Fundamentals of Diagnostic Radiology
3rd Edition

Chapter 7
White Matter and Neurodegenerative Diseases
Jerome A. Barakos
In contrast to gray matter, which contains neuronal cell bodies, white matter is composed of the long processes of these neurons. The axonal processes are wrapped by myelin sheaths, and it is the lipid composition of these sheaths for which white matter is named. In this chapter, a host of diseases characterized by the involvement of white matter is described. This is followed by a discussion of hydrocephalus and neurodegenerative disorders.
The marked sensitivity of T2WIs allows white matter lesions to be readily detected. The difficulty that confronts the radiologist is that a wide gamut of diseases may involve the white matter, and these lesions are often nonspecific in nature. An understanding of these white matter diseases, their clinical features, and parenchymal patterns of involvement is important in enabling the radiologist to generate a useful differential diagnostic list.
Cerebral white matter diseases are classified into two broad categories: demyelinating and dysmyelinating. Demyelination is an acquired disorder that affects normal myelin. The vast majority of white matter diseases, especially in the adult, fall into this category and are the principal focus of this chapter. In contrast, dysmyelination is an inherited disorder affecting the formation or maintenance of myelin, and thus is typically encountered in the pediatric population. Dysmyelination is rare and is discussed later in this chapter.
DEMYELINATING DISEASES
Demyelinating disease can be divided into four main categories based on etiology: (1) primary, (2) ischemic, (3) infectious, and (4) toxic and metabolic (Table 7.1).
Primary Demyelination
Multiple sclerosis (MS) is the classic example of a primary demyelinating disease. MS is a disease characterized by immune dysfunction in the production of abnormal immunoglobulins and T cells, which are activated against myelin and mediate the damage associated with the disease. MS is a chronic, relapsing, often disabling disease affecting more than a quarter of a million people in the United States alone. The age of onset is between 20 and 40 years, with only 10% of cases presenting in individuals older than 50. There is a female predominance of almost two to one. Although several environmental factors have been associated with MS, such as higher geographic latitudes and upper socioeconomic status, the etiology of MS remains unclear.
Establishing a diagnosis of MS is challenging, because no specific examination, laboratory test, or physical finding is unequivocally diagnostic or pathognomonic of this disorder. Making a diagnosis of MS is portentous, as there are significant implications on many aspects of one’s life, including eligibility for health insurance. However,
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establishing the diagnosis is important because promising therapies are available, including β-interferon and antineoplastic drugs. These agents suppress the activity of the T cells, B cells, and macrophages that are thought to lead the attack on the myelin sheath.
TABLE 7.1 Classification of White Matter Diseases
Primary demyelination
   Multiple sclerosis
Ischemic demyelination
   Deep white matter infarcts
   Lacunar infarcts
   Vasculitis (including sarcoidosis and lupus)
   Dissection
   Thromboembolic infarcts
   Migrainous ischemia
   Moyamoya disease
   Postanoxia
Infection-related demyelination
   Progressive multifocal leukoencephalopathy
   HIV encephalopathy
   Acute disseminated encephalomyelitis
   Subacute sclerosing panencephalitis
   Lyme disease
   Neurosyphilis
Toxic and metabolic demyelination
   Central pontine myelinolysis
   Marchiafava-Bignami disease
   Wernicke-Korsakoff syndrome
   Radiation injury
   Necrotizing leukoencephalopathy
Dysmyelination (inherited white matter disease)
   Metachromatic leukodystrophy
   Adrenal leukodystrophy
   Leigh disease
   Alexander disease
The classic clinical definition of MS is multiple CNS lesions separated in both time and space. Patients may present with virtually any neurologic deficit, but they most commonly present with limb weakness, paresthesia, vertigo, and visual or urinary disturbances. Important characteristics of MS symptoms are their multiplicity and tendency to vary over time. The clinical course of MS is characterized by unpredictable relapses and remissions of symptoms. The diagnosis can be supported with clinical studies, which include visual, somatosensory, or motor-evoked potentials and analysis of CSF for oligoclonal banding, immunoglobulin G index, and presence of myelin basic protein. Histopathologically, active MS lesions represent areas of selective destruction of myelin sheaths and perivenular inflammation, with relative sparing of the underlying axons. These lesions may occur throughout the white matter of the CNS, including the spinal cord. The inflammatory demyelination interrupts nerve conduction and nerve function, producing the symptoms of MS. Note that histopathologically, the inflammation is a key differentiating feature between MS and other white matter conditions, such as osmotic myelinolysis (central pontine and extrapontine myelinolysis) and posterior reversible encephalopathy syndrome (PRE), which lack inflammatory changes.
MR is the most sensitive indicator in the detection of MS plaques, but imaging findings alone should never be considered diagnostic. In clinically confirmed cases of MS, MR typically demonstrates lesions in more than 90% of
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cases. This compares with far less than 50% for CT and 70% to 85% for laboratory tests such as brainstem-evoked potentials and CSF oligoclonal bands. Nevertheless, the ultimate diagnosis rests with the careful combination of clinical symptoms, history, and clinical testing, including MR imaging.
FIGURE 7.1. Multiple Sclerosis. T2WI of a 26-year-old woman with MS demonstrates a cluster of periventricular white matter lesions. These lesions are ovoid, and many are perpendicular to the long axis of the ventricles (perivenular in location, referred to as Dawson’s fingers) (arrows). Although the periventricular lesions are very suggestive of MS, these lesions are nonspecific and must be correlated with clinical examination and other clinical studies (visual, somatosensory, or motor-evoked potentials, and analysis of CSF for oligoclonal banding and immunoglobulin G index) before confirming a diagnosis of MS. These lesions may be indistinguishable from other demyelinating conditions, such as acute disseminated encephalomyelitis, Lyme disease, and autoimmune/connective tissue disorders such as systemic lupus erythematosus.
A variety of T2WI techniques have been described for optimizing the detection of white matter lesions, including conventional spin-echo (SE) imaging, fast SE (FSE), short tau inversion recovery (STIR), and fluid-attenuated inversion recovery (FLAIR) sequences. As the name suggests, FLAIR imaging has the advantage of providing heavy T2 weighting while suppressing signal from CSF. As such, FLAIR images provide improved lesion conspicuity of periventricular lesions, which may be obscured by the bright signal of CSF on SE or FSE T2WIs. Comparative studies have demonstrated that FLAIR imaging provides the best visualization of supratentorial white matter lesions. However, the FLAIR sequence may have mild limitations when imaging the posterior fossa and spine, partly because of pulsation artifacts.
MS plaques are typically round or ovoid, with a periventricular or subcortical location (Fig. 7.1). Lesions are bright on T2WIs, reflecting active inflammation or chronic scarring, and only a fraction of MS plaques will demonstrate contrast enhancement. Lesions that enhance are thought to reflect new lesions with active demyelination and disruption of the blood–brain barrier (Fig. 7.2). In older lesions, without residual inflammatory reaction, abnormal high signal on T2WIs persists, reflecting residual scarring. Within the CNS, cells can mount only a limited response to neuronal injury. This scarring typically manifests as a focal proliferation of astroglia at the site of injury, termed gliosis. In severe cases of MS, actual loss of neuronal tissue may occur and the white matter lesions may actually have dark signal on T1WIs, often referred to as the “dark lesions” of MS. These lesions are prognostically significant, since they reflect actual loss of underlying neuronal tissue rather than simple demyelination. Additionally, in chronic cases of MS, there is diffuse loss of deep cerebral white matter, with associated thinning of the corpus callosum and potential ex vacuo ventriculomegaly.
MS lesions are nonspecific, and many of the diseases and conditions discussed in this chapter may have a similar appearance. Patients with migraines are especially challenging, because both their symptoms and imaging findings may closely mimic those of MS. A pattern that is suggestive of MS is one of periventricular lesions that are ovoid and aligned perpendicular to the long axis of the ventricles. This pattern is the result of the alignment of the lesions along the perivenular spaces. Additional characteristic features include lesions along the callosal septal interface, as well as lesions that are confluent in nature and greater than 6 mm in diameter with a periventricular location (Fig. 7.3).
In addition to the periventricular white matter, the cerebellar and cerebral peduncles as well as the corpus callosum, medulla, and spinal cord can be involved in MS (Fig. 7.4). Ischemic changes are rare in these locations; as a result, if periventricular lesions are accompanied by lesions in any of these areas, this dramatically increases the specificity for the diagnosis of MS. For example, because ischemic changes rarely involve the medulla and cerebellar/cerebral peduncles, the presence of posterior fossa lesions is a useful differential diagnostic factor in suggesting
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MS. This is particularly important in patients older than 50 years, because it is difficult to decide whether multifocal white matter lesions are the result of ischemia or a demyelinating process. Additional concepts for making this distinction are discussed in the next subsection.
