Infectious and Noninfectious Inflammatory Diseases of the Brain

Anatomy of the Spaces around the Brain and Its Coverings

Three membranes cover the brain; these layers of connective tissue are collectively called the meninges. They are named, from the outermost layer inward, the dura mater, arachnoid mater, and pia mater. The dura mater (literally, “tough mother”) is also referred to as the pachymeninges and is composed of two layers of very tough connective tissue. The outermost layer is tightly adherent to the skull and represents the periosteum of the inner table. The inner layer is covered with mesothelium and lines the outer subdural space. The two layers separate to form the venous sinuses. The inner layer reflects away from the skull to give rise to the tentorium cerebelli, the falx cerebri, the diaphragma sellae, and the falx cerebelli. The space between the inner table of the skull and the dura mater is the epidural space and it is most closely adherent at the suture lines. The space between the dural covering and the arachnoid is the subdural space. The subdural space is a potential space containing bridging veins, which drain blood from the cortex into the venous sinuses, and outpouchings of the arachnoid (arachnoid villi), which project into the venous sinuses.

Beneath the subdural space are two other layers of connective tissue, the arachnoid mater and pia mater, which together constitute the leptomeninges. The arachnoid is a delicate outer layer that parallels the dura and is separated from the pia by the subarachnoid space, which contains the cerebrospinal fluid (CSF). The pia is closely applied to the brain and spinal cord and carries a vast network of blood vessels. Figure 5-1 illustrates this anatomy.

Epidural Abscess

Epidural abscess is most often the result of infection extending from an operative bed, the mastoids, paranasal sinuses, or infected skull. The imaging findings of epidural abscess are those of a focal epidural mass of low density on computed tomography (CT), low intensity or isointensity on T1-weighted images (T1WI), high signal on T2-weighted images (T2WI/fluid-attenuated inversion imaging [FLAIR]), and restricted diffusion on DWI. Enhancement, particularly on a thickened dural surface or along the margins of the collection, is observed. An epidural abscess can extend into the subgaleal space through emissary veins or intervening osteomyelitis to appear outside the skull, a finding more frequent when the abscess occurs as a postoperative complication. These same veins can lead to thrombophlebitis of draining cerebral veins and sinuses.

Epidural abscesses can dissect across the dural sinuses and thereby cross the midline, distinguishing them from subdural empyemas, which are usually confined by the midline falx. Epidural abscesses, however, like epidural hematomas, are typically confined by sutures ( Fig. 5-2 ).

Subdural Empyema

Disruption of the arachnoid meningeal barrier by infection leads to the formation of CSF collections within the potential compartment of the subdural space. These may present acutely or chronically, and can be sterile or infected at time of presentation. Empyema rather than abscess is the appropriate term for a purulent infection in this potential space. Box 5-1 lists the causes of subdural empyema. Among the several possible mechanisms by which a subdural empyema is thought to form are (1) a distended arachnoid villus, which could rupture into the subdural space and infect it; (2) phlebitic bridging veins (secondary to meningitis), which may infect the subdural space; (3) the subdural space, which may be infected by direct hematogenous dissemination; and (4) direct extension, which may occur through a necrotic arachnoid membrane from the subarachnoid space or from extracranial infections.

Clinical signs and symptoms in this group of patients include fever, vomiting, meningismus, seizures, and increased intracranial pressure. Venous thrombosis or brain abscess develops in about 10% of patients with subdural empyema. The mortality rate from subdural empyema has been reported to range approximately from 12% to 40%. Prompt treatment with appropriate antibiotics and drainage through an extensive craniotomy can result in a favorable outcome.

