A Practical Approach to White Matter Disease

Blake A. Johnson Virtually all categories of pathology may information which helps to limit the Finally, dorsal to the lateral ventricles, there cause white matter abnormalities. White differential diagnosis in the setting of white may be foci of increased signal on long TR matter abnormalities may be seen in matter disease. images which persist, in some patients, until congenital, inflammatory, neoplastic, post- the third decade. The high signal is traumatic, metabolic, toxic, vascular, MIMICS OF WHITE recognized on the intermediate weighted degenerative and demyelinating diseases. images, but is generally not as bright as CSF The primary white matter disorders are MATTER DISEASE on the second echo, or T2-weighted, image. classically divided into two groups: Pathologic processes which may mimic The ill-defined hyperintensities do not dysmyelinating disorders (usually metabolic), primary white matter disease include directly abut the ventricular margin, as is in which normal myelin fails to form, and the neoplasms, which are occasionally diffuse seen with periventricular leukomalacia. demyelinating diseases, in which normal rather than tumefactive. Infiltrating Instead, a border of normal (hypointense) myelin has formed and is later destroyed by neoplasms such as gliomatosis cerebri may white matter is interposed between the a myelinoclastic process. The imaging respect the subcortical U-fibers, and thus ventricle and the focus of hyperintense white appearance of white matter disease caused appear as a primary white matter disorder. matter on the T2-weigted images. by all disease categories is often With acute hydrocephalus, transependymal Histologically, they represent areas of nonspecific. Nonetheless, it is useful to CSF, resulting in periventricular interstitial incomplete white matter myelination in this categorize the white matter diseases based edema, may look similar to small vessel characteristic location. These “terminal“ on their appearance on cross-sectional ischemic white matter disease in this myelination zones are most often seen in modalities. Thus, in this section, we will distribution. Any process which causes children, but may be seen in teenagers and consider: 1) multifocal disease, 2) confluent vasogenic edema, gliosis or white matter young adults as well. or diffuse disease and 3) selective white inflammation may appear similar to white matter disease in which there is a matter pathology. PEDIATRIC WHITE geographic predilection for involvement of a In addition to other diseases, several normal MATTER DISEASE specific white matter distribution. anatomic MR features may be mistaken for When evaluating a patient with suspected white matter pathology if they are not Although demyelinating disease is most white matter pathology, there are several recognized. For example, perivascular commonly seen in adults, a minority of important imaging considerations. Magnetic spaces (Virchow-Robin spaces) may mimic multiple sclerosis patients are children. resonance (MR) is much more sensitive than focal small vessel ischemic white matter Schilder´s disease is a primary computed tomography (CT) for the detection disease. These CSF-filled spaces are actually demyelinating disease of childhood and is of white matter abnormalities, and is extensions of the subarachnoid space into considered by some to represent childhood essential to confidently assess for white the parenchyma surrounding small vessels. multiple sclerosis. Acute disseminated matter disease. MR is also useful for the Ranging in size from 1-2 mm to greater than encephalomyelitis (ADEM) may affect evaluation of normal myelination, which 1 cm, perivascular spaces should parallel children and adults. This condition is appears complete on T1-weighted images CSF signal characteristics on all pulse discussed below. between 8 and 12 months and on T2- sequences. There is no enhancement Vascular causes for white matter weighted images between 20 and 24 associated with perivascular spaces, which abnormalities presenting in the pediatric age months of age. When white matter disease is are most often visualized in the midbrain, group usually occur in utero or at birth. In encountered, supplemental pulse sequences basal ganglia, and subcortical white matter. premature infants, periventricular are often useful for increasing the specificity To rapidly distinguish these from true white leukomalacia (PVL) is the result of ischemic of the MR appearance. These include matter pathology, examine the first echo of a brain injury. In the undeveloped brain, the sagittal T2-weighted images to assess for long TR sequence (“intermediate-weighted“ periventricular white matter represents a lesions in the corpus callosum of patients images). The perivascular spaces, which are “watershed“ zone between the with suspected multiple sclerosis. Inversion hypointense on T1-weighted images and ventriculofugal vessels and vessels recovery and magnetization transfer hyperintense on T2-weighted images, penetrating from the cortex. Infants under sequences may also increase the specificity “disappear“ on the intermediate-weighted 1500 grams are especially at risk for the of white matter lesions identified on T2- sequence due to isointensity with adjacent development of ischemic injury to this weighted images. In the setting of previous brain parenchyma. On fluid attenuated location. The result is loss of white matter, trauma gradient echo imaging to rule out inversion recovery (FLAIR) images, the which is most pronounced in the peritrigonal small foci of hemosiderin are useful. Virchow-Robin spaces are predictably very regions, abutting the lateral ventricles. This Because the appearance of white matter hypointense like the ventricles. results in ventriculomegaly, which is disease is often nonspecific, supplemental Ependymitis granularis is another normal characterized by a crenulated appearance information is crucial when assessing white phenomenon within the brain which may be of the ventricular margin. The contour of the matter lesions. T1- and T2-prolongation, mistaken for white matter pathology. ventricles in this case is due to the close which generally characterizes white matter Ependymitis granularis manifests as high approximation of the cortical gyri which pathology, may be due to vasogenic edema, signal intensity on long TR images, which accompanies loss of the intervening white gliosis, demyelination, and inflammatory caps the frontal horns of the lateral matter. T2 prolongation (gliosis) of the infiltrates within the brain. Thus, patient ventricles. This finding may be seen in all remaining white matter may border the demographics, clinical history, laboratory age groups and should not be mistaken for ventricles. data and physical findings provide periventricular white matter disease. In the term neonate, the watershed zone is

