Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS

Case report.

In September 2002, a 30-year-old previously healthy woman presented with walking difficulties. Neurologic examination showed a bi-pyramidal syndrome, ataxia, and sensory disturbance in all extremities. After MRI of the brain and cervical spinal cord, which showed multiple typical T2-weighted white matter lesions, diagnosis of a clinically isolated syndrome suggestive of a first episode of MS was established.

In January 2003, the patient started interferon-β-1a, which she discontinued in October 2003 because of depressive symptoms. From March 2004 until December 2006, she used glatiramer acetate. Still, several clinical relapses occurred.

In March 2007, the patient started natalizumab infusions. She had no clinical exacerbations since. Routine MRI of the brain 1 year later showed no active lesions.

A second MRI in February 2009 was initially interpreted as showing no new lesions. In retrospect, subtle and diffuse abnormalities were visible in cortical and subcortical areas (figure). Since June 2009, she had mild progressive cognitive problems. For example, she made repetitive phone calls up to 6 times a day and was forgetting appointments. For that reason, in October 2009, a new MRI was performed, showing a new pontine lesion and progression of the diffuse abnormalities in both hemispheres (figure).

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Figure MRI

(A) Evolution of MRI manifestations during treatment with natalizumab. Transverse T2-weighted MRI of the supratentorial and infratentorial brain. The MRI in January 2007 (A.a) was performed prior to the initiation of natalizumab therapy; it shows multiple focal demyelinating lesions. The MRI scan performed in February 2009 (A.b) shows subtle, rather diffuse gray and white matter changes in the cortex and the adjacent white matter of the left middle and inferior frontal gyrus. These changes were not interpreted as representing important pathology. The MRI scan performed in October 2009 (A.c) presents multifocal new and progressive areas of diffuse demyelination in the cortex and white matter of both hemispheres suggestive of progressive multifocal leukoencephalopathy (white arrows). Also note the rapid development of focal (left superior frontal gyrus) as well as diffuse cortical atrophy between February and October 2009. The MRI scan performed on January 18, 2010 (A.d), shows remarkable diffuse lesions. (B) Course of MRI manifestations after cessation of natalizumab treatment. Transverse gadolinium-enhanced T1-weighted MRI of the supratentorial brain. The MRI scan of January 18, 2010 (B.a), performed 2 months after cessation of natalizumab treatment, shows, next to the new lesion in the mesencephalon, diffuse enhancement, especially right temporal and frontal on both sides. This enhancement pattern was interpreted as consistent with immune inflammatory reconstitution syndrome. The MRI scan of January 25, 2010 (B.b), shows progression of the bilateral areas of pathologic enhancement in the white matter. About 10 days after completion of a course of IV immunoglobulins (scan date February 8, 2010; B.c), MRI changes in terms of pathologic enhancement were more pronounced. Immediately after the IV corticosteroid treatment (scan date February 12, 2010; B.d), the pathologic enhancement pattern had almost completely disappeared.

In November 2009, after 36 natalizumab infusions, the patient developed an acute delirium. Because of the suspicion of PML, natalizumab infusions were discontinued. CSF JC virus viral load was positive both in the Laboratory of the University Center of Utrecht (<250 copies/mL) and in the Laboratory of Molecule Medicine and Neuroscience (57 copies/mL), confirming the diagnosis of PML. At the time all CSF results became available, the patient's condition had spontaneously improved. Because of this and the last natalizumab infusion more than 2 months ago, it was decided not to treat the patient with plasma exchange (PLEX) or immunoabsorption.

MRI on January 18, 2010 (figure), showed remarkable diffuse lesions and new focal lesions bilateral in the mesencephalon. Some patchy gadolinium enhancement was seen in both hemispheres. These findings were suggestive of immune reconstitution inflammatory syndrome (IRIS).

As the patient was recovering clinically, 1 week of further observation was considered appropriate. Because the preplanned follow-up MRI of January 25 (figure) showed obvious progression of gadolinium enhancement, IV immunoglobulin (IVIg), 4 days, 0.5 mg/kg, was administered. Two weeks after IVIg, the patient's clinical condition worsened: mental slowness, disorientation, and headaches developed. MRI showed progression of gadolinium enhancement (figure). We decided to start IV methylprednisolone (5 days, 1,000 mg). Her clinical condition improved within days and the MRI performed after this treatment showed a remarkable decrease in gadolinium enhancement (figure). Final clinical assessment at our hospital was on July 15, 2010. At that point the patient was clinically stable.

Discussion.

This case of PML presents a number of uncommon features. Most remarkable is the extremely protracted and indolent course of PML. Whereas clinical symptoms existed at least 3 to 6 months before diagnosis, we could see subtle MRI abnormalities already 9 months before diagnosis. These early MRI abnormalities were very similar to those described in the case reports by Linda et al.³ and Langer-Gould et al.⁴ Lesions in frontal regions might contribute to an even longer delay.

Another remarkable feature is the relatively mild disease severity although another 9 natalizumab infusions were given after the initial MRI manifestations.

In our patient, IRIS could be clearly distinguished from PML as a separate clinical episode, with secondary worsening after initial improvement, during which gadolinium enhancement on MRI was a prominent feature.

Whereas, in general, it is recommended to aggressively treat IRIS with IV methylprednisolone, some experts in Europe advise treatment with IVIg, as was also administered to some patients described by Clifford et al.² Because IRIS was clinically mild, maybe because PML was mild, or because this patient was not treated with PLEX or immunoabsorption, we treated her with IVIg. This case reaffirms the recommendation that progressive symptoms and worsening MRI evidence of PML should be treated aggressively with steroids.

This case shows that in a patient with MS treated with natalizumab clinical and radiologic vigilance is extremely important, because PML can present as an indolent disease with a protracted course which remains relatively benign for many months despite continued treatment with natalizumab.