Features of subdural empyema are those of extracerebral collections over the convexities and within the interhemispheric fissure, which on magnetic resonance (MR) display isointensity on T1WI and high signal on T2WI/FLAIR, and on CT show an isodense to low density extraaxial mass ( Fig. 5-3 ). Empyema may be distinguished from subdural effusion on DWI scans; that is, empyemas are hyperintense on DWI (low apparent diffusion coefficient [ADC]), whereas sterile effusions are low intensity on DWI and have ADCs similar to CSF. There may be effacement of the underlying cortical sulci and compression of the ventricular system. A rim of enhancement may be observed. This enhancement occurs from granulation tissue that has formed over time in reaction to the adjacent infection.

Leptomeningitis

(Lepto) meningitis is inflammation of the pia and arachnoid mater ( Fig. 5-4 ). Leptomeningeal inflammation most often occurs after direct hematogenous dissemination from a distant infectious focus. Pathogens also gain access by passing through regions that may not have a normal blood-brain barrier, such as the choroid plexus. Direct extension from sinusitis, orbital cellulitis, mastoiditis, or otitis media is also common. After septicemia, bacteria may lodge in venous sinuses or arachnoid villi and precipitate inflammatory changes, which in turn can interfere with CSF drainage leading to hydrocephalus. With stagnation of CSF flow, bacteria are offered the opportunity to invade the meninges and indulge themselves. Early in the course of infection, there is congestion and hyperemia of the pia and arachnoid mater. Later an exudate covers the brain, especially in the dependent sulci and basal cisterns. The leptomeninges become thickened. Clinical features are related to patient age. Infants and particularly neonates may have a perplexing clinical picture, lacking physical signs that directly demonstrate meningeal irritation. Young children and adults often declare symptoms of fever, headache, photophobia, and neck pain. Symptoms in the elderly can be perplexing too; these patients not uncommonly present with confusion, depressed levels of consciousness, and stupor.

There may be no abnormal imaging findings in early and successfully treated meningitis. Findings for acute meningitis are (1) high intensity of the subarachnoid fluid on FLAIR; (2) acute cerebral swelling indicative of encephalitis (often leading to herniation and death); and (3) communicating hydrocephalus, with enlargement of the temporal horns and effacement of the basal cisterns. Shortly thereafter, one may identify marked enhancement of the leptomeninges, better visualized on MR than on CT (and much more common with bacterial > viral lesions). Postgadolinium FLAIR images appear to be very sensitive for subarachnoid disease (see Fig. 5-4, B ). Concurrent parenchymal abnormalities may occur from encephalitis or venous infarction. Vasculitis may involve either arteries or veins; hence, patterns of infarction associated with meningitis differ depending on the location, number, and type of vessels involved.

Many additional complications may occur as a result of inflammation involving the meninges. These sequelae are better imaged and characterized than the manifestations of the meningitis itself. Communicating hydrocephalus can occur as both an early and a late manifestation of leptomeningitis, often becoming symptomatic to the point of requiring ventricular shunting. The subacute imaging findings of complicated leptomeningeal infection are those of atrophy, encephalomalacia (infarction), focal abscess, subdural empyema formation, and basilar loculations of CSF ( Box 5-2 ).

Meningitis from sinusitis can produce septic thrombosis of adjacent venous sinuses and pseudoaneurysm formation if the cavernous sinus is affected ( Fig. 5-5 ). In the temporal bone, labyrinthitis ossificans (see Chapter 11 ) may occur as a late finding, secondary to infected CSF, communicating with the endolymph and perilymph presumably through the cochlear aqueduct.

Neonates represent a special case with respect to the cerebral sequelae of bacterial leptomeningitis. The most commonly encountered organisms are gram-negative bacilli, followed by group B Streptococcus, Listeria monocytogenes, and others. The neonatal meningitides are believed to be acquired as a result of the delivery process, chorioamnionitis, immaturity, or iatrogenic problems (e.g., catheters, inhalation therapy equipment). The lack of a developed immune system at birth makes neonates susceptible to organisms that are normally not very virulent. These children frequently have severe parenchymal brain damage as a result of the infection that ultimately produces a multicystic-appearing brain often with hydrocephalus. The imaging findings are those of multifocal encephalomalacia leading to multiple distended intraventricular and paraventricular cysts. This pattern is also seen in Herpes simplex virus (HSV) type 2 viral perinatal infections (with no temporal lobe predilection like HSV-1). In children (1 month to 15 years old), Haemophilus influenzae (H. flu) is a common pathogen associated with upper respiratory infections and can produce a virulent meningitis with vascular infarction. Other bacteria in this group are Neisseria meningitidis and Streptococcus pneumoniae . In adults, S. pneumoniae and N. meningitidis are the most common bacterial organisms producing meningitis. H. flu characteristically has a high rate of subdural effusions.

