Diagnosis of Progressive MuItifocaI Leukoencephalopathy by Computed Tomography 1 Barbara A. Carroll, M.D., Barton Lane, M.D., David Norman, M.D., and Dieter Enzmann, M.D. Progressive multifocal leukoencephalopathy (PMl) is a demyelinating disease of the central nervous system which predominantly affects immunologically compromised hosts. The distinctive CT appearance in three documented cases includes low-density lesions of central and convolutional white matter with scalloped lateral borders. lesions demonstrate no mass effect or contrast material enhancement. Findings are discussed with reference to other entities which may produce a similar CT appearance. INDEX TERMS: Brain, diseases. Brain neoplasms, diagnosis. (Brain, supratentorial, Diffuse central atrophy, 1 .834) • Computed tomography, cranial. (Cranial computed axial tomography, 1 .1211) Radiology 122:137-141, January 1977
• leukoencephalopathy (PML) is a clinically progressive demyelinating disease of the central nervous system which primarily affects the immunologically compromised host. Until recently, diagnostic studies attempting to demonstrate PML have been unrewarding. However, cranial computed tomography (CT) possesses resolution capable of detecting white matter disease. This report presents the specific CT findings in three documented cases of PML.
CASE REPORTS CASE I: A 46-year-Old man with a 7-year history of atypical chronic lymphocytic leukemia (Cll) treated with adriamycin, chlorambucil, Cytoxan, prednisone, and vincristine was admitted to Stanford University Hospital with progressive visual loss and decreased attention span over a 6-week period. Physical examination revealed a crusted, herpetic lesion at the right side of the mouth and ulcerated superficial lesions on the back; cervical, axillary, and inguinal adenopathy was palpable. Neurological examination revealed a dense left homonymous hemianopsia, left hemiparesis, and hyper-reflexia with left-sided neglect, and constructive apraxia. laboratory studies confirmed depressed levels of IgGand IgM, previously documented over a 5-year period. Cerebrospinal fluid (CSF) analysis was normal. A CT scan performed 1 week before admission revealed a high right parieto-occipital lesion of low density confined to white matter without mass effect or enhancement with contrast material (Fig. 1). A radionuclide brain scan was normal. A cerebral angiogram showed dilatation of the right medullary veins consistent with a lesion involving white matter. A right parietal brain biopsy revealed abnormally softened white matter with the typical microscopic features of PML. A trial of adenosine arabinoside (ARA-A) therapy was instituted (1). His symptoms continued to worsen, and a follow-up CT scan revealed progressive extension of the right parieto-occipital white matter lesion to the right frontal lobe (Fig. 2). He was discharged with progressive neurologic deterioration to an extended care facility.
Fig. 1. CASE I: Pre-admission CT scan. High right parietal white matter lucency with scalloped contours is seen. Other sections (not shown) demonstrated no mass effect and no contrast material enhancement. Fig. 2. CASE I: Repeat CT scan 1 month after admission. The right parietal lesion of PMl has progressed to involve the frontal lobe. No mass effect or enhancement with contrast material (300 cm 3 of meglumine diatrizoate 30 % , Hypaque-DIU 30 %, Winthrop) was present on other sections. Average density of the lesion is 10-20 Hounsfield units (5-10 EMI units). Note sparing of cortical gray matter peripherally.
