C/O Numbness on left side of face with weakness of left half of body. Patient is Seropositive (HIV+).
Findings:
There are hyperintense areas on the T2 Weighted and FLAIR images in the medulla, left middle cerebellar peduncle,
left cerebellar hemisphere, in the
pons and a small similar area of altered signal intensity in the right
middle cerebellar peduncle. These are hypointense on the T1 Weighted images. On
administration of contrast there is no significant enhancement.
Pathology/Etiology:
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the CNS caused by reactivation of a latent papovavirus (the JC virus) infection. It affects immune-compromised patients and is usually seen with patients having AIDS. The non-AIDS population affected by PML is generally middle-aged and usually harbors an underlying disease such as leukemia, lymphoma, sarcoidosis, malignancy or tuberculosis, or is receiving immunosuppressive therapy. Rarely, patients with PML have neither an underlying systemic disease nor an immunodeficiency.
The JC virus (so named for the initials of the patient with PML from whom the
virus was first isolated)
attacks oligodendrocytes, which are responsible for manufacturing myelin, hence
PML is manifested as demyelination and edema.
Potential mechanisms of demyelination attributed to viruses include:
1. Direct infection of oligodendrocytes.
2. Immune-induced oligodendrocytes or myelin destruction by immune reactions
against viral antigens.
3. Secondary damage from immune complex formation.
4. Antimyelin autoimmune reactions.
PML is characterized pathologically by focal or confluent areas of demyelination, mainly distributed throughout the cerebral white matter. The gray matter may also be affected. The foci of demyelination can have a resemblance to those of multiple sclerosis, but occasionally they are large and confluent, mimicking foci of ischemic necrosis or cystic degeneration. Cytologic features include large, highly atypical astrocytes with bizarre appearing nuclei and intranuclear inclusions in oligodendrocytes. Rarely inflammatory cells, usually lymphocytes, may also be present.
Clinical Features:
PML typically presents as relentlessly progressive focal central nervous system dysfunction, such as hemiparesis, aphasia, cortical blindness, ataxia or altered mental states with an insidious onset of dementia. It usually leads to death (without therapy) in approximately 4 to 6 months. Improved patient survival has been reported with the use of a variety of drugs in a limited number of studies.
MRI:
MRI shows hyperintensity in the white matter tracts, typically in a parieto-occipital distribution or involving the middle cerebellar peduncles. Initially the lesions tend to be multifocal, scalloping lesions and later they become confluent and large. Typically, no mass effect is seen. Lesions often spare the periventricular region, unlike other diseases, such as multiple sclerosis, that affect the white matter. Contrast enhancement and hemorrhage are rare, but occasionally are seen. Although PML classically occurs in a subcortical parieto-occipital distribution, it increasingly occurs in unusual locations when found in patients with AIDS. Primary involvement of the cortex, the basal ganglia, or the cerebellum and brainstem (all structures initially thought to be spared by PML) is no longer uncommon and may be present in up to 50% of AIDS patients with PML.
The lesions are hypointense on T1W images and hyperintense on T2W and FLAIR images. Increased hypointensity on T1W images has been observed on follow-up MR studies, and has been suggested to be indicative of an aggressive form of the disease. Such imaging findings as increased atrophy, confluence of lesions, and increased hypointensity on follow-up T1W images may be regarded as indicators of a poor prognosis in untreated AIDS patients with PML. In HAART (highly active antiretroviral therapy) treated patients, increased hypointensity on T1W images was observed in both therapy responders and non responders. It probably represented necrotic areas, which were a result of the demyelination before the process was halted by HAART. They were not associated with a concomitant increase in high signal on FLAIR images and may represent a burnt out process. In contrast to this evolution of MR findings in therapy responders, increased low signal on T1W images with corresponding increases in high signal on FLAIR images would represent a progressive destructive process, which is a poor prognostic sign. Typical PML lesions do not usually enhance; however, faint, peripheral enhancement has been described. Recently, contrast enhancement has been thought to be the result of an intense inflammatory reaction and one of the predictive factors for prolonged survival.
Contrast enhancement developing only after therapy and in the early phase may be explained as an effect of the therapy on the blood-brain barrier, which, with breakdown, causes edema, mass effect, and enhancement. The breakdown of the blood-brain barrier could be a result of improved immuno-competence and the ability to produce perivascular inflammatory reaction. Prominent perivascular mononuclear inflammation has been reported to be greatest in the contrast-enhancing region of the PML lesion. After improvement, enhancement was no longer seen. In one study, development of contrast enhancement on MR studies was seen in patients with PML being treated with HAART only when their CD4+ count had increased. In these patients, the PML lesions turned from enhancing to non-enhancing on follow-up MR studies after 3 to 6 months of therapy. In contrast to untreated PML cases, in the early phase of treatment the presence of mass effect and enhancement might represent a positive predictive factor for prolonged survival.
Differential Diagnosis:
PML must be suspected in patients with the proper clinical history, even when the lesions appear atypical in distribution. A similar pattern of diffuse high signal intensity in the white matter also has been reported in patients with AIDS who do not have PML as a result of a direct neurotropic effect of the human immunodeficiency viruses (HIVs). In general, clinical findings precede the imaging diagnosis of this subacute encephalopathy. MRI is relatively insensitive in detecting the primary changes of HIV infection of the brain (i.e., the diffuse microscopic glial nodules with multinucleated giant cells). However, MRI is sensitive to the sequelae of the infection and allows visualization of cortical atrophy and demyelinating lesions.
In patients with AIDS, many other disease processes may affect the white matter and mimic PML. These include diseases with multifocal involvement predominantly of white matter, most notably encephalitides, including cytomegalovirus, toxoplasmosis, or encephalitis from the AIDS virus, HIV-1. Mass effect is more common with lymphoma and toxoplasmosis, but can occasionally be present in PML .
AIDS patients may present with subacute encephalitis. Clinical presentation
includes a progressive dementia associated with motor and/or behavioral
dysfunction. Early difficulties with memory and concentration are often followed
by apparent apathy and social withdrawal. Headache is also a frequent complaint,
and seizures are seen in approximately 10% of cases. The subacute encephalitis
has been attributed to CMV in some cases, although HIV itself appears to be the
etiologic agent in the vast majority of cases A diffuse pattern of
periventricular white matter hyperintensity may suggest HIV encephalitis, in
contradistinction to the multifocal pattern produced by PML. However, the
variability in size, extent, and distribution of lesions in both HIV-related
demyelination and PML, especially early in the course of disease, precludes a
definitive diagnosis based on the MR appearance alone. Cortical atrophy is the
most frequent MR finding and is usually the only early alteration. Both cortical
and central atrophy progress on serial MR examination. T2W images reveal
hyperintense lesions without mass effect in the periventricular white matter and
centrum semiovale that correspond to foci of demyelination and vacuolation.
Lesions do not enhance. Lesions may vary from scattered, isolated, unilateral
foci to confluent bilateral involvement, and may be symmetric or asymmetric. The
extent of disease roughly parallels the clinical neurologic deterioration