FIGURE 7.2. Multiple Sclerosis With Lesion Enhancement. Images of a 28-year-old woman with a recent flareup in clinical symptoms. Axial fast spin-echo T2W (A) and gadolinium-enhanced T1W (B) images reveal interval development (compared to prior MR exam performed 6 months earlier) of a new contrast-enhancing lesion within the right brachium pontis (arrow). The larger left anterior pontine lesion (curved arrow) is unchanged when compared to the earlier exam and fails to enhance. Contrast enhancement is reflective of actively demyelinating lesions and can be used to assess disease activity.
FIGURE 7.3. Multiple Sclerosis With Callosal–Septal Involvement. Sagittal fluid-attenuated inversion recovery images show lesions located along the ventricular ependymal surface (arrows) as well as along the callosal–septal interface (open arrows), which are very characteristic for MS. The callosal–septal interface refers to the region where the septum pellucidum contacts the undersurface of the corpus callosum.
MS lesions may also present as a large, conglomerate, deep white matter mass that can be mistaken for a neoplasm (Fig. 7.5). A characteristic finding in these conglomerate MS plaques is that they often demonstrate a peripheral crescentic rim of contrast enhancement, which
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represents the advancing region of active demyelination. Detecting this pattern of enhancement, and searching carefully for other more characteristic periventricular lesions, are helpful in distinguishing a giant MS plaque from a neoplasm.
FIGURE 7.4. Multiple Sclerosis With Brainstem Involvement. MR images of a 31-year-old male with a history of right-sided weakness and sensory changes. Axial proton density–weighted image (A) and coronal fluid-attenuated inversion recovery image (B) reveal a lesion involving the left corticospinal tracts at the level of the midbrain (cerebral peduncle) (arrow). Lesions within the medulla and cerebellar/cerebral peduncles are quite characteristic for MS and serve to support this diagnosis when supratentorial lesions appear nonspecific in nature.
FIGURE 7.5. Tumefactive Multiple Sclerosis. Images from a 32-year-old woman presenting with transient bouts of left hemiparesis, as well as depression and fatigue. Proton density weighted image (PDWI) (A), T2WI (B), and postgadolinium T1WI (C) reveal a large right parietal mass with a peripheral rim of enhancement (arrow). This lesion could easily be mistaken for a neoplasm or progressive multifocal leukoencephalopathy and undergo biopsy. The sagittal T1WI (D) demonstrates the presence of a characteristic periependymal lesion (arrow), suggesting the diagnosis of MS. These are the “dark lesions” of MS, which are of greater concern than simple demyelinating plaques, because they represent actual neuronal loss. The diagnosis of MS was confirmed with additional clinical testing, including evoked potentials and CSF oligoclonal bands.
The spinal cord may also be involved with MS, and whenever a focal abnormality of the spinal cord is detected, a demyelinating MS plaque must be in the differential diagnosis. Demyelinating plaques may have mild mass effect as well as contrast enhancement, thus mimicking a neoplasm. The majority of spinal cord MS lesions (70% to 80%) will have associated plaques in the brain. In the setting of a cord lesion, performing an MR scan of the head may confirm the diagnosis, thus avoiding a spinal cord biopsy (see Chapter 10).
Ischemic Demyelination
Although MR imaging is extremely sensitive in the detection of white matter lesions, a major difficulty in arriving at a diagnosis is that white matter lesions are often nonspecific. Thus, distinguishing MS lesions from other white matter lesions can be difficult. The most commonly encountered white matter lesions are ischemic in origin.
Age-Related Demyelination
Small-vessel ischemic changes within the deep cerebral white matter are seen with such frequency in the older population (>60 years) that they are considered a normal part of aging. This represents an arteriosclerotic vasculopathy of the penetrating cerebral arteries. The deep white matter is more susceptible to ischemic injury than gray matter, because it is supplied by long, small-caliber penetrating end arteries, without significant collateral supply. In contrast, cortical gray matter, as well as parts of the brainstem such as the midbrain and medulla, have robust collateral blood supply, thus minimizing the risk of ischemia. The deep penetrating vessels supplying the white matter become narrowed by arteriosclerosis and lipohyalin deposits. The result is the formation of small ischemic lesions, primarily involving the deep cerebral and periventricular white matter as well as the basal ganglia (Fig. 7.6). The cortex, subcortical “U” fibers, central corpus callosum, medulla, midbrain, and cerebellar peduncles are usually spared because of their dual blood supply, which decreases their vulnerability to hypoperfusion. As previously described, if lesions are identified in these locations, a cause other than ischemia should be entertained.
Histologically, areas of infarction demonstrate axonal atrophy with diminished myelin. Early neuropathologists noted the areas of paleness associated with these changes and coined the term “myelin pallor.” These white matter changes have received many names over the years, including leukoaraiosis, microangiopathic leukoencephalopathy, and subcortical arteriosclerotic encephalopathy. None of these terms are very satisfying, as they do not accurately reflect all the changes observed histologically and overstate the clinical significance of these lesions. A more appropriate term may simply be “age-related white matter changes.” These small ischemic white matter lesions are often asymptomatic, and clinical correlation is always required before a diagnosis of subcortical arteriosclerotic encephalopathy or multi-infarct dementia (Binswanger disease) is made. The white matter infarcts just described differ from lacunar infarcts. Lacunae refer to small infarcts (5 to 10 mm) occurring within the basal ganglia, typically the upper two thirds of the putamina. Both lacunar and deep white matter infarcts have similar etiologies and are the result of disease involving the deep penetrating arteries.
FIGURE 7.6. Ischemic Demyelination. This 72-year-old woman presented with forgetfulness. Axial fast spin-echo T2WI reveals diffuse patchy lesions throughout the subcortical and deep white matter. These lesions are in keeping with ischemic demyelination of the deep white matter, with several old lacunar infarcts of the basal ganglia (arrow). Note the ex vacuo ventriculomegaly resulting from loss of deep cerebral white matter.
Differentiating white matter lesions related to ischemic changes from MS lesions can be difficult, especially in the older patient. This is important because 10% of patients who present with MS are older than 50 years of age.
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Clinical testing and history are helpful. Additionally, deep white matter infarcts tend to spare the subcortical arcuate fibers and the corpus callosum, both of which can be involved with MS. Involvement of the callosal–septal interface is quite specific for MS.
FIGURE 7.7. Antiphospholipid Antibody Syndrome. This 32-year-old woman presented with headaches and a history of several miscarriages. T2WIs demonstrated scattered focal subcortical and deep white matter lesions. Although these lesions are nonspecific, serum testing revealed elevated circulating pathogenic immunoglobulins/antibodies specifically targeting DNA and other nuclear constituents collectively termed antibodies to nuclear antigens, e.g., lupus anticoagulants and anticardiolipin antibodies. This represents an immune complex disease referred to as antiphospholipid antibody syndrome.
Nonspecific punctuate white matter lesions (small bright lesions on T2WIs) are more prominent in any patient with a vasculopathy, whether related to atherosclerosis (age, hypertension, diabetes, hyperlipidemia, coronary artery disease); hypercoagulable conditions; or vasculitis (lupus, sarcoid, polyarteritis nodosa, Behçet syndrome). In younger individuals with punctuate white matter lesions, hypercoagulable states, as well as embolic and vasculitic etiologies, figure prominently (Figs. 7.7, 7.8, 7.9). Hypercoagulable conditions include a diverse set of diseases with the common theme of increased risk of microvascular thrombotic disease. Serum testing can be used to evaluate for the presence of these disease conditions, which include homocystinemia, antiphospholipid syndrome, Factor V Leiden, prothrombin gene mutation, and deficiencies of natural proteins that prevent clotting (the anticoagulant proteins such as antithrombin, protein C, and protein S deficiencies). A classic case presentation is that of a young adult female with prior miscarriages presenting with headaches/migraines and ischemic white matter changes. These findings are suggestive of antiphospholipid syndrome (a.k.a. phospholipid antibody syndrome), where circulating antiphospholipid antibodies (cardiolipin or lupus anticoagulant antibodies) lead to a hypercoagulable state with resultant white matter and ischemic changes.
In the young adult population presenting with small white matter lesions, in addition to hypercoagulable conditions and migrainous ischemia, consider cardiogenic embolic etiologies. An echocardiogram plays an important role in the evaluation of a potential patent foramen ovale
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or valvular vegetation. In many normal children and young adults, subcortical lesions and periventricular hyperintensities are common; they are reported to be present in these locations in 6% and 74%, respectively, of the young normal population. Commonly these punctuate foci of white matter T2 hyperintensity will have no known etiology despite evaluation for all the conditions outlined above. In this setting, these lesions are simply the gliotic residue of a remote unspecified insult, usually an immune-mediated postviral condition.