CASE II: A 40-year-old man with stage III Hodgkin's disease, treated 2 years previously with total nodal radiation and MOPP(methotrexate, vincristine, procarbazine, and prednisone), was admitted with increasing diplopia, dysarthria, incoordination, headaches, and lethargy. Physical examination at admission revealed herpetic lesions of the face and palpable cervical and axillary adenopathy. Neurological examination demonstrated left homonymous hemianopsia and unsteady gait. CSF analysis showed elevated protein (92 mg/ 100 ml), mild mononuclear leukocytosis, and negative culture and cytology. The electroencephalogram (EEG)demonstrated diffuse cortical dysfunction. A 99mrc brain scan revealed increased uptake in the right parieto-occipital area (Fig. 3) while a cerebral angiogram was normal. On CT scan there
1 From the Division of Diagnostic Radiology (B. A. C., B. L., D. E.), Department of Radiology, Stanford University School of Medicine, Stanford, Calif., and the Department of Radiology (D. N.), University of California, San Francisco, Calif. Accepted for publication in June 1976. Supported in part by USPHS Grant GM1707 from the National Institute of General Medical Sciences, National Institutes of Health, Bethesda, Md. elk
CARROLL AND OTHERS
ieto-occipital, white-matter, low-density lesion (5-10 units)had enlarged since the CT scan 6 months earlier. The right lateral ventricle was enlarged with associated ipsilateral shift of the midline structures (Fig. 5). Cerebral angiography demonstrated focal atrophy in the right parieto-occipital area. The brain scan was again positive in the right posterior hemisphere. The patient died 5 months later and autopsy revealed extensive changes of PMl; the involved areas correlated well with the abnormalities on CT scan. CASE III: A 68-year-old man with a 12-year history of chronic lymphocytic leukemia (Cll) was admitted with complaint of decreased vision for 3 months. The initial left homonymous hemianopsia progressed during 6 months to cortical blindness. Concurrently the patient exhibited a mild but progressive left hemiparesis and a right parietal syndrome. CSF analysis was normal. A brain image and vertebral angiogram were negative. CT scans with and without contrast material (300 ern" of meglumine iothalamate 30 %, Conray 30, Mallinckrodt) were performed on three occasions over a 2-month period. The initial scan showed characteristic, scalloped low-density areas (5-10 units) in the parieto-occipital white matter bilaterally which did not enhance with contrast material (Fig. 6). On subsequent scans the lesions progressively enlarged (Fig. 7). The patient was treated with adenosine arabinoside (ARA-A) but continued to deteriorate (1). Autopsy revealed the characteristic gross and microscopic findings of PML. The lesions correlated well with those demonstrated on CT scans (Fig. 8).
Fig. 3. CASE II: 99mTc brain scan performed durin,g the first admission. Posterior, A, and right lateral, B, images with increased uptake in right parieto-occipital area. Fig. 4. CASE II: CT scan at first admission. There is a small lucent lesion in the right occipital white matter just posterior to the trigone. Cortical gray matter superficial to the lesion is preserved. There is no mass effect. Fig. 5. CASE II: CT scan from the second hospital admission. A. The characteristic scalloped lucency of PMl has increased in size. Average density is 10-20 Hounsfield units (5-10 EMI units). B. Focal atrophic dilatation of the right trigone with minimal ipsilateral midline shift is present. There was no change with contrast material infusion (not shown).
was a right, parieto-occipital, low-density area confined to white matter without mass effect or enhancement with contrast material (Fig. 4). The patient was felt to have central nervous system (CNS)Hodgkin's disease and was given adriamycin, bleomycin, and Velban and 1,600 rads whole brain irradiation. Six months after hospital discharge, increasing lethargy, slurred speech, confusion, and progressive left-sided weakness and incoordination developed. Admission CSF analysis was normal. EEGrevealed a slow-wave focus over the right posterior hemisphere. The right par-
Progressive multifocal leukoencephalopathy was first demonstrated by Hallervorden in 1930, although it remained unclassified and unnamed until the description by Astrom and co-workers in 1958 (2, 3). In 1974, Richardson reviewed the world literature and found 100 reported cases (4). PML is a subacutely evolving disorder affecting all parts of the CNS; white matter involvement of the cerebral hemispheres is a constant feature of the disease (5). Symptomatology correlates with the area of involvement, and relentless progression to coma and death usually occurs 3 to 6 months following the onset of symptoms. The pathological changes of PML are unique and distinctive. Enlarged distorted oligodendroglial nuclei containing eosinophilic inclusion bodies associated with enlarged astrocytes with bizarre nuclear configuration are found within focal areas of demyelination. Inflammatory changes may be minimal to absent. The death of oligodendroglia, the cells which form the myelin sheaths for CNS axons, is felt to be responsible for the demyelination. The foci of demyelination vary in size from microscopic to massive and may progress to extensive areas of cystic atrophy. These foci tend to begin in the subcortical white matter or, rarely, in deep layers of cortex, maximally involving the central white matter. In 1965, virus-like particles resembling DNA papova virions were demonstrated within diseased oligodendroglial nuclei by electronmicroscopy (6, 7). This finding is now accepted as an essential and specific feature of PML (Fig. 9) (4). In 1971, cultivation of JC virus from the tissues of patients with PML was accomplished (8), and later SV40-PML virus was similarly isolated (9). The disorder is felt to result from atypical viral infection in a compromised host, either by activation of latent papova virus in the brain or dissemination of an extracerebral viral infection.
