82.1 Clinical Features
and Laboratory Investigations Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating infection of the CNS caused by a polyomavirus, the JC virus. It usually occurs in im- munodeficient patients. Its association with such un- derlying diseases as lymphoma, multiple myeloma, leukemia, sarcoidosis, tuberculosis, Whipple disease, systemic lupus erythematosus, systemic carcinomas, renal transplantation, bone marrow transplantation, AIDS, and immunosuppressed states is well docu- mented, although the disease has also been reported in patients without evidence of an immunological deficit. During the last few years, PML has most often occurred in the context of AIDS. The prevalence of PML in AIDS patients is estimated to be in the range of 4–7%, which is probably an underestimation. In most cases, PML is a late complication of a pre-exist- ing chronic systemic disease, which has typically been present for a long time before the neurological abnor- malities appear. This underlying disease does not dif- fer appreciably either in its clinical or pathological as- pects from the same disease in other patients in whom PML does not occur. There is no way of pre- dicting the occurrence of PML. PML occurs predom- inantly in adults. There is a male preponderance in the proportion of about 5:3.
The clinical signs and symptoms of PML are those expected from the presence of multiple CNS lesions of varying size, mainly affecting the white matter of the cerebral hemispheres but indiscriminate in their lo- calization. In the early stages the most frequently ob- served signs are monoparesis, hemiparesis, personal- ity change, cognitive impairment, ataxia, dysarthria, dysphasia, and cerebral visual impairment. Quadri- paresis, severe dementia, and coma characterize the more advanced stages. Headaches and seizures are unusual, and there is no evidence of increased in- tracranial pressure. Rarely, involuntary movements indicative of an extrapyramidal disorder are ob- served, such as choreiform movements, dystonia, athetosis, or parkinsonism. Once the disease appears, it generally progresses until the patient dies. Usually, as with many incapacitating cerebral diseases, death results from terminal bronchopneumonia. In most patients a period of about 2–6 months elapses be- tween the first appearance of neurological symptoms and death. In a few patients the illness is extremely
brief, lasting only a few days. At the other end of the scale, the disease can last for a year or more. In AIDS patients with secondary PML some survival time can be gained by treatment with highly aggressive anti- retroviral therapy (HAART). Patients showing spon- taneous improvement have also been described.
It is clear that a wide range of clinical neurological abnormalities may be encountered in PML and no syndrome is especially distinctive of the disease. The combination of a coexisting chronic systemic disease with fairly rapidly progressive multifocal or diffuse cerebral disease should suggest the presence of PML.
As a great proportion of the general population, probably 80–90%, has been exposed to JC virus in the form of a banal childhood upper respiratory tract infection and thus has developed IgG antibodies against the JC virus, serological tests are not helpful in establishing the diagnosis. Routine cytochemical CSF examinations, such as cell count and protein concen- tration, are also of little value, because abnormalities may be due to the underlying pre-existent disease.
The JC virus has never been cultured from blood or CSF, nor have viral antigens been identified in the CSF. In patients who are not suffering from HIV infec- tion, detection of intrathecal antibodies against the JC virus has a sensitivity of about 70% and a specificity of 99%. As in other microbial diseases, the PCR tech- nique of amplifying DNA has had a major impact on the diagnosis of PML. Detection of JC viral DNA by PCR in the CSF has a sensitivity of about 75% and specificity between 90% and 99%. The high specifici- ty obviates in many cases the need for a brain biopsy.
However, the problem of false negative results in 25%
of the cases remains, which may prompt a second CSF examination or still make a brain biopsy necessary.
Semiquantitative measurements of JC viral DNA load in CSF shows correlation with survival and could be used as a method of monitoring therapeutic efficacy, in addition to clinical and neuroimaging findings.
82.2 Pathology
The brain displays no external abnormalities in PML.
On sectioning, multiple grayish granular-appearing lesions are seen in the white matter, often associated with a loss of the distinct border between the cortex and subcortical white matter. Asymmetrical involve- ment is the rule. Although the lesions are often found
Progressive Multifocal Leukoencephalopathy
Chapter 82
bilaterally, they are usually more extensive in one cerebral hemisphere than in the other.
Microscopically the lesions vary from small foci of demyelination to extensive areas of myelin loss, occu- pying a major portion of a cerebral lobe or hemi- sphere. The small foci tend to be round or oval, but the larger areas of demyelination are irregularly out- lined, probably resulting from coalescence of smaller lesions. The lesions may occur anywhere in the white matter of the CNS, no part of the CNS being entirely spared. However, the lesions tend to be less frequent in the brain stem and the cerebellum, and involve- ment of the spinal cord and peripheral nerves is uncommon. Localization of lesions in the corti- comedullary junction and subcortical white matter is very typical. The deep cortical layers often also show loss of myelin sheaths, but the cortical cytoarchitec- ture remains intact.
