01
Theoretical Background
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the brain caused by the John Cunningham (JC) polyomavirus. PML is one of the acquired immune deficiency syndrome (AIDS)-defining diseases and historically occurred predominantly in human immunodeficiency virus (HIV)-infected patients. In this patient group, the clinical course is often severe to lethal if no adequate immune response can be restored.
Increasingly, PML is also observed in patients treated with immunosuppression. The course of PML in those patients may differ from that of HIV-associated PML, both clinically and on magnetic resonance imaging (MRI), as the extent and dynamics of immune reconstitution are different. PML can occur as a complication of natalizumab therapy in multiple sclerosis (MS) patients.
02
Early Detection
The clinical presentation of PML depends on the anatomical location and is manifold. MRI detects PML before clinical symptoms occur as it is highly sensitive to demyelination caused by oligodendrocyte injury from the JC polyomavirus. Reports suggest there is often a time window of about 3–4 months until a PML lesion becomes symptomatic. MRI-based early detection thus aims to detect PML in the presymptomatic stage, when even cerebrospinal fluid (CSF) analyses may still be negative.
Retrospective analyses suggest that early detection of asymptomatic PML lesions is associated with a more favorable clinical outcome and a higher probability of survival. When immunosuppressive therapy is stopped early, immunocompetency can be reached faster. The early onset of inflammatory immune reconstitution syndrome (IRIS) usually facilitates defect healing of PML lesions.
Several recommendations have been published on the management of patients at high risk of PML on natalizumab therapy. In general, an MRI follow-up interval of 3–6 months is recommended. The MRI protocol should include at least a FLAIR sequence, a T2 weighted sequence, and a diffusion weighted sequence (b-1000 s/mm²). Preferably sequences should be 3D or thin-sliced (3 mm). The protocol should be expanded to include a contrast-enhanced (CE) T1 weighted sequence if PML is suspected. It is necessary to exclude carry-over PML by MRI when new symptoms occur and a switch from natalizumab to another therapy is considered.
03
MRI Characteristics
PML lesions are foci of progressive demyelination that usually present without sharp borders but are ill-defined. They often show faint hyperintensity on T2 weighted images but show rapid centrifugal extension on short-term follow-up. There is often cortical or juxtacortical location involving the short association fibers (or "U"-fibers), giving the impression of a "flame"-like lesion with sharp demarcation from the cortex. Cortical involvement is common but often technically difficult to detect.
PML may manifest less frequently as a singular lesion in the basal ganglia, in the medullary camp, or infratentorially. Microcysts within the lesion may be apparent, especially on T2 weighted sequences, giving rise to a "milky-way"-like appearance. In most cases, there is little space-occupying effect relative to lesion extent — useful to differentiate it from other pathologies.
04
Appearance on Diffusion Weighted Imaging
Frequently early PML lesions give rise to hyperintensity on (b-1000 s/mm²) diffusion weighted sequences.
There is evidence that PML activity correlates with a DWI signal as a result of swelling oligodendrocytes. A ring-shaped hyperintense DWI signal is frequently found at the margin of actively expanding PML lesions. A hypointense DWI signal in the center of the PML lesion has been described as an expression of severe demyelination and advanced tissue destruction.
05
Appearance on Contrast-Enhanced Images
In contrast to the typically non-contrast-enhanced PML lesion in patients with HIV infection, 30–50% of PML lesions in natalizumab-treated patients already show some contrast uptake at the time of initial diagnosis. The contrast uptake can often appear irregular to "patchy" at the lesion margin, which may indicate a limited focal immune response.
Furthermore, numerous punctate contrast-enhanced lesions may occur, mimicking a "milky-way"-like pattern. This pattern appears to have high specificity for PML.
When the IRIS phase sets in, contrast enhancement usually becomes much more prominent and is associated with vasogenic edema before the lesions eventually reach a stage of defect healing, leading to persistent focal atrophy and residual lesions.
06
Differentiation from MS Lesions
If MRI changes are subtle, there is often uncertainty regarding whether a new lesion is attributable to MS or PML. A short-term follow-up MRI after 2–4 weeks can offer valuable insights. The absence of well-defined lesion borders on FLAIR, the presence of DWI hyperintensity on b-1000 s/mm² images, and the lack of typical contrast enhancement lean towards PML. Centrifugal extension with peripheral DWI hyperintensity further suggests PML. Conversely, a new focal T2 hyperintense lesion with robust contrast enhancement leans towards MS.
A unique scenario arises during the IRIS phase: the individual's immune competency triggers an inflammatory response followed by healing of the PML lesion. In this stage, new MS lesions might also manifest, because the therapeutic immunosuppressive effect that previously controlled MS is no longer active.
Sequential MRI scans furnish the essential information required to differentiate between MS and PML lesions — particularly relevant during the phase of PML progression where these lesions may emerge concurrently.
Overview: MS vs. PML Based on MRI Features
| Feature | MS | PML |
|---|
| Any new lesion in a high-risk constellation should be critically evaluated for the presence of PML |
| Localization | Periventricular, juxtacortical or intracortical, infratentorial, spinal cord; several lesions can occur simultaneously | Often fronto-parietal and cerebellar; subcortical or juxtacortical; may occur multifocally |
| Cortical involvement | May occur | May occur |
| Lesion morphology | Finger-shaped, oval; spread along central vein; roundish intracortical or subpial; well-circumscribed borders | "Flame"-like spread along short association fibers; ill-defined borders |
| Time course | Frequently subacute; initial acute lesion may decrease in size over time | Progressive course with rapid size increase and appearance of further lesions |
| T1 weighted | Partially surrounding oedema in acute lesions | T1-hypointense signal in center of advanced lesions; severe tissue destruction |
| T2 weighted | Partially surrounding oedema in acute lesions | Inhomogeneous or microcystic appearance |
| DWI | DWI signal may be hyperintense in acute lesions | Hyperintense signal (initially entire lesion, then at lesion edge); hypointense center in advanced lesions |
| Contrast-enhanced | Often ring-like or central contrast uptake | No enhancement or "patchy" / punctate / "milky-way"-like; latter patterns have high specificity for PML |
| SWI | Hypointense rim; central vein sign; slightly hypointense core | SWI-hypointense changes along fiber tracts and surrounding cortex |
| Other | Space-occupying effect in tumefactive MS; typically no haemorrhages | Minor space-occupying effect relative to lesion extent; haemorrhages rare |