CT DIAGNOSIS OF lEUKOENCEPHALOPATHY
CASE III: Initial CT scan.
A. The characteristic scalloped lesion [10-20 Hounsfield units (5-10 EMI unitsj] in the right parieto-occipital white matter shows no mass effect. B. A smaller similar lesion is present in the left occipital area. Normal peripheral convolutional gray matter is well shown. Fig. 7. CASE III: CT scan performed 2 weeks later. The postcontrast study shows interval progression of the bilateral lesions of PML. Fig. 8. CASE III: Horizontal brain section in the EMI plane. Right hemisphere. Massive destructive lesion of PML is seen in the parietooccipital white matter. The central portions of the lesions are granular an~ cystic. Margins are demarcated by the relatively spared cerebral cortex.
Hodgkin's disease and Cll are the disorders most commonly associated with PML; other lymphomas and leukemias are less frequent. PML has also been found in cases of tuberculosis, sarcoidosis, renal transplantation with immunosuppression (10), and, rarely, in patients with no known underlying pathology (4, 5). Diagnostic tests in PML are usually negative. CSF examination is almost always normal, except for occasional mild protein elevation as in our CASE II. Hematologic studies are noncontributory. The EEG has been the most useful ancillary test in PML, but the abnormalities are nonspecific (4, 5). Radiographic evaluations of PML have been similarly unrewarding. Skull films are normal. Angiography in all cited cases has been normal, and only a single isolated abnormal isotope brain scan has been reported (11). Pneumoencephalography is unrevealing except in late stages of the disease when cerebral atrophy may be demonstrable (5). The CT scans in these three proved cases of PML demonstrate characteristic low-density lesions of the central and convolutional white matter in areas corresponding precisely to sites of pathological involvement.
Fig. 9. Glial cell nucleus in demyelinated area packed with papova virions, some of which are arranged in crystalline arrays; obtained from postmortem specimen of CASE II (glutaraldehyde fixation). Original print mag. X 40,000.
