread bone erosion with adjacent soft tissue infiltration can mimic neoplasm. Bone CT with reconstructions in all three standard planes is helpful to assess skull base involvement, and T1 C+ FS MR is the best modality to delineate disease spread beyond the nose and sinuses (13-19).

MR Findings

Fungal meningitis appears as “dirty” CSF on T1WI. Parenchymal lesions are typically hypointense on T1WI but demonstrate T1 shortening if subacute hemorrhage is present. Irregular walls with nonenhancing projections into the cavity are typical.

T2/FLAIR scans in patients with fungal cerebritis show bilateral but asymmetric cortical/subcortical white matter and basal ganglia hyperintensity (13-17A). Focal lesions (mycetomas) show high-signal foci that typically have a peripheral hypointense rim surrounded by vasogenic edema. T2* scans may show “blooming” foci caused by hemorrhages or calcification (13-17C). Focal paranasal sinus and parenchymal mycetomas usually restrict on DWI.

T1 C+ FS scans usually show diffuse, thick, enhancing basilar leptomeninges (13-14) or dura-arachnoid thickening (13-17D). Angioinvasive fungi may erode the skull base, cause plaque-like dural thickening, and occlude one or both carotid arteries (13-18)(13-19). Parenchymal lesions show punctate, ring-like, or irregular enhancement (13-15)(13-16).

MRS shows mildly elevated Cho and decreased NAA. A lactate peak is seen in 90% of cases, whereas lipid and amino acids are identified in ~ 50%. Multiple peaks resonating between 3.6-3.8 ppm are common and probably represent trehalose.

Differential Diagnosis

The major differential is pyogenic abscess(es)and tuberculoma. TB can appear similar to fungal abscesses on standard imaging studies. Gross hemorrhage is more common with fungal than either pyogenic or tubercular abscesses. Fungal abscesses have more irregularly shaped walls and internal nonenhancing projections. Resonance between 3.6-3.8 ppm on MRS is typical.

Other mimics of fungal abscesses are primary neoplasm (e.g., glioblastoma with central necrosis) or metastases.

Parasitic Infections

Preamble

Once considered endemic only in countries with poor sanitation and adverse economic conditions, parasitic diseases have become a global health concern, exacerbated by widespread travel and immigration. We begin our discussion of CNS parasitic infections with the most worldwide parasitic infection, cysticercosis. Brain involvement by parasites other than neurocysticercosis (NCC) is relatively uncommon.

Neurocysticercosis

Cysticercosis is the most common parasitic infection in the world, and CNS lesions eventually develop in 60-90% of patients with cysticercosis.

Terminology

When cysticercosis infects the CNS, it is termed NCC. A “cysticercus” cyst in the brain is actually the secondary larval form of the parasite. The “scolex” is the head-like part of a tapeworm, bearing hooks and suckers. In the larval form, the scolex is invaginated into one end of the cyst, which is called the “bladder.”

Etiology

Most NCC cases are caused by encysted larvae of the pork tapeworm Taenia solium and are acquired through fecal-oral contamination. Humans become infected by ingesting T. solium eggs. The eggs hatch and release their larvae that then disseminate via the bloodstream to virtually any organ in the body.

Pathology

Location

T. solium larvae are most common in the CNS, eyes, muscles, and subcutaneous tissue. The intracranial subarachnoid spaces are the most common CNS site followed by the brain parenchyma and ventricles (fourth > third > lateral ventricles) (13-20). NCC cysts in the depths of sulci may incite an intense inflammatory response, effectively “sealing” the sulcus over the cysts and making them appear intraaxial.

Size and Number

Most parenchymal NCC cysts are small (a few millimeters to 1 cm). Occasionally, multiple large NCC cysts up to several centimeters can form in the subarachnoid space (the “racemose” form of NCC that resembles a bunch of grapes). Either solitary (20-50% of cases) or multiple small cysts may occur.

Gross Pathology

Four stages of NCC development and regression are recognized. Patients may have multiple lesions at different stages of evolution.