The lesions are characterized by loss of myelin with relative sparing of the axons. Sometimes the ax- ons are destroyed along with the myelin, leaving nothing but a meshwork of astrocytic processes and glial fibrils or actual cavities. In the center of the le- sion, where myelin sheaths have been destroyed, oligodendrocytes are absent. At the periphery of the lesions the oligodendrocytes are markedly altered, with enlargement of their nuclei and effacement of the normal chromatin pattern. These abnormal nu- clei often contain basophilic or eosinophilic inclusion bodies. Another cellular change is a conspicuous al- teration of astrocytes. Some of the astrocytes in and around the lesion are enlarged into gigantic forms, and their nuclear structure is profoundly altered. Hy- perchromatism, occasionally bizarre lobulation of the nucleus, multinucleation, and mitotic figures are characteristic abnormalities. The change in individ- ual cells is at times so severe that the cells become in- distinguishable from the neoplastic cells that charac- terize malignant astrocytomas. The relative absence of a cellular inflammatory reaction is striking. In many cases inflammatory cells are absent altogether, and in other cases they are few. Numerous lipid-laden macrophages can be identified within the area of demyelination.
PML does little damage to nerve cell bodies. Le- sions may be situated in gray matter structures, espe- cially the deep cortical layers.Within these lesions the myelin sheaths are destroyed, and the astrocytes and oligodendrocytes show the characteristic changes, whereas most of the nerve cells appear to be intact.
Electron microscopic studies show virus-like par- ticles within the abnormal oligodendrocytic nuclei and, to some extent, also in altered astrocytes. These particles are seen in isolation, in irregular groups, in a crystal-like pattern, or in the form of filaments. The size, shape, surface details, and arrangement of these particles are characteristic of the polyomavirus sub-
group of papovaviruses. This observation is con- firmed by immunofluorescent studies with the use of specific antibodies against polyomavirus. Using the in situ hybridization techniques with a polyomavirus DNA probe, the infection of oligodendrocytes and astrocytes with this virus can also be shown.
82.3 Pathogenetic Considerations
PML is a demyelinating disease associated with a polyomavirus, which belongs to the Papovaviridae.
The family Papovaviridae consists of two genera, Papillomavirus and Polyomavirus. These are small DNA-containing viruses.A human polyomavirus, des- ignated JC virus after the individual from whom it was first isolated, has been implicated as the etiological agent in nearly all cases of PML. In a minority of the cases a related polyomavirus, simian virus 40 (SV40), has been held responsible for the disease. Although the disease PML is rare, infection with the JC virus is quite common. Antibodies to JC virus have been found in up to 90% of the population, and the preva- lence of antibodies rises with increasing age. Infection is usually acquired early in life: by the age of 15, 65%
of children have anti-JC virus antibodies. In any given PML patient there is no information about whether these antibodies were present before the onset of the disease. The virus is distributed throughout the world.
The question of how JC virus can be ubiquitous yet
not cause more widespread clinical illness is not sim-
ple to answer. Recent research has provided informa-
tion about the pathways the JC virus utilizes to enter
the human host and ultimately the brain. Traffic of JC
virus through the body is complex, involving cellular
receptors, DNA-binding proteins, and a variety of
viral regulatory regions in multiple target cells. JC
virus DNA has been detected in human tonsil tissue,
including stromal cells and lymphocytes. Therefore,
tonsils may be the initial site of infection. For this in-
fection to occur virions have to bind to special recep-
tors, enter cells, and have their DNA integrated into
host cell DNA. Viral DNA is replicated and translated
into proteins, and via a number of steps JC virions are
assembled and passed to circulating tonsillar lym-
phocytes. As with other human viral pathogens, sus-
ceptibility to infection is determined at least partly by
viral attachment to cellular receptors. This specificity
of receptors plays a role in the types of cells that are
most vulnerable to infection. Different JC virus geno-
types with different regulatory regions have consis-
tently been found in different tissues, probably con-
tributing to differential vulnerability of different tis-
sues to infection. Viral reactivation occurs by im-
munosuppression of the host. Reactivated JC virus
will infect B lymphocytes. These cells can cross the
blood–brain barrier and infect oligodendrocytes.
Oligodendrocytes have a receptor profile that makes them extremely vulnerable to JC virus infection.
Viremia would be another explanation of the trans- port of JC virus from infected organs to the brain, but this has never been observed. T cells cannot be carri- ers either, because JC virus cannot infect T lympho- cytes or bind to T cell membranes. Infected B lym- phocytes have been found in multiple PML brain tis- sue samples.