Inevitably, CSF must be sampled. Clearing a patient for lumbar puncture (LP) requires spotting findings that could lead to acute herniation from the pressure gradient created by the lumbar CSF tap. Be sure that you do not see cerebellar tonsils engaged in the foramen magnum, cerebellar herniation syndromes, obliterated or trapped fourth ventricles (see Chapter 7 ), cerebellar masses or strokes, transtentorial downward herniation, completely effaced basal cisterns/sulci or significant subfalcine herniation. Obliteration of the superior cerebellar and quadrigeminal plate cisterns with sparing of the ambient cisterns is concerning. Better to err on suggesting use of clinical acumen in diagnosing meningitis than clearing a patient for LP and having them herniate and die from the “approved tap.” Words to the wise…from the law firm of Dewey, Cheatham, and Howe.

Leptomeningitis versus Pachymeningitis

Leptomeningitis and pachymeningitis ( Fig. 5-6 ) are entities that may be legitimately separated by their enhancement pattern on MR. Leptomeningeal enhancement follows the pia into the gyri/sulci and/or involves the meninges around the basal cisterns (because the dura-arachnoid is widely separated from the pia-arachnoid here). Pachymeningeal enhancement is thick and linear/nodular following the inner surface of the calvarium, falx, and tentorium and without extension into the sulci or involvement of the basal cisterns. One entity that simulates infectious pachymeningitis is idiopathic hypertrophic cranial pachymeningitis. This rare disorder, characterized by severe headache, cranial nerve palsies, and ataxia, peaks during the sixth decade. The clinical course is chronic with some initial improvement with steroids. Box 5-3 provides a list of conditions that can produce pachymeningeal versus leptomeningeal enhancement.

BOX 5-3

Conditions That Produce Pachymeningeal and Leptomeningeal Enhancement

Pachymeningeal

• Cerebrospinal fluid leak

• Idiopathic hypertrophic pachymeningitis

• Sarcoidosis

• Metastases including those involving the skull

• Shunting

• Postsurgical

• Spontaneous intracranial hypotension

Leptomeningeal

• Acute stroke

• Leptomeningeal infection

• Sarcoidosis

• Subarachnoid hemorrhage

• Metastatic carcinomatosis

Pyogenic Brain Abscess

Cerebral abscess is most often the result of hematogenous dissemination from a primary infectious site. The various causes of cerebral abscess are listed in Box 5-4 . The most frequent locations are the frontal and parietal lobes in the distribution of the middle cerebral artery. Intracranial abscess affects predominantly preadolescent (DMY) and middle-age groups (RN). In part, this is related to the incidence of congenital heart disease, intravenous (IV) drug abuse, acquired immunodeficiency syndrome (AIDS), and tympanomastoid and paranasal sinus infections. In all series there is a preponderance of male patients over female. Abscesses may be unilocular or multilocular, solitary or multiple. A variety of bacterial organisms are commonly cultured from brain abscesses depending upon skin/IV sources (staphylococcus, streptococcus, enterobacteria), heart (streptococcus, staphylococcus) or lung (streptococcus, bacilli, fusobacterium) sources. In addition, numerous other pathogens can infect the brain when the immune system is compromised such as in transplant patients (candida, aspergillus, nocardia, gram-negative bacilli).