In the vesicular stage, viable larvae (the cysticerci) appear as translucent, thin-walled, fluid-filled cysts with an eccentrically located, whitish, invaginated scolex (13-21)(13-22).

In the colloidal vesicular stage, the larvae begin to degenerate. The cyst fluid becomes thick and turbid. A striking inflammatory response is incited and characterized by a collection of multinucleated giant cells, macrophages, and neutrophils. A fibrous capsule develops, and perilesional edema becomes prominent.

The granular nodular stage represents progressive involution with collapse and retraction of the cyst into a granulomatous nodule that will eventually calcify. Edema persists, but pericystic gliosis is the most common pathologic finding at this stage.

In the nodular calcified stage, the entire lesion becomes a fibrocalcified nodule (13-23). No host immune response is present.

Clinical Issues

Epidemiology

In countries where cysticercosis is endemic, calcified NCC granulomas are found in 10-20% of the entire population. Of these, ~ 5% (400,000 out of 75 million) will become symptomatic.

Demographics

NCC occurs at all ages, but peak symptomatic presentation is between 15-40 years. There is no sex or race predilection.

Presentation

NCC has a range of clinical manifestations. Signs and symptoms depend on the number and location of larvae, developmental stage, infection duration, and presence or absence of host immune response.

Seizures/epilepsy are the most common symptoms (80%) and are a result of inflammation around degeneration cysts. Headache (35-40%) and focal neurologic deficit (15%) are also common. Between 10-12% of patients exhibit signs of elevated intracranial pressure.

NCC—particularly the subarachnoid forms—can also cause cerebral vascular diseases. These include cerebral infarction, transient ischemic attacks, and cerebral hemorrhage.

Natural History

During the early stages of the disease, patients are frequently asymptomatic. Many patients remain asymptomatic for years. The average time from initial infestation until symptoms develop is 2-5 years. The time to progress through all four stages varies from 1-9 years with a mean of five years.

Treatment Options

Oral albendazole with or without steroids, excision/drainage of parenchymal lesions, and endoscopic resection of intraventricular lesions are treatment options.

Imaging

General Features

Imaging findings depend on several factors: (1) Life cycle stage of T. solium at presentation, (2) host inflammatory response, (3) number and location of parasites, and (4) associated complications, such as hydrocephalus and vascular disease.

Vesicular (Quiescent) Stage

NECT shows a smooth thin-walled cyst that is isodense to CSF. There is no surrounding edema and no enhancement on CECT.

MR shows that the cyst is isointense with CSF on T1 and T2/FLAIR. The scolex is discrete, nodular, and hyperintense (target or dot in a hole appearance) and may restrict on DWI. Enhancement is typically absent. Disseminated or “miliary” NCC has a striking salt and pepper brain appearance (13-25)(13-26) with notable lack of perilesional edema.

Colloidal Vesicular Stage (Dying Scolex)

Cyst fluid is hyperdense relative to CSF on NECT and demonstrates a ring-enhancing capsule on CECT. Moderate to marked edema surrounds the degenerating dying larvae.

MR shows that the cyst fluid is mildly hyperintense to CSF on T1WI and that the scolex appears hyperintense on FLAIR (13-27). Moderate to marked surrounding edema is present (13-24B) and may even progress to a diffuse encephalitis.

Enhancement of the cyst wall is typically intense, ring-like, and often slightly “shaggy”(13-24D)(13-28E). Restricted diffusion in the scolex and viscous degenerating cyst can be present (13-28).

Granular Nodular (Healing) Stage

NECT shows mild residual edema. CECT demonstrates a progressively involuting, mildly to moderately enhancing nodule.

The cyst wall appears thickened and retracted, and the perilesional edema diminishes substantially, eventually disappearing. Nodular or faint ring-like enhancement is typical at this stage (13-24D).

Nodular Calcified (Inactive) Stage

A small calcified nodule without surrounding edema or enhancement is seen on CT (13-24A). Shrunken, calcified lesions are seen as hypointensities on T1WI and T2WI. Perilesional edema is absent.