Various papovaviruses are known to induce cell transformation in vitro and are oncogenic in ham- sters. Papovaviruses, as mentioned before, are subdi- vided into two subgroups: the papillomaviruses, known to cause warts and cervical carcinoma, and polyomaviruses, such as the JC virus, causing PML and of which the oncogenicity is a suspicion of more recent date. Papovaviruses, their antigens, or viral DNA sequences have been detected in some human tumor cells. Pathologically, two cell types in the brain are infected by the polyomavirus in PML. First, oligo- dendrocytes are lytically infected, and virus particles fill the nucleus to give it a characteristic appearance.
Oligodendroglial cell death causes demyelination. It is postulated that there is also an infection of the astro- cytes, in which the viral genome is integrated into the cellular DNA, leading to cell transformation. The fact that astrocytic cell transformation in PML is virally induced is indirectly supported by the known onco- genic potential of papovaviruses in hamsters, the re- ported simultaneous occurrence of PML and gliomas, and the demonstration of shared internal capsid anti- gens of a polyomavirus in the nucleus of giant astro- cytes in PML.
A defect in cell-mediated immune defenses ap- pears to be a central factor in the reactivation process of JC virus and the development of PML. The lack of cellular inflammatory reaction in white matter le- sions also supports the notion of a deficit in cellular immunity. Yet this deficit alone does not provide an adequate explanation for the occurrence of PML since diseases associated with such immunological deficiency and treatment with immunosuppressive drugs are relatively frequent, while PML is rare. The problem is made even more difficult by the fact that PML may even occur in the presence of apparently intact immune responses.
Simian virus 40 is of minor importance in PML. In general, infection with this virus is rare in humans, only 5% showing antibodies. The source of the virus is unknown.
82.4 Therapy
At present the prognosis in PML is generally poor.
Treatment with idoxuridine and vidarabine, both an- tiviral agents, has been shown to be nonbeneficial.
Cytarabine (arabinosylcytosine) administered intra- venously and intrathecally has been demonstrated to be more promising in PML. The rationale for the use of this agent is that polyomaviruses are DNA viruses, and that cytarabine impairs DNA synthesis. Long- term survival of PML patients treated with cytarabine has been reported. The improvement of the neurolog- ical condition varies from moderate to marked in these patients. In some patients there is very rapid improvement, occurring within 48 h of initiation of therapy. In others there is a delay of several weeks.
Sometimes cytarabine is only transiently beneficial, and sometimes it has no beneficial effect at all.
Neither type and duration of underlying disease nor duration and course of neurological symptoms prior to treatment appear to yield a clue as to the different responses to therapy. Some studies, however, have been unable to find the same positive results using cytarabine. Treatment of PML with a combination of cytarabine and interferon has occasionally been re- ported as successful. Treatment of patients with HIV- 1 infection and PML with highly aggressive antiretro- viral therapy has led to a better immune status in pa- tients, and sometimes also to a positive effect on the coexisting PML.
Therapy should be directed at eradication of the viral infection not only by specific antiviral agents but also by enhancing host immune defenses. Lowering of the immunosuppressive medication may be appro- priate. Early diagnosis before actual destruction of nervous tissue has occurred may be necessary for treatment to be successful.
82.5 Magnetic Resonance Imaging
CT scan shows low-density white matter lesions with characteristically scalloped lateral borders following the contours of the gray–white matter junction, whereas the medial border is smoother in outline.
Enhancement of some of the lesions may be seen.
Small and early lesions are not detected, and CT often shows no abnormalities in the early stages of the dis- ease.
MRI shows that PML lesions can be found any- where in the white matter of the cerebral hemi- spheres, the brain stem, and the cerebellum, but most often involve the cerebral subcortical area (Figs. 82.1–
82.3). The lesions have an intermediate to low signal intensity on T
1-weighted images, and a high or very high signal intensity on T
2-weighted images. The af- fected white matter appears somewhat swollen, which becomes more evident in those areas where the U fibers are involved. The subcortical white matter le- sions then have a scalloped appearance, outlining the overlying cortex and stretching it (Figs. 82.1, 82.2 and 82.4). The sharp edge between affected white matter
Chapter 82 Progressive Multifocal Leukoencephalopathy 630
and cortical gray matter is due to the anatomical bar- rier formed by the noninfected neuronal layer with its relative myelin paucity as opposed to the myelin-rich white matter and infected oligodendrocytes. In ex- ceptional cases MRI shows some extension of a white matter lesion into the cortex, probably where intra- cortical myelin has been attacked (Fig. 82.3). Lesions of the external capsule have been found in 38% of PML patients, and posterior fossa lesions in 32%
(Fig. 82.4). Isolated posterior fossa lesions have been reported occasionally. Basal ganglia may be involved, particularly in the myelin-containing laminae sepa- rating the various nuclei and subnuclei (Figs. 82.3 and 82.4). The myelin content of the thalamus and globus pallidus is higher than of the putamen and caudate nucleus, and lesions would be expected to occur more often in these areas. Involvement of the corpus callo- sum is often seen (Figs. 82.1 and 82.4). Although the epithet “multifocal” suggests more than one lesion in all cases, this is not necessarily true. Single lesions may occur. Confluence of several lesions may give rise
to the appearance of a widespread white matter disor- der (Fig. 82.4). Enhancement after the injection of gadolinium is seen in a minority of patients, but is not exceptional (Figs. 82.2 and 82.4). If enhancement is seen, it is usually only present in some of the lesions;
it is faint and peripheral. More solid enhancement is seen in rare cases. There is evidence that mass effect and (temporary) enhancement on MR images, as ex- pressing the presence of an immune reaction of the patient, represent positive predictive factors for more prolonged survival. PML lesions have different ap- pearances on diffusion-weighted images depending on the stage of the disease. Newer lesions and the ad- vancing edge of large lesions have a high signal on Trace diffusion-weighted images and a normal to low ADC. Older lesions and the center of large lesions have a low signal on Trace diffusion-weighted images and increased ADC values. High signal on Trace diffu- sion-weighted images and low ADC mark the regions of active infection with cell swelling, distinguishing them from burnt-out areas of gliosis.