FIGURE 7.8. Lupus Cerebritis. Image from a 38-year-old woman presenting with cognitive deficits and history of a connective tissue disorder. The T1WI demonstrates numerous dark periventricular lesions with striking loss of deep white matter and associated ex vacuo ventriculomegaly. These dark lesions represent underlying axonal loss with neuronal dropout, reflecting a more severe stage of white matter disease. These findings are characteristic of any severe or long-standing white matter disease such as chronic MS, or as in this case, chronic lupus cerebritis.
FIGURE 7.9. Moyamoya Disease. Six-year-old boy presents with episodes of focal motor weakness. T2WI (not shown) showed multiple scattered subcortical white matter T2 hyperintensities. MR angiography (A) and conventional angiography (B) reveal marked stenosis of the supraclinoid internal carotid vasculature (open arrow), with a dramatic proliferation of tiny collateral vessels (arrows) presenting as a “puff of smoke” (the literal Japanese translation of moyamoya). The cause of this vascular disorder is unknown but can be treated with various external to internal vascular bypass surgeries such as encephaloduroarteriosynangiosis. MR angiography plays a useful role in assessing the patency of these shunts once surgically completed.
Ependymitis granularis is a normal anatomic finding that may mimic pathology. Ependymitis granularis consists of an area of high signal on a T2WI along the tips of the frontal horns (Fig. 7.10). These foci of signal range in width from several millimeters to a centimeter. Histologic studies of this subependymal area reveal a loose network of axons with low myelin count. This porous ependyma allows transependymal flow of CSF, resulting in a focal area of T2 prolongation. Unfortunately, this entity has been given a name that sounds more like a disease entity than a simple histologic observation. Similarly, with the use of FLAIR imaging, a region of periventricular T2 hyperintensity can be noted about the ventricular trigones as a normal finding. With age, prominent periventricular T2 hyperintensity may be noted along the entire length of the lateral ventricles as a normal finding, and this may be referred to as senescent periventricular hyperintensity.
Prominent perivascular spaces can also mimic deep white matter or lacunar infarcts. As blood vessels penetrate into the brain parenchyma, they are enveloped by CSF and a thin sheath of pia. These CSF-filled perivascular clefts are called Virchow-Robin spaces and present as punctate foci of high signal on T2WIs (Fig. 7.11). They are typically located in the centrum semiovale (high cerebral hemispheric white matter) and the lower basal ganglia at the level of the anterior commissure, where the lenticulostriate arteries enter the brain parenchyma. These perivascular spaces are typically 1 to 2 mm in diameter but can be considerably larger. They can be seen as a normal variant at any age but become more prominent with increasing age as atrophy occurs.
An important means for differentiating a periventricular space from a parenchymal lesion is the use of the proton density–weighted (first-echo T2W) or FLAIR images. On the proton density–weighted sequence, CSF has similar signal intensity as white matter. A perivascular space is composed of CSF and will parallel CSF signal intensity on all sequences (i.e., isointense to brain parenchyma on proton density sequences). In contrast, ischemic lesions, unless cavitated with cystic change, will be bright on the proton density sequence as a result of the presence of associated gliosis. Both a deep infarct and a perivascular space will be bright on the second-echo T2WI, but only the infarct will remain bright on the first-echo image. Similarly, on a FLAIR image, because fluid signal is attenuated, only true parenchymal lesions with gliosis will yield abnormal signal. On occasion, however, a small amount of persistent T2 hyperintensity can be associated with
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perivascular spaces on the proton density or FLAIR sequences. An additional differentiating feature between giant perivascular spaces and lacunae is location. Lacunar infarcts tend to occur in the upper two thirds of the corpus striatum because they reflect end-arteriole infarcts in the distal vascular distribution. In contrast, periventricular spaces are typically smaller, bilateral, and often symmetric within the inferior third of the striatum, where the vessels enter the anterior perforated substance.
FIGURE 7.10. Ependymitis Granularis (Normal Finding). A. and B. Axial fluid-attenuated inversion recovery images in a 42-year-old man presenting with headaches. The periventricular hyperintensity noted about the tips of the frontal and occipital ventricular horns is a normal finding (arrows). These areas of periependymal hyperintensity may be exacerbated by any process that results in underlying white matter disease. Note the circular artifact located within the left basal ganglia; it is related to magnetic susceptibility artifact from the patient’s orthodontic braces (curved arrow). One should be aware of artifacts that may mimic pathologic lesions, especially flow and magnetic susceptibility artifacts that can give rise to lesions that are not necessarily contiguous to the cause of the artifact. B. Incidental note is made of a small focus of subcortical hyperintensity along the left temporoparietal lobe related to a site of posttraumatic gliosis (open arrow).
FIGURE 7.11. Virchow-Robin Spaces. Small punctuate foci of water signal are noted within the centrum semiovale (A) and basal ganglia (B), consistent with perivascular (PV) spaces. These spaces penetrate the brain parenchyma and reflect PV extensions of the pia mater that accompany the arteries entering and the veins emerging from the cerebral cortex. These PV spaces are almost imperceptible on the proton density–weighted image (C), which help confirm their identity as water, rather than white matter ischemic gliotic lesions. Although PV spaces are typically 1 to 2 mm in diameter, they can be considerably larger. Large PV spaces (about 0.5 to 1 cm) are occasionally noted within the caudal aspect of the basal ganglia and referred to as giant PV spaces. Coronal T1WI (D) and fast spin-echo T2WI (E) in a 38-year-old man demonstrate well-rounded, left-sided cysts along the course of the lenticulostriate arteries as they enter the basal ganglia through the anterior perforated substance (arrow). An old cavitated lacunar infarction may have a similar appearance but would be distinctly unusual in the inferior portion of the striatum. Note that lacunar infarcts are the result of vessel occlusion and thus occur along the distal extent of the lenticulostriate arteries; therefore, they tend to be located more superiorly within the basal ganglia. Additionally, lacunar infarcts may have associated gliotic T2 hyperintensity on proton density and fluid-attenuated inversion recovery images, a finding not seen with giant PV spaces.
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Infection-related Demyelination
Various infectious agents may result in white matter disease, either directly or indirectly, and most commonly are viral. Some of the more common agents are described here. For further discussion of virus-induced white matter pathology, see Chapter 6.
Progressive multifocal leukoencephalopathy (PML) is seen with increasing frequency because of the growing number of AIDS patients. PML represents a reactivation of a latent JC polyoma virus. This opportunistic infection is usually seen in severely immunocompromised patients with very low T-cell counts, particularly individuals with AIDS, lymphoma, organ transplantation, and disseminated malignancies. The JC virus infects oligodendrocytes, which are the axonal support cells that generate the myelin sheath. As a result, damage to the oligodendrocytes results in widespread demyelination. PML typically involves the deep cerebral white matter, with subcortical U-fiber involvement, but spares the cortex and deep gray matter (Fig. 7.12). Lesions are characterized by a lack of mass effect, contrast enhancement, and hemorrhage and are typically located in the parietooccipital region. These lesions progress rapidly and coalesce into larger confluent asymmetric areas. Although most lesions involve supratentorial white matter, gray matter and infratentorial involvement (cerebellum and brainstem) are not uncommon. PML is relentlessly progressive, with death typically ensuing within several months from the time of initial diagnosis.
HIV Encephalopathy
HIV involvement of the brain presents as a subacute encephalitis, referred to as AIDS dementia complex or diffuse HIV encephalopathy. This is characterized clinically by a progressive dementia without focal neurologic signs. HIV encephalopathy does not appear to be the result of a direct infection of the neurons or macroglia (i.e., CNS support cells, astrocytes, oligodendrocytes). Instead, the active HIV infection develops in the microglia (brain macrophages). The cytokines and excitatory compounds that are produced as a result of this infection have a toxic effect on adjacent neurons.
HIV encephalopathy most often results in mild cerebral atrophy without a focal abnormality. Occasionally, HIV encephalopathy causes focal or diffuse white matter hyperintensities on T2WIs. Typically, HIV white matter involvement presents as subtle, diffuse T2 hyperintensity that often is bilateral and relatively symmetric (Fig. 7.13). This supratentorial white matter signal abnormality is ill defined and often involves a large area, in contrast to the dense lesions that are characteristic of PML. HIV encephalopathy can also present with more
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focal punctate lesions. HIV lesions do not demonstrate contrast enhancement.
FIGURE 7.12. Progressive Multifocal Leukoencephalopathy. A 32-year-old HIV-positive man presents with cognitive deterioration and weakness. Proton density weighted image (PDWI) (A) and T2WI (B) reveal large confluent areas of T2 hyperintensity in the subcortical white matter of the parietooccipital lobes (arrows). Characteristic features of this demyelinating process include minimal mass effect, despite the large size of these patchy white matter lesions, and essentially no contrast enhancement or hemorrhage. A very low T-cell count reflecting an immunocompromised status is key to the diagnosis. In an immunocompetent patient, differential diagnostic considerations would include posterior reversible encephalopathy syndrome, which can have an identical imaging appearance.