ADVANCED MRI 2002 – FROM HEAD TO TOE 1 A Practical Approach to White Matter Disease similar to that in the adult brain. Hypoxic- important to bear in mind, however, that all like. Such lesions have been misdiagnosed ischemic injury in this population is thus of the dysmyelinating disorders may result in as tumor, abscess, and other intracranial characterized by parasagittal cortical global white matter involvement late in later masses. With time, the lesions cease to atrophy. In addition, the basal ganglia and, stages of the disease. enhance (usually after 1-2 months) and occasionally, the brain stem and subiculum assume a more ovoid or cylindrical of the hippocampus may be involved. These WHITE MATTER DISEASE configuration. Orientation of these elliptical areas represent both vascular watershed lesions perpendicular to the long axis of the distributions (cortex) as well as areas of high AFFECTING ALL AGE lateral ventricles is more characteristic of metabolic demand. Hypotheses regarding GROUPS MS. Sagittal T2-weighted or FLAIR images the cause of increased sensitivity to hypoxia are useful to evaluate for lesions within the Adult leukoencephalopathies (and white in these selective regions within the brain corpus callosum, especially at the matter disorders which are not age-specific) include increased metabolic activity due to: callososeptal junction. Lesions at this may be caused by several categories of 1) active myelination and/or 2) sites of location lend specificity to the imaging disease. Primary demyelinating disorders, excitatory amino acid receptors. The appearance. T2-weighted images may also infectious, neoplastic, post-traumatic and characteristic appearance in the cortex is a reveal hypointense thalami and putamina metabolic disorders are the most common. decrease in bulk of the deep gyral tissue, bilaterally, which are characteristic of long When white matter disease is encountered which results in characteristic “mushroom- standing disease. Cerebral atrophy is also on an imaging study, it is useful to first shaped“ gyri, termed ulegyria. characteristic of chronic MS. To further characterize the white matter involvement as distinguish multiple sclerosis from other There are several metabolic causes of white multifocal, confluent / diffuse, or selective white matter lesions, inversion recovery matter disease which affect the pediatric (geographic). This approach, combined with sequences have been recommended, as population. Dysmyelinating diseases are the clinical information regarding patient they may reveal a marked hypointense those disorders in which normal white matter demographics, clinical history and physical appearance of MS lesions which is not is not formed or maintained. This may be findings, helps the imager limit the demonstrated in vascular and other sources due to disorders in lipid metabolism or other differential diagnosis. As with the pediatric for white matter disease. enzymatic deficiencies which include the white matter disorders, the multifocal mucopolysaccharidoses, mitochondrial diseases may have a confluent appearance, Acute disseminated encephalomyelitis (ADEM) disorders and the amino acidopathies. especially late in the course of the disease. is essentially a monophasic analog of These disorders present variably with Thus, the categories described below are not multiple sclerosis. This post-infectious atrophy, prominent perivascular spaces, and mutually exclusive. demyelinating disease is usually seen in multifocal white matter abnormalities. younger patients, children and young adults. Distinguishing these disorders on the basis MULTIFOCAL WHITE The autoimmune-mediated white matter of imaging features alone may be difficult. inflammation and subsequent demyelination Evaluation of these patients must include