Fig. 82.1. The characteristic image of PML: a large lesion in the right parietal lobe, involvement of the corpus callo- sum, and a smaller lesion in the left hemisphere. These T2-weighted images show a sharp border between the hyperintense white matter lesion and the normal cortex. The cortex is stretched out over the lesion. In this case there was no enhancement
Fig. 82.2. A 63-year-old male with AIDS and PML.These images show a large frontal lesion on the right side with partial enhance- ment after contrast injection, as is seen on the transverse and coronal T1-weighted contrast-enhanced images
PML has to be differentiated from other multifocal white matter disorders, especially from those occur- ring in AIDS patients, such as cytomegalovirus infec- tions, and from acute and subacute HIV encephalitis itself. These latter infections, however, do not usually involve the U fibers, do have different signal intensity characteristics on T
1- and T
2-weighted images, and tend to be symmetrical. Lesions in systemic lupus erythematosus may sometimes mimic PML, while PML may also occur in the context of systemic lupus erythematosus. Multifocal white matter involvement with some swelling of the subcortical lesions and stretching of the overlying cortex may also be seen in noninfectious inflammatory disorders, in particular multiple sclerosis and acute disseminated en- cephalomyelitis. Similar lesions have been reported in the context of the reversible posterior encephalo- pathy syndrome. In vasculitis, posterior reversible
encephalopathy syndrome, and noninfectious in- flammatory disorders, white matter lesions are as a rule also asymmetrical, and differentiation from PML may be impossible on the basis of MRI features alone.
Clinical and laboratory information is necessary. In several inborn errors of metabolism and in several toxic encephalopathies, spongiform white matter changes occur, resulting in some white matter swelling and stretching of the overlying cortex, which is otherwise intact. The appearance of the white mat- ter changes shows similarities to those observed in PML, but the white matter abnormalities are usually symmetrical and usually generalized rather than multifocal. Some cases of PML resemble gliomatosis cerebri on MRI. However, in gliomatosis cerebri the border between white and gray matter is as a rule blurred, contrasting with the sharp border seen in PML.
Chapter 82 Progressive Multifocal Leukoencephalopathy 632
Fig. 82.3. One parasagittal T1-weighted and a series of T2- weighted MR images obtained in a 48-year-old man with AIDS and PML are shown. The images show multiple lesions in the white matter. Note that gray matter structures are also in-
volved: putamen, globus pallidus, and caudate nucleus on the left are affected, and some lesions extend into the cortical gray matter
Fig. 82.4.
Chapter 82 Progressive Multifocal Leukoencephalopathy 634
Fig. 82.4. (continued). A 43-year-old man with rapidly pro- gressive neurological deterioration caused by PML. This series of T2-weighted images (first, second, and third rows) show ex- tensive involvement of white matter structures. The cerebral white matter is affected, more seriously on the right side, with involvement of the corpus callosum.The abnormal white mat- ter is mildly swollen with thickening of the corpus callosum.
The images could be considered suggestive of gliomatosis cerebri, but there is a sharp demarcation between the affected cerebral white matter and the unaffected overlying cortex.The basal ganglia are involved, but the structures mainly affected
are the internal capsule and the laminae separating the differ- ent nuclei, resulting in a pattern of concentric partial circles.
The brain stem and middle cerebellar peduncle on the right are affected. The affected white matter is mildly hypointense on T1-weighted images (fourth row).There is one small focus of contrast enhancement. Diffusion-weighted Trace images (b = 1000, fifth row) show large areas of hyperintensity, which correspond to low ADC values and restricted diffusion. These findings indicate active infection of large areas, consistent with the dramatic clinical picture in the patient