FIGURE 7.13. HIV Encephalopathy. T2WI of a 27-year-old man demonstrates diffuse hazy hyperintensity of the deep cerebral white matter (arrows), as well as cortical atrophy. Note how this hazy T2 hyperintensity differs from the dense confluent lesions of progressive multifocal leukoencephalopathy shown in Figure 7.12.
Demyelination may also occur as an indirect result of a viral infection. Specifically, demyelination may follow a viral illness, the result of a virus-induced autoimmune response to white matter.
Acute disseminated encephalomyelitis (ADEM), a postinfectious and postvaccinal encephalomyelitis, typically occurs after a viral illness or vaccination, with measles, rubella, varicella, and mumps being the most common agents. This condition is considered an immune-mediated inflammatory demyelinating disease, but sometimes it has no recognized antecedent infection or inciting malady.
It is theorized that the body’s antiviral immune reaction cross-reacts with myelin sheaths, resulting in an acute, aggressive form of demyelination. This unintended antiviral response against myelin is a result of shared molecular homology between viral proteins and normal human CNS proteins. Recall that oligodendrocytes are responsible for the formation and maintenance of the myelin sheaths, and their damage results in demyelination.
Demyelinating lesions associated with ADEM typically begin approximately 2 weeks after a viral infection with the abrupt clinical onset of neurologic symptoms, which include decreased levels of consciousness varying from lethargy to coma; convulsions; multifocal neurologic symptoms such as hemiparesis, paraparesis, and tetraparesis; cranial nerve palsies; movement disorders; and seizures. In the majority of cases, there is spontaneous resolution of symptoms, but permanent sequelae can be seen in up to 25% of patients, with some even progressing to death. Although ADEM occurs most commonly in children, persons of any age can be affected. Lesions primarily involve white matter, but gray matter may also be affected. MR imaging demonstrates multifocal or confluent white matter lesions similar to those of MS (Fig. 7.14). A differential feature is that ADEM is a monophasic illness, unlike MS, which has a remitting and relapsing course. This is a feature often useful in differentiating ADEM from MS. Specifically, if the majority of the identified white matter lesions enhance, this suggests a monophasic demyelinating process (i.e., ADEM).
Subacute sclerosing panencephalitis represents a reactivated, slowly progressive infection caused by the measles virus. Children between the ages of 5 and 12 years who have had measles, usually before the age of 3, are typically affected. MR demonstrates patchy areas of periventricular demyelination as well as lesions of the basal ganglia. The disease course is variable and may be rapidly progressive or protracted.
Herpes encephalitis is the most common fatal encephalitis. Although this condition is also discussed in Chapter 6, its importance warrants repetition. The form of herpes encephalitis that we will discuss occurs in children and adults and is caused by herpes simplex virus (HSV) type 1 (oral herpes); this is in contrast to neonatal herpes encephalitis, which is caused by herpes simplex virus 2 (genital herpes). Presenting symptomology may be nonspecific, such as headache, fever, mental deterioration, and seizures. As a result of this variable clinical presentation, diagnosis may be difficult. This emphasizes the crucial role of the radiologist in entertaining this diagnosis when appropriate imaging findings are noted. Antiviral treatment is simple and effective, but failure to treat yields 100% mortality. Although the diagnosis may be confirmed by polymerase chain reaction detection of herpes DNA in CSF, therapy must be instituted prior to the return of this test result.
HSV type 1 has a particular predilection for the limbic system, with localization of infection to temporal lobes, insular cortex, subfrontal area, and cingulate gyri (Fig. 7.15). The limbic system is responsible for integration of emotion, memory, and complex behavior, and involvement of these structures accounts for some of the behavioral symptoms at presentation. Imaging reveals primarily T2 hyperintensity of the involved cortex and subcortical structures presenting as an encephalitis with variable contrast
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enhancement. Initially, herpes encephalitis is usually unilateral; however, sequential bilateral involvement is highly suggestive of the disease. Histopathologically, herpes infection is a fulminant necrotizing meningoencephalitis associated with edema, necrosis, hemorrhage, and eventually encephalomalacia. As a result, hemorrhage within the area of involved parenchyma is strongly supportive of this diagnosis.
FIGURE 7.14. Acute Disseminated Encephalomyelitis. T2WIs (A, B) and postgadolinium T1WI (C) in a 7-year-old boy who presented with deteriorating mental status 10 days following viral gastroenteritis. Imaging reveals multiple patchy subcortical white matter lesions as well as involvement of deep gray matter structures, including the corpus striatum (lentiform nucleus plus caudate nucleus) and the thalamus (arrows). Following the administration of gadolinium-DTPA, numerous punctate foci of enhancement are noted consistent with an acute demyelinating process. The enhancement of most lesions is suggestive of a monophasic demyelinating process. The patient improved after treatment with steroids.
Toxic and Metabolic Demyelination
Central pontine myelinolysis (CPM) is a disorder that results in characteristic demyelination of the central pons. This is most commonly seen in patients with electrolyte abnormalities, particularly involving hyponatremia, that are rapidly corrected, giving rise to the term “osmotic demyelination syndrome.” This condition occurs most commonly
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in children and alcoholics with malnutrition. Occasionally, cases have been associated with diabetes, leukemia, transplant recipients, chronically debilitated patients, and others with conditions resulting in chronic malnutrition. The clinical course is classically described as biphasic, beginning with a generalized encephalopathy caused by the hyponatremia, which usually transiently improves following initial correction of sodium. This is followed by a second neurologic syndrome, which occurs 2 to 3 days following correction or overcorrection of hyponatremia caused by myelinolysis. This latter phase is classically characterized by a rapidly evolving corticospinal syndrome with quadriplegia, acute changes in mental status, and a “locked-in” state in which the patient is mute, unable to move, and occasionally comatose. Patients tend to be extremely ill and often have a very poor prognosis.
FIGURE 7.15. Herpes Encephalitis. T2WI of a 31-year-old man who presented with behavioral disturbance and new-onset seizures. MR demonstrates diffuse hyperintensity of the right insular cortex, and the adjacent orbitofrontal and temporal lobes are characteristic for herpes encephalitis (arrows). The radiologist must have a low threshold for considering this diagnosis when signal abnormality of the temporal lobes, insular cortex, or cingulate gyrus is noted, as failure of treatment results in 100% mortality.
The pathophysiology of CPM relates to a disturbance in the physiologic balance of osmoles in the brain. Oligodendroglial cells are most susceptible to CPM-related osmotic stresses, with the distribution of CPM changes paralleling the distribution of oligodendroglial cells within the central pons, thalamus, globus pallidus, putamen, lateral geniculate body, and other extrapontine sites. The mechanism of myelinolysis remains to be completely elucidated, but it appears to be distinct from a demyelinating process like that of MS, in which an inflammatory response predominates. CPM is characterized by intramyelinitic splitting, vacuolization, and rupture of myelin sheaths, presumably because of osmotic effects. However, there is preservation of neurons and axons. Note that there is no inflammatory reaction associated with osmotic demyelination, differentiating this process from MS, which is characterized by marked perivascular inflammation. MR characteristically demonstrates abnormal high signal on T2WI, corresponding to the regions of central pontine demyelination (Fig. 7.16). Additionally, extrapontine sites of involvement have been described in this condition, including the white matter of the cerebellum, thalamus, globus pallidus, putamen, and lateral geniculate body, giving rise to the term extrapontine myelinolysis.
Posterior reversible encephalopathy syndrome (PRE) is a condition characterized by signal changes within the brain parenchyma, primarily involving the posterior vascular distribution. This condition has also been referred to as reversible posterior leukoencephalopathy syndrome. Patients present with headache, seizures, visual changes, and altered mental status, with MR revealing symmetric areas of bilateral subcortical and cortical vasogenic edema within the parietooccipital lobes (Fig. 7.17). The leading theory regarding the etiology of this condition is a temporary failure of the autoregulatory capabilities of the cerebral vessels, leading to hyperperfusion, breakdown of the blood–brain barrier, and consequent vasogenic edema, but no acute ischemic changes. Autoregulation maintains a constant blood flow to the brain, despite systemic blood pressure alterations, but this can be overcome at a “breakthrough” point, at which point the increased systemic blood pressure is transmitted to the brain, resulting in brain hyperperfusion. This increased perfusion pressure is sufficient to overcome the blood–brain barrier, allowing extravasation of fluid, macromolecules, and even red blood cells into the brain parenchyma. The preferential involvement of the parietal and occipital lobes is thought to be related to the relatively poor sympathetic innervation of the posterior circulation.