Abscess formation has been divided into four stages: (1) early cerebritis (1 to 3 days); (2) late cerebritis (4 to 9 days); (3) early capsule formation (10 to 13 days); and (4) late capsule formation (14 days and later). The cerebritis phase of abscess formation consists of an inflammatory infiltrate of polymorphonuclear cells, lymphocytes, and plasma cells. By the third day, a necrotic center is formed. This deliquescent (we liked the word, so check your medical dictionary) region is surrounded by inflammatory cells, new blood vessels, and hyperplastic fibroblasts. In the late cerebritis phase, extracellular edema and hyperplastic astrocytes are seen. Thus the cerebritis phase of abscess formation starts as a suppurative focus that breaks down and begins to become encapsulated by collagen at 10 to 13 days. This process continues with increasing capsule thickness.

The deposition of collagen is particularly important because it directly limits the spread of the infection. Factors that affect collagen deposition include host resistance, duration of infection, characteristics of the organism, and drug therapy. Steroids may decrease the formation of a fibrous capsule and the effectiveness of antibiotic therapy in the cerebritis phase and may reduce antibiotic penetration into the brain abscess.

Brain abscesses that are spread hematogenously usually occur at the junction of the gray and white matter. Collagen deposition is asymmetric, with the side towards the white matter and ventricle having a thinner wall, resulting in a propensity for intraventricular rupture or daughter abscess formation, which is sometimes useful in distinguishing abscess from tumor (neoplastic walls are uniformly thick). Death from cerebral abscess is due to its mass effect with herniation, abrupt hydrocephalus, and/or the development of a ventricular empyema. In the late capsule phase, there is continued encapsulation and decreasing diameter of the necrotic center.

The imaging characteristics of cerebral infection depends on the pathologic phase during which the inflammation is being examined. In the cerebritis phase, CT demonstrates low-density abnormalities with mass effect. Patchy enhancement may be present. On MR, one may see low intensity on T1WI and high signal intensity on T2WI/FLAIR ( Fig. 5-7 ), typically centered at the corticomedullary junction as well as patchy enhancement. In the late cerebritis phase, ring enhancement may be present. The presence of ring enhancement should not unequivocally imply capsular formation. The surgeon contemplating drainage should appreciate that a firm, discrete abscess may not be present despite ring enhancement. (In patients with multiple abscesses, in eloquent locations, and poor surgical risk, conservative therapy with antibiotics alone has been advocated in conjunction with close monitoring of the clinical and imaging findings.)

On CT, the encapsulated intracerebral abscess shows a low-density center and low-density surrounding the lesion (edema). Ring enhancement is virtually always present on contrast-enhanced computed tomography (CECT) in pyogenic brain abscess. Thickness, irregularity, and nodularity of the enhancing ring should raise the suspicion that one is dealing with a tumor (most of the time) or an unusual infection (e.g., fungus). An uncommon observation on noncontrast CT is the presence of a complete slightly hyperdense ring. This noncontrast ring is most often identified in metastases, but does occur with abscesses and astrocytomas as well.

By the same token, a thin rim of low signal on T2WI and high signal on T1WI ( Fig. 5-8 ) may characterize the wall of an abscess and would help distinguish an abscess from a necrotic tumor. This may be related to free radical formation (secondary to oxidative effect of the respiratory burst of the bacteria), hemorrhage, or other factors. At this point the DWI scan may be bright; however, some cases of cerebritis/encephalitis may also show cytotoxic edema. The low ADC is probably related to high protein, high viscosity, and cellularity (pus) within the abscess cavity.

After 2 to 3 weeks, a mature abscess appears on T1WI as a round, well-demarcated low-intensity region with mass effect and peripheral low intensity (edema) beyond the margin of the lesion. On T2WI/FLAIR, high intensity is noted in the cavity and in the parenchyma surrounding the lesion ( Figs. 5-9, 5-10 ). Most pyogenic lesions enhance with a thin rim surrounding the necrotic center. Tiny abscesses may appear to have nodular enhancement. Multiple ring-enhancing lesions are more consistent with hematogenous dissemination of an infectious focus. Multiple rings in a single location can be seen with daughter abscesses but have also been noted with glioma (and other lesions). Box 5-5 is a partial differential diagnosis of the ring-enhancing lesion.