CARROLL AND OTHERS
These lesions have density values ranging from 10-20 Hounsfield units (5-10 EMI units) centrally and up to 30 Hounsfield units at their periphery. Areas of involvement have no relationship to cerebral blood vessel distribution nor to the ventricular system. The scalloped lateral borders follow the contours of the subcortical graY-White junction, whereas the medial border is smoother in outline. No mass effect is present. In late stages there may be local atrophy indicated by ventricular enlargement and ipsilateral midline shift. There is no enhancement with intravenous infusion of contrast material. The predilection for posterior hemisphere involvement by PML, as seen in each of our three cases, has been previously noted by Richardson (3). Other neurological diseases may produce findings on CT scan similar to those of PML. Cerebral infarctions result in low-density abnormalities of 6-30 Hounsfield units (3-15 EMI units) (12-19). These are often patchy and heterogeneous in the first 24 hours but usually become more circumscribed and homogeneous after a few days. The characteristic feature of infarctions is their distribution within the territory of the major cerebral arteries, usually the middle cerebral or posterior cerebral. These lesions commonly involve both white and gray matter and extend to the surface in a triangular (apex centrally) or quadrangular shape. Mass effect is usually absent in infarcts more than 1 week old. Significant atrophy eventually supervenes, with appropriate ventricular dilatation and enlarged cortical sulci overlying the lesion. Small infarctions can be more difficult to differentiate since they may not extend to the surface and appear limited to the subcortical regions. Infarctions are enhanced by contrast material in up to 60 % of cases where double scanning (with and without contrast material) is utilized between 1 and 4 weeks of the ictus (20). Contrast material enhancement is infrequent in infarctions less than 1 week old and rare past 1 month. It is noteworthy that none of our three cases of PML, despite multiple CT scans on each patient, demonstrated contrast material enhancement in any of the lesions at any time. We propose that cerebral infarctions can be distinguished by CT scan from the lesions of PML by their superficial location, shape, distribution in vascular territories, frequent contrast material enhancement, evolution on serial studies, and by the different clinical course. A second differential diagnostic consideration in PML is that of CNS infection. Initially, cerebritis presents on CT scan as an ill-defined low-density area (14). The lesions are often multiple and located at the gray-white matter junction; limitation to the white matter is unusual. If cerebritis progresses toward abscess formation, contrast material enhancement invariably occurs, and mass effect is also frequent. Bacterial abscesses are characterized by thin-walled, round, rim-like contrast material enhancement, while fungal lesions tend to be thick-walled or solid (21). Other focal demyelinating diseases may appear similar to PML on CT scan although they differ in clinical presentation. CT scans in multiple sclerosis (MS) in limited series have shown small low-absorption zones in the brain
without mass effect thought to represent the plaques of MS (14,22,23). Classically, the foci of demyelination in MS are found in subependymal and perivenous distribution in contrast to the lesions of PML. Other focal white matter diseases including familial leukodystrophy and Schilder's disease have been seen on CT scanning (22), but none show the characteristic scalloped occipital lesions of PML. Finally, primary and secondary brain tumors often produce low-density areas on the CT scan (12, 14, 17,24). However, they usually have mass effect, show contrast material enhancement, and are not limited to white matter. The associated cerebral edema can be very similar to PML, but the contrast-materiaI-enhanced tumor clarifies the diagnosis. It appears that the CT scan is the most specific laboratory or imaging examination currently available for the diagnosis of PML. Recent reports of symptomatic improvement in PML following cytosine arabinoside therapy (25-27) make early accurate diagnosis increasingly important. In addition, CT scans may enable the diagnosis of PML to be made without exposing the patient to more invasive, expensive, and time-consuming procedures. The CT scan will also provide a means of radiographically assessing response to therapy.
SUMMARY Progressive multifocal leukoencephalopathy is an increasingly important disease entity as larger numbers of patients with decreased host immunity survive systemic malignancies and therapeutic intervention for longer periods of time. To our knowledge, the present study presents the first description in the literature of the CT scan appearance of PML. The CT scans reveal low-density lesions (10-20 Hounsfield units) of central and convolutional white matter with characteristic scalloped lateral borders. The lesions demonstrate no mass effect or contrast material enhancement and do not conform to specific vascular distribution. We believe the CT appearance to be highly specific in the appropriate clinical setting. The possibility of therapeutic intervention makes early accurate diagnosis essential. ACKNOWlEDGMENT: The Department of Pathology (Neuropathology), Stanford University School of Medicine, established the histological and electron microscopic diagnosis of the cerebral biopsy of CASE I. and the pathological and electron microscopic diagnosis of CASE II (Fig. 9). The Department of Neurology at the Veterans Administration Hospital, San Francisco, established the pathological diagnosis of CASE III (Fig. 8). Department of Radiology Stanford University School of Medicine Stanford. Calif. 94305
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CT DIAGNOSIS OF LEUKOENCEPHALOPATHY
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