A very diverse set of conditions leads to this characteristic clinical and radiologic presentation, including treatment with cyclosporin A or tacrolimus (FK506), acute renal failure/uremia, hemolytic uremic syndrome, eclampsia, thrombotic thrombocytopenia purpura, and treatment with a wide variety of chemotherapeutic agents, including interferon. This suggests a final common etiologic pathway involving either endothelial injury, elevated blood
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pressure, or a combination of these factors. Associated clinical conditions presumably contribute to this physiologic effect by cytotoxic effects on the vascular endothelium (endotoxins), causing increasing capillary permeability that allows this process to occur at near normal blood pressures, or by inducing or exacerbating hypertension. Hypertension is commonly associated with PRE but may be relatively mild and is not universally present, especially in the setting of immunosuppression. Note that this condition is not always reversible and may occasionally result in hemorrhagic infarctions.
FIGURE 7.16. Central Pontine Myelinolysis (CPM). A 52-year-old alcoholic was admitted with a serum sodium of 110 mEq/mL. After rapid normalization of sodium, the patient became comatose. The T2WI (A) demonstrates well-defined intense high signal within the basis pontis (arrows). Often, the central corticospinal tracts remain preserved, giving rise to this characteristic appearance of two rounded areas of spared central pontine tracts. Note that CPM should be differentiated from ischemic demyelination, as both conditions may have T2 hyperintensity within the basis pontis. B. and C. A 72-year-old man presented with progressive confusion and known vasculopathy related to longstanding hypertension and diabetes, without evidence of osmotic or electrolyte disturbance. The T2WIs reveal diffuse patchy T2 hyperintensity of the basis pontis (arrows). Given the clinical history, this finding is consistent with small vessel ischemic changes within the pons rather than CPM. Statistically speaking, hyperintensity within the pons will be more often related to ischemic demyelination than CPM, simply because of the relative frequency of ischemic pathology. However, clinical history will allow easy differentiation between these conditions.
Marchiafava-Bignami disease is a rare form of demyelination seen most frequently in alcoholics. This condition was first described in Italian red wine drinkers, but it has since been reported with other types of alcohol use as well as in nonalcoholics. The disease is characterized by demyelination involving the central fibers (medial zone) of the corpus callosum, although other white matter tracts may be involved, including the anterior and posterior commissures, the centrum semiovale, and the middle cerebral peduncles. This is felt to reflect a form of osmotic demyelination, as discussed earlier in extrapontine myelinolysis.
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Onset is usually insidious, with the most common symptom being nonspecific dementia.
FIGURE 7.17. Posterior Reversible Encephalopathy Syndrome (PRES). A 43-year-old transplant patient who was being treated with cyclosporine presented with visual disturbances and confusion. Axial (A) and coronal (B) T2WIs reveal patchy areas of cortically based signal abnormality within the parietooccipital lobes (arrows), corresponding to the posterior vascular distribution. These findings are in keeping with dysfunction of vascular permeability, the result of a combination of endothelial toxicity and elevated blood pressure. Both clinical symptoms and imaging findings resolved after the cyclosporine doses were reduced.
Wernicke encephalopathy and Korsakoff syndrome are metabolic disorders caused by thiamine (B1 vitamin) deficiency secondary to poor oral intake in severe chronic alcoholics (most common association), hematologic malignancies, or recurrent vomiting in pregnant patients. In fact, this condition may occur in many different non-alcohol-related pathologic conditions that share the common denominator of malnutrition. In general, there is a good clinical response to thiamine administration. Classically, Wernicke encephalopathy is characterized by the clinical triad of acute onset of ocular movement abnormalities, ataxia, and confusion. Korsakoff, a Russian psychiatrist, described the disturbance of memory in long-term alcoholics. Therefore, if persistent learning and memory deficits are present in patients with Wernicke encephalopathy, the symptom complex is termed Wernicke-Korsakoff syndrome.
In the acute stage of this disease, MR may reveal T2 hyperintensity or contrast enhancement of the mamillary bodies, basal ganglia, thalamus, and brainstem, with periaqueductal involvement. In contrast, the chronic stage may show atrophy of the mamillary bodies, midbrain tegmentum, as well as dilatation of the third ventricle. Except for the mamillary body involvement, these findings are very similar to Leigh disease, which supports the notion that enzymatic deregulation in Leigh disease is tied in some fashion to thiamine metabolism.
Radiation Leukoencephalitis
Radiation may result in damage to the white matter secondary to a radiation-induced vasculopathy. Radiation leukoencephalitis usually follows a cumulative dose in excess of 40 Gy delivered to the brain and occurs 6 to 9 months after treatment. Findings consist of areas of abnormal high signal on T2WIs, typically involving confluent areas of white matter extending to involve the subcortical U fibers in the distribution of the irradiated brain (Fig. 7.18). Note that this represents an indirect effect of radiation on the brain and results from an arteritis (endothelial hypertrophy, medial hyalinization, and fibrosis) involving small arteries and arterioles.
Radiation Necrosis and Radiation Arteritis
In contrast to the rather benign nature of radiation leukoencephalitis, radiation necrosis and radiation arteritis are major hazards related to CNS radiation. Both of these radiation effects are strongly dose related and are less
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commonly seen today because of greater fractionation of CNS radiation doses. Radiation necrosis may occur several weeks to years after radiation, but it most commonly occurs between 6 and 24 months after radiation. Radiation necrosis is rarely noted at less than 6 months after treatment unless gamma knife is employed (Fig. 7.19). Note that gamma knife is an ablative procedure designed to destroy targeted tissue and thus may more easily incite frank radiation necrosis. This is in contrast to radiation therapy, which is not ablative in nature. Radiation necrosis can be progressive and fatal. Radiation necrosis typically presents as an enhancing lesion with mass effect and ring enhancement or as multiple foci of enhancement, mimicking recurrent neoplasm. Radiation may also induce telangiectasia within the radiation field, which may appear similar to cryptic vascular malformations.
FIGURE 7.18. Radiation Leukoencephalopathy. MR of a 62-year-old woman obtained 1 year after whole brain radiation for metastatic breast carcinoma to the brain shows a delayed neurologic sequelae of radiotherapy. Coronal fluid-attenuated inversion recovery image reveals confluent areas of high signal involving the periventricular white matter (arrows). This finding may be associated with loss of deep cerebral white matter with concomitant ex vacuo ventriculomegaly, as noted in this case. Although this condition may result in some degree of neurocognitive deficits, this patient was entirely asymptomatic and was simply returning for a routine follow-up examination.
Radiation necrosis is found most commonly in or near the irradiated tumor bed, but it sometimes is more remote from the tumor bed. It is theorized that the partially injured brain parenchyma within and adjacent to the tumor bed is more susceptible to radiation injury, thus accounting for the distribution of radiation necrosis. After resection of a brain neoplasm and subsequent radiation therapy, it can be very difficult to differentiate tumor recurrence from radiation-associated necrosis, because both conditions may continue to grow and demonstrate imaging features characteristic of neoplasm, i.e., lesion growth, irregular ring enhancement, edema, and mass effect (Fig. 7.20). If during serial scanning a lesion within the treated tumor bed stabilizes and regresses, this is obviously radiation necrosis, but if the lesion progresses, differentiation between tumor and radiation necrosis is difficult. PET and MR spectroscopy (MRS) are valuable in distinguishing between tumor recurrence and radiation necrosis. With PET scanning, a short-lived radioactive isotope (e.g., 18F fluorodeoxyglucose) that decays by emitting a positron, is combined with glucose, a metabolically active molecule. This tracer mimics glucose and is taken up and retained by tissues with higher than normal metabolic activity, such as tumor recurrence. This is in contrast to radiation necrosis, which is not metabolically active (Fig. 7.21).
Proton (hydrogen) MRS imaging characterizes the metabolite profiles of tumoral and nontumoral brain lesions. This biochemical information helps distinguish areas of tumor recurrence from areas of radiation necrosis. Major brain metabolites include choline (Cho), creatine (Cr), and n-acetylaspartate (NAA) (located at 3.2, 3.0, and 2.0 ppm, respectively). Choline reflects cellular density and proliferation, and is often elevated with tumor. Creatine is a normal cellular metabolite and is often stable in a variety of disease conditions. Thus creatine is often used as a denominator in calculating choline and NAA ratios (Cho/Cr and NAA/Cr), which corrects for individual variation and allows for comparison between individual subjects. NAA is a neuronal marker and reflects neuronal density. Loss of the NAA signal is consistent with neuronal loss or damage, which can be seen in a wide variety of disease conditions, including radiation necrosis and even MS.