The vast majority of pyogenic abscesses evoke considerable edema. Remember that the vasogenic edema surrounding the pyogenic abscess will be bright on ADC maps indicating no restricted diffusion, unlike the abscess itself which is dark on ADC with restriction of diffusion. A ring-enhancing lesion that does not evoke much edema and does not have restricted diffusion should steer you away from a diagnosis of abscess. A differential diagnosis, including granuloma, primary or metastatic tumor, and demyelinating disease, is more appropriately proffered in such ambiguous cases. DWI is usually positive in pyogenic abscesses. Unfortunately, many nonbacterial pathogens have not read the literature.

Occasionally, the abscess may spread into the ventricles because of lower collagen content in the medial wall, producing periventricular enhancement and/or layering debris within the ventricles. Hemorrhage is rare in acute bacterial abscesses. However, toxoplasmosis, after treatment, may show hemorrhagic byproducts. Fungal septic emboli may elicit heme.

Ventriculitis

Ventriculitis (ependymitis) can be seen as part of the spectrum of infection including meningitis as a postoperative complication (particularly related to ventricular shunting), or as an isolated finding. Ventriculitis is more commonly seen in neonates with meningitis and is a feature of cytomegalovirus (CMV) infection as well as some puerperal anaerobic infections. Organisms are introduced into the ventricle as a result of bacteremia, from abscess, trauma, or instrumentation of the ventricle or CSF spaces. The ventricles can be enlarged, and on T2WI/FLAIR high intensity can be observed surrounding the ventricles or even within the CSF. The key to the diagnosis is DWI bright layering material or subependymal/choroid plexus enhancement ( Fig. 5-11 ). Periventricular calcification can be seen on CT after neonatal ventriculitis.

Enhancement of the ependyma is also observed in lymphoma and other malignant lesions with subependymal spread.

Choroid Plexitis

Capillaries of the choroid plexus, because of their fenestrated epithelium, serve as a conduit through which infections may gain access to the brain. A second barrier between blood and CSF, the choroidal epithelium, possesses tight junctions and prevents passive exchange of proteins and other solutes. Usually, choroid plexitis is seen in association with encephalitis, meningitis, or ventriculitis. It is rarely seen as an isolated infection. Pathogens with a propensity for producing choroid plexitis include Nocardia and Cryptococcus.

Xanthogranulomatous change to the choroid plexus is bright on DWI and sometimes FLAIR but does not enhance much. The differential diagnosis of choroid plexus disease is provided in Box 5-6 .

Septic Embolus

The most frequent manifestation of infective endocarditis is stroke, with Staphylococcus aureus by far the most common organism. However, sepsis from any cause including pulmonary arteriovenous malformations, pulmonary infection, intravenous drug abuse, infected catheters with cardiac septal defects, and occult infection may produce septic emboli to the brain. Septic emboli are associated with persistent mass effect, edema, and enhancement beyond a 6-week period. This should alert the radiologist to consider septic infarction with development of abscess formation in association with cerebral infarction. The vast majority of septic emboli we see in our population in East Baltimore are related to intravenous drug abuse, and most lead to septic emboli in the lungs, not the brain. When they pass through the lungs or are derived from septic endocarditis/valvular vegetations on the arterial side, they may result in brain abscess, mycotic aneurysm (these occur in distal vessels, usually the middle cerebral artery, and are less likely to hemorrhage; Fig. 5-12 ) or obliterative vasculitis. Mycotic aneurysm often present with intraparenchymal hemorrhage (see Fig. 5-12, B ) leaking into the subarachnoid space in the periphery of the brain, not the circle of Willis.