MATTER DISEASE usually presents 1-3 weeks following correlation with the age-of-onset, clinical Multifocal white matter abnormalities are exposure to a virus or a vaccine. ADEM is findings, the biochemical profile and characteristic of multiple sclerosis (MS), a steroid-responsive, and usually resolves information regarding any familial disorders. primary demyelinating disease. Multiple within 1-2 months, although a minority of In some cases, however, there are sclerosis most commonly affects females, patients have permanent sequelae. distinguishing features which facilitate an and is most prevalent in the 20-40 year old Occasionally the disease is fatal. On imaging diagnosis. For example, age group. In middle aged adults, the imaging studies, high signal intensity is macrocephaly is a feature of two of the female-to-male radio is 1.5-2:1, but in demonstrated on long TR images within the dysmyelinating conditions: Alexander´s younger patients the female preponderance subcortical and deep white matter. Brain disease and Canavan´s disease. Alexander´s is greater. Although 75% of patients with stem, cerebellar and basal ganglia disease manifests initially as white matter multiple sclerosis present between the ages involvement are common. Gray matter hypodensity (on CT) and T2 prolongation of 20 and 50 years of age, it is important to involvement is seen more commonly than (on MR) in the frontal white matter, whereas bear in mind that 15% present in the first with multiple sclerosis. Canavan's disease is generally associated and second decade, and 10% present after Another cause of multifocal white matter with global white matter involvement, as well 50 years of age. A negative brain MR does abnormalities results from closed head as cortical atrophy and ventriculomegaly. A not exclude multiple sclerosis, as the disease injury, typically from rapid deceleration with posterior distribution, involving the periatrial may present with spinal cord involvement rotation. Diffuse axonal injury results from and occipital lobe white matter, is only (with a normal cranial MR). In patients severe torque/shear forces impacting the characteristic of adrenoleukodystrophy with intracranial involvement, the brain parenchyma. The interfaces between (ALD). The corpus callosum and fornix are periventricular white matter is most various brain parenchymal components with also typically involved. Both ALD and commonly involved, usually with an disparate densities are the most sensitive to Alexander´s disease may show peripheral asymmetrical distribution. Increased such injuries. Thus, the subcortical white enhancement, whereas the other specificity is afforded by the presence of matter at the gray/white matter interface, the dysmyelinating disorders have not been lesions in the corpus callosum, cerebellar corpus callosum and the brain stem are reported to show significant enhancement. peduncle, cerebellar white matter, and most commonly involved. Regions of T1- In patients with global dysmyelination, spinal cord. However, not even lesions in and T2-prolongation are seen in the acute Canavan´s disease and Pelizaeus- these locations are pathognomonic for phase of the disease. Chronically, focal Merzbacher´s disease are considerations. multiple sclerosis. A potentially confusing hemosiderin deposition may be present as Unlike Pelizaeus-Merzbacher´s disease, appearance of this disease is produced the only evidence of injury in the wake of Canavan´s disease spares the internal when lesions appear tumefactive during the diffuse axonal injury. These chronic residua capsule and, as mentioned above, is acute phase, and demonstrate variable of closed head injury are best detected using associated with macrocephaly. It is enhancement, ranging from solid to rim- gradient-echo MR sequences.