Large vessels included within the radiation port may undergo radiation-induced endothelial hypertrophy, medial hyalinization, and fibrosis. The net result is a progressive vascular narrowing that may be obliterative in nature. This often involves the cavernous and supraclinoid portions of the carotid arteries in children who have undergone irradiation of the parasellar region for treatment of tumors, for example, craniopharyngiomas or optic and hypothalamic gliomas. The near complete obliteration of the supraclinoid carotid arteries results in cerebral and striatal ischemic changes. Occasionally, there may be a compensatory proliferation of lenticulostriate collaterals. When performing angiography, these collateral vessels present with a blush, which in Japan has been referred to as Moyamoya, meaning “puff of smoke.” Moyamoya disease classically refers to a supraclinoid obliterative arteriopathy that occurs primarily in children and is idiopathic in nature (Fig. 7.8).
When methotrexate chemotherapy (intrathecal or systemic) is administered in combination with CNS radiation,
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these agents may have a synergistic effect in causing marked white matter abnormalities. It is theorized that low-dose radiation alters the blood–brain barrier, allowing increased penetration of methotrexate to neurotoxic levels. This has been noted most frequently in children being treated for leukemia, and two specific conditions have been described. The first has been called mineralizing microangiopathy, which is seen in up to one third of these children. This results in diffuse destructive changes to the brain characterized by symmetric corticomedullary junction and basal ganglia calcifications. There is also diffuse signal abnormality throughout the white matter. A more serious but less common complication of combined radiation and methotrexate therapy is called necrotizing leukoencephalopathy. This process results in widespread damage to the white matter, consisting of demyelination, necrosis, and gliosis. MR reveals large, diffuse, confluent areas of white matter signal abnormality with cortical sparing. Clinically, these children may have symptoms ranging from slight reductions in cognitive function to progressive dementia, seizures, hemiplegia, and coma.
FIGURE 7.19. Acute Radiation Necrosis. A. Pretreatment axial proton density–weighted image in a 37-year-old woman with a deep temporoparietal arteriovascular malformation (arrows). B. and C. Less than 6 months after treatment with gamma knife radiation, the patient returned with marked vasogenic edema and contrast enhancement, consistent with radiation necrosis. Note that without clinical history, these imaging findings are indistinguishable from a neoplastic or infectious process. D. MR spectroscopy of the lesion reveals marked elevation of lactate and lipids (0.9 to 1.3 ppm), with reductions of all other major metabolites (choline, creatine, and N-acetylaspartate).
FIGURE 7.20. Radiation Necrosis. This 47-year-old man presented at 6 months (A) and 8 months (B) after resection and irradiation of a high right frontoparietal glioma. Coronal gadolinium-enhanced T1WI reveals interval appearance (A) and progression (B) of a ring-enhancing mass lesion within the operative bed (arrows). Despite this ominous appearance, this lesion revealed no radioisotope uptake on 18F-2-fluoro-2-d-deoxyglucose PET. C. MR spectroscopy (MRS) of the lesion reveals marked elevation of lactate and lipids (0.9 to 1.3 ppm) with reduction in all other major metabolites (choline, creatine, and N-acetylaspartate). Both PET and MRS confirm the diagnosis of radiation necrosis. Serial MR scanning performed at 3-month intervals revealed a slowly regressing lesion that resolved by the 24-month follow-up study.
DYSMYELINATING DISEASES
The disease processes that have been described up until this point are demyelinating, as they represent the destruction of normal myelin. In contrast, the dysmyelinating conditions, also referred to as leukodystrophies, are disorders in which myelin is abnormally formed or
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cannot be maintained in its normal state because of an inherited enzymatic or metabolic disorder. Although most of these conditions are not treatable, establishing a diagnosis is valuable in providing a prognosis and enables parental genetic counseling. These conditions are characterized by the progressive destruction of myelin owing to the accumulation of various catabolites, depending on the specific enzyme deficiency. Children often present clinically with progressive mental and motor deterioration. Radiographically, these diseases present with diffuse white matter lesions that are very similar to one another; however, some distinguishing features do exist (Table 7.2). The radiologist may play an important role in the diagnosis of these conditions, because astute interpretation of abnormal imaging findings may allow them to be the first physician to suggest the possibility of a metabolic disease. Factors that are helpful in differentiation between the leukodystrophies include the age of onset and the pattern of white matter involvement. Ultimately, serum biochemical and enzymatic analyses allow a specific diagnosis to be made. Dysmyelinating diseases are rather uncommon, and we will focus on a few of the classic conditions.
TABLE 7.2 Dysmyelinating Diseases
Disease Head Size Age of Onset (yr) White Matter
Involvement
Gray Matter
Involvement
Metachromatic leukodystrophy Normal Infantile form: 1–2
Juvenile form: 5–7
Diffusely affected None
Adrenoleukodystrophy Normal 5–10 Symmetric occipital and splenium of corpus callosum None
Leigh disease Normal <5 Focal areas of subcortical white matter Basal ganglia and periaqueductal gray
Alexander disease Normal to large ≤1 Frontal None
Canavan disease Normal to large ≤1 Diffusely affected Vacuolization of cortical gray matter
Metachromatic leukodystrophy is the most common of the leukodystrophies. It is transmitted by an autosomal recessive pattern and is the result of a deficiency of the enzyme arylsulfatase A. The most common type is an infantile form that becomes apparent at approximately 2 years of age with gait disorder and mental deterioration. There is steady disease progression, with death occurring within 5 years of the time of onset. MR demonstrates progressive symmetric areas of nonspecific white matter involvement with sparing of the subcortical U fibers. Imaging findings are typically nonspecific.
Adrenal leukodystrophy is a sex-linked recessive condition (peroxisomal enzyme deficiency) occurring only in boys. Typical age of onset is between 5 and 10 years of age. As the name implies, these patients often have symptoms related to the adrenal gland, such as adrenal insufficiency or abnormal skin pigmentation. Adrenal leukodystrophy has a striking predilection for the visual and auditory pathways, presenting with symmetric involvement of the periatrial white matter with extension into the splenium of the corpus callosum (Fig. 7.22). The predilection for periatrial involvement results in early extension to the medial and lateral geniculate nuclei, which represent relays for the auditory and visual pathways, respectively. This accounts for the early presentation of visual and auditory symptomatology in these children.
Leigh disease, also called subacute necrotizing encephalomyelopathy, is a mitochondrial enzyme defect that commonly manifests in infancy or childhood (usually younger than 5 years). Leigh disease has histopathologic findings similar to those of Wernicke encephalopathy (metabolic disorder caused by thiamine [B1 vitamin] deficiency secondary to poor oral intake in chronic alcoholics); hence the suspicion that it is related to an inborn defect in thiamine metabolism. Clinical findings are extremely variable and often nonspecific. Symmetric focal necrotic lesions are found in the basal ganglia and thalamus as well as in the subcortical white matter (Fig. 7.23). Lesions may also extend into the midbrain, medulla, and posterior columns of the spinal cord. A characteristic finding is involvement of the periaqueductal gray matter. In contrast to Wernicke encephalopathy, there is sparing of the mamillary bodies. In the same family of mitochondrial disorders are two additional encephalopathies, which have the acronyms MELAS (mitochondrial myelopathy, encephalopathy, lactic acidosis, and strokelike episodes) and MERRF (myoclonic epilepsy and ragged-red fibers). These inherited mitochondrial abnormalities are caused by point mutations of mitochondrial DNA or mitochondrial RNA and represent progressive neurodegenerative disorders characterized clinically by strokes, strokelike events, nausea, vomiting, encephalopathy, seizures, short stature, headaches, muscle weakness, exercise intolerance, neurosensory hearing loss, and myopathy.
Alexander and Canavan diseases are the rarest of the leukodystrophies and may appear as early as the first few weeks of life. Patients often have an enlarged brain
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and have macrocephaly on examination. Typically, these patients present with seizures, spasticity, and delayed developmental milestones. In Alexander disease, white matter lesions often begin in the frontal white matter and progress posteriorly (Fig. 7.24). Canavan disease is caused by a deficiency of the enzyme aspartoacylase, which leads to the buildup of NAA in the brain and subsequent myelin destruction. This results in a pathognomonic MR spectra consisting of a giant NAA peak.
FIGURE 7.21. Radiation Necrosis Versus Tumor Recurrence. Contrast-enhanced CT and PET (18F-2-fluoro-2-d-deoxyglucose) scans. A. CT reveals a new linear area of enhancement within the tumor bed 10 months after surgery and focal irradiation for a high-grade glioma (arrows). B. The PET scan demonstrates no significant activity in this area, suggesting that the enhancement represents radiation necrosis. C. A CT of a different patient 6 months after surgery and focal irradiation for a high-grade glioma reveals a focus of ring enhancement (arrows). D. The PET scan reveals increased metabolic activity in this region, suggesting recurrent tumor. E. This finding is confirmed on the representative single-voxel MR spectroscopy, performed in the area of enhancement, which demonstrates an elevated choline peak (largest peak), with reduced creatine and N-acetylaspartate levels (next peaks, respectively, moving from left to right).