“Blooming” on T2* GRE is seen and may show multifocal “Blooming” black dots if multiple calcified nodules are present (13-24C). Quiescent lesions do not enhance on T1 C+.

Special Features

“Racemose” NCC shows multilobulated, variably sized, grape-like lesions in the basal cisterns (13-29). Most cysts lack an identifiable scolex. Arachnoiditis with fibrosis and scarring demonstrates rim enhancement around the cysts and along the brain surfaces. Obstructive hydrocephalus is common (13-30).

NCC-associated vasculitis with stroke is a rare but important complication of “racemose” NCC that can mimic TB. Most infarcts involve small perforating vessels, although large territorial infarcts have been reported.

Intraventricular NCC is associated with poor prognosis. Intraventricular cysts may be difficult to detect on CT. FLAIR and CISS are the most sensitive sequences for detecting the cysts on MR. The fourth ventricle is the most common site (50-55%) (13-27) followed by the third ventricle (25-30%), lateral ventricle (10-12%), and aqueduct (8-10%).

Differential Diagnosis

The differential diagnosis of NCC depends on lesion type and location. Subarachnoid/cisternal NCC can resemble TB meningitis. In contrast to NCC, the thick purulent basilar exudates typical of TB are solid and lack the cystic features of “racemose” NCC. Carcinomatous meningitis and neurosarcoid are also rarely cystic.

Abscess and multifocal septic emboli can resemble parenchymal NCC cysts but demonstrate a hypointense rim on T2WI and restrict strongly on DWI. A succinate peak on MRS helps distinguish a degenerating NCC cyst from abscess.

A giant parenchymal colloidal-vesicular NCC cyst with ring enhancement can mimic neoplasm, tuberculoma, or toxoplasmosis. Differential diagnosis of intraventricular cyst includes colloid cyst (solid), ependymal cyst (cystic but lacks a scolex), and choroid plexus cyst.

Echinococcosis

Terminology and Etiology

Two species of Echinococcus tapeworms, Echinococcus granulosis (EG) and Echinococcus multilocularis/alveolaris (EM/EA), are responsible for most human CNS infections. EG infection is also called hydatid disease or hydatid cyst (HC). Infection with EM/EA is also known as alveolar echinococcosis.

Epidemiology

After NCC, echinococcosis is the second most common parasitic infection that involves the CNS. Humans become accidental intermediate hosts by ingesting eggs in soil contaminated by excrement from a definitive host. Approximately 1-2% of patients with EG and 3-5% of patients with EM/EA develop CNS disease.

EG usually affects children, whereas EM/EA is more common in adults.

Pathology

EG and EM/EA differ in gross appearance. EG typically produces a well-delineated cyst (13-31). EM/EA has numerous irregular small cysts and appears as an infiltrative, invasive, tumor-like lesion in both the liver and brain.

HCs can be uni- or multilocular with “daughter” cysts. The wall of an HC has three layers: An outer dense fibrous pericyst, a middle laminated membranous ectocyst, and an inner germinal layer (the endocyst). It is the germinal layer that can produce “daughter” cysts.

Imaging

The most common imaging appearance of HC is that of a large, unilocular thin-walled cyst without calcification, edema, or enhancement on CT and MR (13-32). Occasionally, a single large cyst will contain multiple “daughter” cysts (13-34).

Cyst fluid is generally isointense with CSF on both T1- and T2WIs. Sometimes, a detached germinal membrane and hydatid “sand” can be seen in the dependent portion of the cyst (13-33).

EA consists of numerous irregular cysts that are not sharply demarcated and exhibit irregular peripheral, ring-like, nodular, or even cauliflower-like enhancement (13-35).

Amebiasis

Terminology and Etiology

Amebae are species of free-living organisms that are distributed worldwide. Acanthamoeba can be found in soil and dust, fresh or brackish water, and a variety of other locations, from hot tubs and hydrotherapy pools to contact lens solutions and dental irrigation units. Balamuthia mandrillaris is a soil-dwelling organism. Naegleria fowleri is found in both soil and fresh water. Entamoeba histolytica occurs in food or water that has become contaminated with feces.