2 ADVANCED MRI 2002 – FROM HEAD TO TOE A Practical Approach to White Matter Disease

Perhaps the most commonly encountered distinguishing these disorders, as metastatic In children, a late sequela of radiation injury form of white matter disease in adults is due disease to the central nervous system may include mineralizing microangiopathy. to small vessel ischemic disease. Although virtually always enhances. This disorder may also result from combined diabetes mellitus, hypertension, and other Multifocal white matter changes may be also radiation and chemotherapy. It produces risk factors may predispose patients to an be seen with inflammatory disorders such as diffuse low attenuation (on CT) and T1- and earlier onset and more severe involvement, Lyme disease and neurosarcoidosis. Associ- T2-prolongation (on MR) in the white matter. there is significant overlap in the degree of ated features with these inflammatory Focal calcifications are characteristically parenchymal small vessel change in conditions may include enhancement of the present in the basal ganglia and at the otherwise healthy patients and those with the cranial nerves or basilar meninges. gray/white matter interface in this disorder. aforementioned underlying disorders. And Cortical atrophy is another feature evident except in very severe cases, the degree of DIFFUSE/CONFLUENT on imaging studies. white matter involvement does not predict Sporadic viral encephalitis will occasionally brain function. The sites most commonly WHITE MATTER DISEASE present with diffuse white matter involved include the periventricular and Diffuse or confluent white matter disease abnormality. This appearance is nonspecific, subcortical white matter, the pons and basal may be seen in the later stages of any of the as opposed to the distinctive geographic ganglia. Cavitary changes may be a feature above multifocal processes. Also, vasogenic predilection for the medial temporal lobes of small vessel ischemia, and result in signal edema may appear as a confluent region of seen with herpes encephalitis. In AIDS characteristics which parallel CSF on all T1- and T2-prolongation confined to the patients, HIV encephalitis is present in pulse sequences. In contrast to white matter. An underlying mass should majority of cases. It manifests clinically with demyelinating disease, the corpus callosum distinguish vasogenic edema surrounding a progressive dementia. On MR studies, ill- and posterior fossa are usually spared by defined and symmetric white matter small vessel ischemic disease. With more neoplasm or infection from a primary white matter process. As mentioned above, hyperintensities with no associated severe involvement, the white matter enhancement or mass effect. hyperintensities coalesce and the process infiltrating neoplasms may make this distinction difficult. Cytomegalovirus commonly infects the brain appears diffuse, rather than multifocal. in this population. The periventricular white Vasculitis is another vascular cause for Radiation changes may induce diffuse white matter is typically involved and, unlike HIV multifocal disease, which may mimic matter hyperintensity on long TR MR images. encephalitis, enhancement is usually de- multiple sclerosis in terms of imaging The clinical history usually explains this monstrated on post-contrast images. appearance and patient demographics. finding. Acutely, edema is present within the CNS vasculitis may be seen with systemic white matter. Small vessel damage resulting GEOGRAPHIC WHITE lupus erthematosus, Sjogren´s syndrome, in eventual vascular lumen compromise Behcet´s disease and polyarteritis nodosa. results in demyelination and atrophy. More MATTER DISEASE localized disease may be demonstrated if a Hyperintense foci on long-TR images are Some white matter disorders are limited radiation port was employed. characteristic. The T1- and T2-prolongation geographically selective, and thus manifest may reverse. Hemorrhage is not uncommon In patients who have received high dose with characteristic MR imaging appearances in these patients, but it would be an unusual radiation therapy for intracranial neoplasms, which convey the diagnosis. Central pontine feature of either small vessel ischemic it may be difficult to distinguish a neoplasm myelinolysis, or osmotic demyelination disease or multiple sclerosis. from radiation necrosis, which often syndrome, is a striking example. This Progressive multifocal leukencephalopathy demonstrates mass affect, and variable disorder, which is likely due to a rapid or (PML) is essentially restricted to the enhancement in the setting of T1- and T2- over correction of hyponatremia, is often immunocompromised patient population, prolongation. Serial exams in this case will seen in chronic alcoholics, and in victims of with a male predominance. This disease reveal involution, rather than expansion, of malnutrition or chronic debilitating disease. results from reactivation of a papova virus, the lesion. Positron emission tomography The corticospinal tracts and peripheral pons the so-called JC virus. Although this entity imaging is occasionally useful to distinguish are characteristically spared early in the was originally described as a multifocal these entities, as radiation necrosis is course of the disease, and a characteristic process, it may present with confluent or hypometabolic, as opposed to neoplasms. “bat wing“ configuration is localized to the diffuse regions of white matter involvement. Perfusion MR imaging may also prove useful central pons. There may be extension to the The subcortical white matter and the corpus for distinguishing recurrent tumor from midbrain and basal ganglia (so-called extra callosum are most commonly involved, radiation necrosis. pontine myelinolysis). The disease manifests although gray matter may be involved in up Another complication of tumor therapy is with low density on CT images, and T1- and to 50% of these patients. The predilection diffuse necrotizing leukoencephalopathy T2-prolongation on MR. for the subcortical white matter may help (DNL), which causes diffuse white matter Another white matter disorder with a distinguish it from HIV encephalitis, which injury following chemotherapy, with or characteristic distribution is Marchiafava- favors the periventricular white matter. With without concomitant radiation therapy. DNL Bignami disease. This entity was originally corpus callosum involvement, this process likely results from synergistic deleterious described in Italians with excessive (low- usually crosses the midline. Enhancement, effects of radiation therapy and quality) red wine intake. The disease has mass affect and hemorrhage are chemotherapy (methotrexate is a common since been described in other populations uncommon, but reported, features of PML. offender). This disorder has a rapid clinical and in association with other products of the Early metastatic disease may have an course usually leading to death. The vine. In patients with Marchiafava-Bignami appearance similar to multifocal small confluent regions of T1- and T2- disease, demyelination and necrosis vessel ischemic changes in the white matter prolongation are characterized by variable characteristically involved the corpus (multiple punctate foci of T1- and T2- peripheral enhancement on post- callosum and adjacent white matter. It prolongation involving white matter). Gado- gadolinium studies. The centrum semiovale manifests as low density in the corpus linium-enhanced images are useful for is characteristically involved. callosum on CT. With MR, the corpus