FIGURE 7.22. Adrenal Leukodystrophy. MR of a 5-year-old boy who presented with gradual gait disturbance, hearing and visual symptoms, and adrenal insufficiency. Axial T2WI reveals high signal within the periatrial and occipital white matter extending into the splenium of the corpus callosum as well as the region of the medial and lateral geniculate bodies, accounting for the patient’s hearing and visual symptoms, respectively.
CEREBROSPINAL FLUID DYNAMICS
In patients with acute hydrocephalus, transependymal flow of CSF may mimic periventricular white matter disease. CSF is produced predominantly by the choroid plexus of the lateral, third, and fourth ventricles. CSF flows from the lateral ventricles into the third ventricle through the foramina of Monro and then by way of the cerebral aqueduct into the fourth ventricle. The CSF leaves the ventricular system via the lateral and medial fourth ventricular foramina (the foramina of Luschka and Magendie, respectively). CSF then travels through the basilar cisterns and over the surfaces of the cerebral hemispheres. The principal site of absorption is into the venous circulation through the arachnoid villi, which project into the dural sinuses, primarily the superior sagittal sinus. Although the principal routes of CSF production and absorption are as outlined, a significant amount of CSF may be both produced and reabsorbed via the ependymal lining of the ventricles. This transependymal flow of CSF can become an important means of CSF reabsorption during ventricular obstruction.
Hydrocephalus is caused by an obstruction of the CSF circulatory pathway and is classified into two principal types: noncommunicating and communicating. Noncommunicating hydrocephalus refers to an obstruction occurring within the ventricular system that prevents CSF from exiting the ventricles (Fig. 7.25). In contrast, with communicating hydrocephalus, the level of obstruction is beyond the ventricular system, located instead within the subarachnoid space. CSF is able to exit the ventricular system but fails to undergo normal resorption by the arachnoid villi. In theory, with communicating hydrocephalus, most of the ventricular system is enlarged, whereas with noncommunicating hydrocephalus, dilation occurs up to the point of obstruction. The fourth ventricle often does not dilate because of the relatively confined nature of the posterior fossa and thus cannot be used as a reliable means by which to differentiate communicating from noncommunicating hydrocephalus. Communicating hydrocephalus will commonly demonstrate supratentorial ventriculomegaly, with a fourth ventricle that appears normal. Although dilation of the fourth ventricle is suggestive of communicating
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hydrocephalus, it is not a reliable sign, because obstruction at the outlet foramina of the fourth ventricle (Luschka and Magendie) may result in a similar appearance.
FIGURE 7.23. Leigh Disease. Leigh disease (mitochondrial enzyme defect) in a 3-year-old patient presenting with progressive hypotonia and seizures. A. T2WI demonstrates a wide spectrum of gray and white matter lesions reported in Leigh disease, including basal ganglia (globus pallidus, putamen, caudate); brainstem (midbrain and periaqueductal gray); and subcortical white matter involvement (arrows). B. Involvement of the periaqueductal gray matter (arrows) is quite characteristic for either Leigh disease or Wernicke syndrome. Both conditions are associated with thiamine deficiency; the former is related to mitochondrial enzymatic deficiencies involved with the metabolism of thiamine, and in the latter, it is nutritional. A differentiating feature is involvement of the mamillary bodies in Wernicke syndrome, which is absent in Leigh disease. C. MR spectroscopy reveals an elevated lactate peak at 1.3 ppm, which supports the diagnosis of Leigh disease. Mitochondrial enzyme deficiencies associated with Leigh disease include pyruvate dehydrogenase complex, pyruvate carboxylase, and electron transport chain, which result in elevated blood, CSF and CNS lactate, and pyruvate levels.
FIGURE 7.24. Canavan Disease. A 12-month-old child presented with progressive spastic quadriparesis and macrocephaly. Axial T2WI reveals diffuse high signal extending throughout the cerebral white matter. This is a nonspecific finding that could reflect an advanced stage of any of the leukodystrophies. However, if MR spectroscopy were to reveal markedly elevated N-acetylaspartate (NAA), this would be diagnostic of a deficiency of the enzyme aspartoacylase (Canavan disease), which leads to the buildup of NAA in the brain and subsequent myelin destruction.
In assessing for the presence of hydrocephalus, specific attention should be directed to the third ventricle and the temporal ventricular horns. Convex bowing of the lateral walls and inferior recesses of the third ventricle is characteristic for hydrocephalus. As with fourth ventricular enlargement, however, this finding is seldom present. A far more sensitive indicator of hydrocephalus is enlargement of the temporal horns. The temporal horns sometimes will demonstrate enlargement, even before lateral ventricular involvement is evident. Bowing and stretching of the corpus callosum, easily detected on the sagittal images, is an additional finding that is suggestive of hydrocephalus.
Ex Vacuo Ventriculomegaly
A distinction must be made between hydrocephalus and ex vacuo ventriculomegaly. The latter represents an enlarged ventricular system that is simply the result of parenchymal atrophy. With atrophy, the loss of brain matter results in prominence of all CSF spaces, both the cerebral sulci as well as the ventricles. In contrast, with hydrocephalus the ventricles are enlarged out of proportion to the sulci. The third ventricle and temporal ventricular horns are particularly helpful in making this distinction. Both of these ventricular spaces are surrounded by tissue that is not typically subject to significant atrophy. The third ventricle is surrounded by the thalamus (gray matter), and there is a relative paucity of white matter within the temporal lobes. This is in contrast to the large amount of white matter surrounding the lateral ventricles, which may atrophy. Enlargement of the third ventricle, with bowing of its lateral and inferior recesses as well as temporal horn enlargement, suggests hydrocephalus.
Subarachnoid hemorrhage and meningitis are the most frequent causes of acute hydrocephalus and may result in either communicating or noncommunicating hydrocephalus, with obstruction at any level of the ventricular system, the basilar cisterns, or the arachnoid villi. The obstruction is caused by adhesions and inflammation, and no obstructing mass is typically detected. Noncommunicating hydrocephalus can be the result of either an acquired or a congenital obstructive process. Benign congenital webs may form across the cerebral aqueduct, resulting in aqueductal stenosis. Additionally, the Chiari and Dandy-Walker malformations are believed to represent adhesions occurring during CNS development, at the outlet foramina of the fourth ventricle and posterior fossa. A variety of neoplasms may result in obstructive hydrocephalus, often in very characteristic locations. Colloid cysts typically block the anterior third ventricle, pineal tumors and tectal gliomas obstruct the aqueduct, and ependymomas and medulloblastomas interrupt CSF flow at the level of the fourth ventricle. Whenever hydrocephalus is detected, it is important to inspect the ventricles for an obstructing mass. A location that should be specifically evaluated is the cerebral aqueduct. On routine axial and sagittal images, a normal pulsatile flow void should be detected; otherwise, the diagnosis of aqueductal stenosis should be considered.
The duration of hydrocephalus affects the imaging findings. In acute hydrocephalus, there is insufficient time for compensatory mechanisms, and a striking amount of transependymal CSF flow will be noted. This results in a dramatic accumulation of high signal in the periventricular white matter on T2WIs. In chronic forms of hydrocephalus, compensatory mechanisms of CNS production and resorption have occurred and the degree of transependymal flow is minimal.
Normal pressure hydrocephalus (NPH) is a chronic, low-level form of hydrocephalus. The classic clinical triad is dementia, gait disturbance, and urinary incontinence. In this condition, the CSF pressure is within normal limits,
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but a slight gradient exists between the ventricular system and the subarachnoid space because of an incomplete subarachnoid CSF block. This most commonly results from a previous subarachnoid hemorrhage or meningeal infection. The result is diffuse ventriculomegaly that is out of proportion to the degree of sulcal prominence. Differentiating mild hydrocephalus from atrophic ventriculomegaly can be very difficult. Studies suggest that MR CSF velocity and stroke volume calculations can be used to predict which patients may have favorable response to ventriculoperitoneal shunting. In addition to cross-sectional studies, radioisotope studies may be of value. The classic findings on radioisotope cisternogram are early entry of the radiopharmaceutical into the lateral ventricles, with persistence at 24 and 48 hours, and considerable delay in the ascent to the parasagittal region. Differentiating NPH from atrophic ventriculomegaly can be very difficult, and unfortunately, no imaging study is definitive in making this diagnosis. NPH is not a radiographic diagnosis, and close correlation of clinical and imaging findings is required to establish the diagnosis. The definitive diagnosis of NPH is made on demonstrating clinical improvement following ventricular shunting.