Pathology

Primary amebic meningoencephalitis (PAM) causes a necrotizing, hemorrhagic meningitis and angiitis (13-36). Granulomatous amebic encephalitis (GAE) demonstrates granulomatous inflammation. Amebic abscesses do occur but are rare.

Clinical Issues

PAM is an acute, rapidly progressive necrotizing hemorrhagic meningoencephalitis caused by N. fowleri and is most often contracted by swimming in fresh but contaminated water, usually in summer. GAE shows no seasonal predilection and is caused by Acanthamoeba or B. mandrillaris.

Imaging

A broad spectrum of imaging findings in amebic meningoencephalitis has been described, including meningeal exudates, multifocal hemorrhagic parenchymal lesions (13-37), and necrotizing angiitis.

Malaria

Terminology and Etiology

Cerebral malaria (CM) is caused by infection with the protozoan parasite Plasmodium and is transmitted by infected Anopheles mosquitoes. Four species cause human disease: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. Of these, P. falciparum has the most severe manifestations and causes 95% of all CM cases.

Pathology

Grossly, the brain appears swollen, and its external surface is often a characteristic grayish or dusky dark red. Petechial hemorrhages are often seen in the subcortical white matter, corpus callosum, cerebellum, and brainstem (13-40).

The major microscopic feature of CM is sequestration of parasitized red blood cells in the cerebral microvasculature (13-38). This causes perivascular ring and punctate microhemorrhages and focal infarcts. Malaria parasites remain intravascular, so encephalitic inflammatory changes are absent.

Clinical Issues

Between 250-500 million new cases of malaria develop every year, and more than 500,000 people die from the disease.

Malaria is generally restricted to tropical and subtropical areas but may affect travelers or immigrants coming from endemic regions. The incubation period from infection to symptom development is generally 1-3 weeks.

Prognosis is variable. Patients with sickle cell trait generally have milder disease. In other cases, headache, altered sensorium, and seizures develop and can be followed within 1-2 days by impaired consciousness, coma, and death. Mortality in CM is 15-20% even with appropriate therapy.

Imaging

The most typical finding is focal infarcts in the cortex, basal ganglia, and thalami (13-39). Gross hemorrhage can occur but is rare. Multifocal “blooming” petechial hemorrhages in the basal ganglia and cerebral white matter may be present on susceptibility-weighted imaging (13-41).

Differential Diagnosis

The major differential diagnosis of CM is multiple cerebral emboli/infarction. Multifocal white matter petechial hemorrhages on T2* and SWI are nonspecific and can be seen in fat emboli syndrome, acute hemorrhagic leukoencephalitis, trauma with diffuse vascular injury, thrombotic microangiopathies, viral infections (e.g., COVID-19), and critical-illness associated microbleeds.

Other Parasitic Infections

Several less common parasites can invade the CNS, particularly if humans serve as intermediate or nonpermissive hosts. These include schistosomiasis, paragonimiasis, sparganosis, trichinosis, and trypanosomiasis.

Many parasites cause very bizarre-looking masses that can mimic neoplasm (13-42). A history of travel to—or residence in—an endemic area is key to the diagnosis.

“Parasitomas” usually present as mass-like lesions with edema and multiple “conglomerate” ring-enhancing foci (13-43). CNS parasitic infestations can be mistaken for neoplasms like metastasis and glioblastoma. Inflammatory granulomas (e.g., TB granulomas) can also mimic parasitic granulomas and are often endemic in the same geographic areas.

Miscellaneous and Emerging CNS Infections

Preamble

We begin this section with two important CNS infections caused by spirochetes—Lyme disease (LD) and neurosyphilis (NS)—then turn our attention to emerging CNS infections. We pay special attention to zoonoses (i.e., diseases transmitted from animals to humans) with a focus on the manifestations of COVID-19 and the deadly viral hemorrhagic fevers.