ADVANCED MRI 2002 – FROM HEAD TO TOE 3 A Practical Approach to White Matter Disease callosum and deep white matter show high C, Tansey CM, Hall WJ. The accuracy of magnetic signal on long-TR image. resonance imaging in patients with suspected The rare hereditary sensorimotor neuropathy multiple sclerosis. JAMA Jun which affects some native Americans, Navajo neuropathy (type A), can be 23/30,1993;269:3146-3151. distinguished from the leukodystrophies clinically. On cranial imaging, characteristic [7] Nesbit GM, Forbes GS, Scheithauer BW, lesions in the cerebellar white matter may be Okazaki H, Rodriguez M. Multiple sclerosis: identified. They are crescentic in configuration, low attenuation on CT, and Histopathologic and MR and/or CT correlation in show T1- and T2-prolongation on MR. 37 cases at biopsy and three cases at autopsy.

More of a physiological phenomenon than a Radiology 1991;180:467-474. disease, Wallarian degeneration usually involves the corticospinal tracts. Injury to [8] Olson EM, Healy JF, Wong WHM, Youmans nerve axons anywhere along their course DC, Hesselink JR. MR detection of white matter results in axonal involution and demyelination. In the chronic phase, a focus disease of the brain in patients with HIV infection: of T1 and T2 prolongation with Fast spin-echo vs conventional spin-echo pulse accompanying atrophy may be seen along the course of the involved white matter tract. sequences. AJR 1994;162:1199-1204. The cerebral peduncles are characteristically [9] Rowley HA, Dillon WP. Iatrogenic white matter involved. diseases. Neuroimaging Clinics of North America

SUMMARY 1993;Vol 3-Number 2:379-400. Although the imaging appearance of white [10] Simon JH. Neuroimaging of multiple matter pathology may be nonspecific, the diagnosis of white matter disease may be sclerosis. Neuroimaging Clinics of North America managed through the judicious use of 1993;Vol 3-Number 2:229-244. magnetic resonance imaging. In combination with knowledge of the imaging [11] Smith RR. Central pontine myelinolysis. manifestations of white matter diseases and Neuroimaging Clinics of North America 1993;Vol the patient's clinical history, laboratory data and physical exam findings MR facilitates the 3-Number 2:319-328. generation of a limited and accurate differential diagnosis. [12] Walsh LE, Moran CC. The mucopolysaccharidoses: Clinical and

Selected Bibliography neuroradiographic features. Neuroimaging Clinics [1] Byrd SE, Darling CF, Wilczynski MA. White of North America 1993;Vol 3-Number 2:291-302. matter of the brain: Maturation and myelination on magnetic resonance in infants and children. Neuroimaging Clinics of North America 1993;Vol [13] Whiteman MLH, Post JMD, Bowen BC, Bell 3-Number 2:247-265. MD. AIDS-related white matter diseases. Neuro- [2] Cajade-Law AG, Cohen JA, Heier LA. Vascular causes of white matter disease. Neuroimaging imaging Clinics of North America 1993;Vol 3- Clinics of North America 1993;Vol 3-Number 2:361-375. Number 2:331-354. [3] Caldemeyer KS, Edwards MK, Smith RR, Moran [14] Williams KD, Drayer BP, Johnsen SD, Johnson CC. Viral and postviral demyelination central nervous system infection. Neuroimaging Clinics of PC. MR imaging of leukoenephalopathy North America 1993;Vol 3-Number 2:305-316. [4] Gean-Marton AD, Vezina GL, Marton KI, associated with Navajo neuropathy. AJNR Mar/Apr Stimac GK, Peyester RG, Taveras JM, Davis KR,. 1990; 11:400-402. Abnormal corpus callosum: A sensitive and specific indicator of multiple sclerosis. Radiology [15] Yetkin FZ, Fischer ME, Papke RA, Haughton 1991;180:215-221. [5] Lee BCP. Magnetic resonance imaging of VM. Focal hyperintensities in cerebral white matter metabolic and primary white matter disorders in children. Neuroimaging Clinics of North America on MR imagesof asymptomatic volunteers: Corre- 1993;Vol 3-Number 2:267-287. lation with social and medical histories. AJR [6] Mushlin AI, Detsky AS, Phelps CE, O'Connor PW, Kido DK, Kucharczyk W, Giang DW, Mooney 1993;161:855-858.

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