FIGURE 7.25. Hydrocephalus. Images of a 36-year-old woman who presented with postural headaches. A. Sagittal T1WI reveals an obstructing mass within the roof of the third ventricle consistent with a colloid cyst (arrow). Pressure changes reflective of hydrocephalous are noted, including upward bowing of the corpus callosum (curved arrow) as well as tonsillar ectopia (open arrow). B. and C. Axial PDWIs reveal dilated ventricles with periventricular hyperintensity consistent with transependymal flow of CSF.
NEURODEGENERATIVE DISORDERS
Neurodegenerative disorders frequently have no known cause and result in progressive neurologic deterioration that is faster than expected given the patient’s age.
FIGURE 7.26. Alzheimer Disease (AD). Axial fast spin-echo T2WI (A) in a 60-year-old man with early dementia reveals prominent parietotemporal atrophy and minimal white matter ischemic disease. AD is a neurodegenerative disorder and the most common cause of dementia. Imaging is relatively nonspecific in the diagnosis of AD, but the presence of parietotemporal cortical atrophy with a paucity of white matter ischemic changes supports the diagnosis of a neurodegenerative disease rather than ischemic or multi-infarct dementia. B. Three PET images (lateral volumetric summated image, axial, and sagittal) from the same patient reveal metabolic reductions throughout the parietotemporal lobes (arrows) corresponding to the MR findings and characteristic for AD. (See color image)
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Alzheimer disease (AD) is the most common neurodegenerative disease and the most common cause of dementia. It is estimated that in the United States alone there are about 4 million people with this disorder. The number of those affected by AD is rapidly increasing as the world’s population ages. It is estimated that by the year 2050, the number of people with AD will increase threefold, to about 60 million worldwide, with about 14 million in the United States alone. Although the cause of AD is not clear, histopathologically the disease is characterized by two abnormal structures in the brain: neuritic plaques and neurofibrillary tangles. Neuritic plaques are composed of tortuous neuritic processes surrounding a central amyloid core, which consists primarily of a small peptide known as β-amyloid, derived from a larger amyloid precursor protein. Neurofibrillary tangles contain an abnormal tau protein that is associated with microtubules. Both plaques and tangles seem to interfere with normal neuronal functioning.
Neuroimaging studies of patients with AD demonstrate diffuse atrophy, with a predilection for the hippocampal formation, temporal lobes, and parietotemporal cortices. As a result, enlargement of the temporal horns, suprasellar cisterns, and sylvian fissures may be useful in discriminating AD from normal age-related atrophy (Fig. 7.26). A variety of functional imaging modalities (PET as well as perfusion MR with regional cerebral blood flow calculations) are being used to diagnosis and differentiate AD from senescent dementia. PET may play an important role in diagnosis and treating AD; specifically, 18F-labelled PET
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ligands (specific for AD-related proteins) may allow for the early detection of this disease as well as help to identify treatments by evaluating the early response to drugs, far before any changes in clinical symptoms would be evident.
FIGURE 7.27. 18F-Labelled Levodopa (DOPA) PET Scan. A 52-year-old man was misdiagnosed with early-onset Parkinson disease. A. and B. Images from 18F-DOPA PET scanning reveal a normal distribution of dopamine receptors, with expected uptake in the caudate head and putamen. With Parkinson disease there is loss of uptake in the putamen. As a result of this study, the correct diagnosis of essential tremor was made. C. A 63-year-old man presented with clinical symptoms that were nondiagnostic for Parkinson disease. 18F-DOPA PET scan reveals loss of uptake in the putamen (arrows), consistent with Parkinson disease, which allowed a definitive diagnosis to be made.
Parkinson disease is the most common basal ganglia disorder and one of the leading causes of neurologic disability in individuals older than age 60. This disease is characterized clinically by tremor, muscular rigidity, and loss of postural reflexes. About 25% of Parkinson patients also develop dementia. Parkinsonism results from a deficiency of the neurotransmitter dopamine caused by dysfunction of the dopaminergic neuronal system, specifically the pars compacta of the substantia nigra. The loss of these nerve cells results in a decreased concentration of endogenous striatal dopamine, and after approximately 80% of these cells die, the patient begins to develop symptoms. MR imaging is relatively insensitive in the detection of this loss of tissue, but it can be used to image patients with movement disorders to exclude other underlying pathologies, such as stroke or tumor. MR may occasionally reveal thinning of the pars compacta. The substantia nigra is made of the pars compacta (high signal intensity band on T2WIs) posteriorly, which is sandwiched between the pars
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reticularis anteriorly and the red nuclei posteriorly. With thinning of the pars compacta, the high signal intensity band between the pars reticularis and the red nuclei is lost. However, this finding is only occasionally noted in very severe forms of the disease. In contrast, PET is a more sensitive tool in the study of diseases of the dopaminergic system. Specifically, 18F-labelled PET ligands have been developed for imaging the postsynaptic dopamine D1 and D2 receptor system. The involvement of this receptor system in numerous brain disorders such as schizophrenia, Parkinson disease, and other movement disorders has prompted an intense research in this field. With 18F-labelled levodopa (DOPA), Parkinson patients show a characteristic deficit in putaminal DOPA uptake (Fig. 7.27). The symptoms of Parkinson disease can sometimes be alleviated by treatment with levodopa, which increases the amount of dopamine that is endogenously synthesized, facilitating the activity of the remaining dopaminergic neurons. A variety of parkinsonian syndromes exist, including Parkinson disease, progressive supranuclear palsy, and striatonigral degeneration. Idiopathic Parkinson disease is referred to as paralysis agitans and affects 2% to 3% of the population at some time during their life.
FIGURE 7.28. Huntington Disease. Axial fast spin-echo T2WI in a 51-year-old woman who presented with movement and behavioral disorders, with familial history of similar presentation in her father. The striking caudate head atrophy results in characteristic enlargement of the frontal horns. This condition is a movement disorder that is autosomal dominant with full penetrance, with typical onset in the fifth decade of life.
The following are degenerative diseases of the extrapyramidal nuclei.
Huntington disease is a progressive hereditary disorder that appears in the fourth and fifth decades of life. This disease is characterized by a movement disorder (typically choreoathetosis), dementia, and emotional disturbance. Huntington disease is inherited in an autosomal dominant pattern with complete penetrance. Although neuroimaging studies demonstrate diffuse cortical atrophy, the caudate nucleus and putamen are most severely affected. Atrophy of the caudate nucleus results in characteristic enlargement of the frontal horns, which take on a heart-shape configuration (Fig. 7.28).
Wilson disease, also known as hepatolenticular degeneration, is an inborn error of copper metabolism that is associated with hepatic cirrhosis and degenerative changes of the basal ganglia. A deficiency of ceruloplasmin (serum transport protein of copper) results in deposition of toxic levels of copper in various organs. Patients present with
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varied neurologic and psychiatric findings, including dystonia, tremor, and rigidity. The Kayser-Fleischer ring, an intracorneal deposit of copper, is virtually diagnostic of the disease when present (75% of cases). MR findings include diffuse atrophy with signal abnormalities involving the deep gray matter nuclei and deep white matter.
FIGURE 7.29. Carbon Monoxide Toxicity. This 35-year-old man presented with confusion following carbon monoxide exposure during recreational boating. Bilateral hyperintense lesions of the globus pallidus are noted (arrows). Bilateral lesions of the basal ganglia can be seen in a variety of insults, including methanol toxicity (putaminal); metabolic conditions such as Wilson disease (hepatolenticular degeneration, a disorder of copper metabolism); Hallervorden-Spatz disease (iron deposition within the globus pallidus); and mitochondrial disorders (Leigh disease and Kearns-Sayre syndrome).
In addition to these neurodegenerative diseases, abnormalities of the basal ganglia can have a wide range of causes. Toxins such as carbon monoxide or methanol poisoning may result in signal abnormalities of the basal ganglia, characteristically the globus pallidus and putamen, respectively (Fig. 7.29). Also, infectious conditions such as West Nile Virus (WNV) and Creutzfeldt-Jakob disease (CJD) may present with areas of signal abnormality within the basal ganglia. Both of these conditions have become of great concern recently, given their increased incidence and unusual modes of transmission (WNV via mosquitoes and CJD via consumption of infected beef products). T1 shortening (high signal on T1WIs) has been described within the basal ganglia and brainstem, associated with hepatic dysfunction, such as hepatic encephalopathy as well as hyperalimentation. The cause of these findings has not been fully determined. Occasionally, faint calcification of the basal ganglia may also appear as high signal on T1WIs. This is the result of the hydration layer effect, where water molecules that are adjacent to the calcification have reduced relaxation times. This same effect causes T1 shortening with proteinaceous fluids. As a result, any condition that results in subtle calcifications within the basal ganglia may demonstrate T1 shortening within the basal ganglia.
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