Neuroimaging of Natalizumab Complications in Multiple Sclerosis: PML and Other Associated Entities

Abstract

Natalizumab (Tysabri) is a monoclonal antibody (α4 integrin antagonist) approved for treatment of multiple sclerosis, both for patients who fail therapy with other disease modifying agents and for patients with aggressive disease. Natalizumab is highly effective, resulting in significant decreases in rates of both relapse and disability accumulation, as well as marked decrease in MRI evidence of disease activity. As such, utilization of natalizumab is increasing, and the presentation of its associated complications is increasing accordingly. This review focuses on the clinical and neuroimaging features of the major complications associated with natalizumab therapy, focusing on the rare but devastating progressive multifocal leukoencephalopathy (PML). Associated entities including PML associated immune reconstitution inflammatory syndrome (PML-IRIS) and the emerging phenomenon of rebound of MS disease activity after natalizumab discontinuation are also discussed. Early recognition of neuroimaging features associated with these processes is critical in order to facilitate prompt diagnosis, treatment, and/or modification of therapies to improve patient outcomes.

Figure 1

Pathophysiology of MS and mechanism of action of natalizumab.

Figure 2

25-year-old woman with RRMS who developed worsening symptoms including weakness and inability to ambulate after beginning natalizumab. MRI FLAIR image demonstrates classic appearance of PML including a sharply demarcated peripheral border along the subcortical U-fibers (arrow) and a hazy, ill-defined central border (dashed arrow).

Figure 3

63-year-old woman with MS presenting with profound neurologic deterioration. (a) FLAIR image demonstrates characteristic PML lesions involving the subcortical U-fibers which also extent centrally to the periventricular surface. (b) T2-weighted image on the same patient demonstrates “granular” or “microcystic” foci (arrows).

Figure 4

32-year-old woman with RRMS and no new neurologic symptoms developed MR findings on FLAIR images (a) without enhancement (b) consistent with PML (arrows) after having been on natilizumab for approximately 4.5 years. The drug was discontinued and she received PLEX and steroids. Follow-up imaging was obtained at (c-d) one month, (e-f) three months, and (g-h) four months later demonstrating progressive PML lesions, which corresponded to progressive clinical neurological decline. FLAIR (c) and postcontrast (d) images obtained at one month demonstrate disease progression without enhancement. Images obtained at three months show progressive disease (e-f) without enhancement to suggest active MS or IRIS. Like other aggressive infiltrating white matter lesions PML can cross the corpus callosum (arrows). Note also that there is now involvement of the left caudate (dotted arrow). The final images obtained four months after presentation (g-h) demonstrate swelling and compression of the gyri. There is now marked involvement of the deep gray matter structures (dotted arrows) which occurs in up to one-third of cases. However, note that despite involvement of almost the entire hemisphere, the lateral ventricle remains only mildly compressed and there is no midline shift, as would be expected with other lesions of this size, and no enhancement has developed.

Figure 5

45-year-old woman with a 10-year history of RRMS was started on natalizumab. She did well for six years and then developed gait abnormality and fatigue. MR imaging demonstrates large lesions in the cerebellar peduncles demonstrating a “crescent” shape.

Figure 6

Diffusion weighted images in a patient with large PML lesions demonstrate peripheral restricted diffusion where the lesion is active (arrows) and central facilitated diffusion where the lesion is more quiescent (dotted arrows).

Figure 7

(a) T2 FLAIR and (b) DWI images demonstrate a large PML lesion. (b) DWI demonstrates cytotoxic edema along the advancing edge of the lesion (arrows) surrounding the quiescent center. (c) Repeat MR DWI image following PLEX demonstrates absence of the hyperintense rim suggesting that disease progression has resolved.

Figure 8

Pathophysiology of PML-IRIS: (a) natalizumab blocks the α4β1 integrin, preventing lymphocyte tracking into the CNS. (b) To treat PML natalizumab must be rapidly cleared from the blood, often through PLEX. (c) With natalizumab effectively cleared from α4β1 integrin receptors the lymphocytes reenter the CNS to attack the PML virus. The response is often overwhelming, possibly exacerbating IRIS and leading to further destruction of brain tissue.

Figure 9

39-year-old woman with RRMS treated with natalizumab developed worsening symptoms. (a) MRI was performed at an outside institution demonstrating a new subcortical lesion in the right frontal lobe (arrow). She was treated for MS exacerbation. The patient presented to our institution approximately 3 months later with progressive symptoms and functional decline. (b) Repeat MRI shows increase in size of the right frontal lesion with characteristic bilateral, asymmetric distribution of lesions involving the subcortical U-fibers (arrows). (c) DWI shows a bright rim of signal along the advancing edge of the lesion (dashed arrows) with darker signal more anteriorly where the lesion is no longer active (dotted arrows). At this time there was no contrast enhancement (not shown). The patient was diagnosed with PML and PLEX was performed. Approximately one month later the patient experienced functional decline. Repeat MRI shows expansion of the (d) FLAIR lesions with increased swelling and mass effect and (e) the development of patchy central enhancement consistent with PML-IRIS. Note that the DWI image (f) no longer demonstrates an advancing edge of restricted diffusion.

Figure 10

27-year-old female with a typical relapse severity prior to natalizumab of 0–2 enhancing lesions on MRI. The patient was treated with natalizumab for 30 months without clinical or radiologic relapse but ceased natalizumab due to JCV Ab conversion. 3.3 months after cessation, patient relapsed and imaging demonstrated rebound with >14 enhancing lesions.