Spirochete Infections of CNS

Two spirochete species can cause significant CNS disease: Borrelia (e.g., LD, relapsing fever borreliosis) and Treponema (NS).

Lyme Disease

Terminology

LD is a.k.a. Lyme borreliosis. LD with neurologic disease is called Lyme neuroborreliosis (LNB) or neuro-LD. LD is a multisystem inflammatory disease caused by Borrelia burgdorferi in the United States and Borrelia garinii or Borrelia afzelii in Europe. LD is a zoonosis maintained in animals, such as field mice and white-tailed deer.

Etiology

LD is transmitted to humans by Ixodes tick bite and requires at least 36 hours of tick attachment as the spirochete moves from the tick midgut to the salivary glands to be transmitted. Most cases result from the bite of an infected nymph (about the size of a poppy seed) and may easily go unnoticed.

Epidemiology and Demographics

LD is now the most common tick-borne disease in the United States and Europe with 20,000 new cases reported each year. Prevalence varies significantly with geography. Between 90-95% of cases in the USA occur in the mid-Atlantic states, the Northeast, and the upper Midwest (primarily Minnesota and Wisconsin). Occurrence peaks during the early summer, especially May and June.

The clinical presentation and imaging features of CNS LD are protean and vary with location. Altered mental status and encephalopathy are the most common manifestations.

Clinical Features

LD occurs at all ages, but peak presentation is between 16-60 years. 30% of cases occur in children.

Altered mental status and encephalopathy are the most common general manifestations of LD. The classic triad of LD consists of aseptic (usually lymphocytic) meningitis, cranial neuritis, and radiculoneuritis. In North America, erythema migrans, “Lyme arthritis,” and carditis are also common.

Pathology

Microscopic features include nonspecific, perivascular, T-lymphocytic cuffing and plasma cell infiltrates. Spirochetes can be identified in the leptomeninges, nerve roots, and dorsal root ganglia but not in the CNS parenchyma.

Imaging

Approximately 12-15% of patients with untreated B. burgdorferi infection develop CNS involvement. NECT and CECT scans are usually normal.

Multiple small (2- to 8-mm) subcortical and periventricular white matter hyperintensities on T2/FLAIR sequences are typical and identified in ~ 1/2 of all patients (13-44). Enhancement varies from none to moderate. Multiple punctate and ring-enhancing lesions may be present (13-46). Occasionally, “horseshoe” or incomplete ring enhancement occurs and can mimic demyelinating disease.

Cranial nerve (CN) enhancement is seen on T1 C+ but can be clinically occult. CN enhancement is especially common in North American LNB (13-45). CNVII is the most frequently involved followed by CNV and CNIII. Involvement of other CNs is less common.

Myelitis and radiculitis are more common in European LD. Diffuse or multifocal hyperintense lesions on T2WI with patchy cord and linear nerve root enhancement are typical.

Differential Diagnosis

The major differential diagnosis of LNB is demyelinating disease. Multiple sclerosis (MS) frequently involves the periventricular white matter. Callososeptal involvement is more common in MS compared with LNB. CN enhancement—especially CNVII—is less common than with LNB.

Neurosyphilis

Syphilis is a chronic systemic infectious disease caused by the spirochete Treponema pallidum. Syphilis is usually transmitted via sexual contact. Between 5-10% of patients with untreated syphilis develop neurosyphilis (NS).

Syphilitic gumma is the most common intracranial manifestation. Most are located along the brain subpial surfaces and consist of a dense inflammatory infiltrate surrounding a central caseous necrotic core. Imaging is that of a mixed-density/signal intensity mass with intense ring-like or diffuse enhancement (13-47). Because of their rarity, most syphilitic gummas are initially misdiagnosed as primary or metastatic neoplasms.

SPIROCHETE CNS INFECTIONS

Lyme Disease (Neuroborreliosis)

• 12-15% of infected individuals develop CNS infection

• Cranial neuropathy

 CNVII > CNV, CNIII; others less common

 Can affect multiple nerves

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