Value of MRI as a surrogate marker for PML in natalizumab long-term therapy.

Five years after the introduction of natalizumab into therapy of active multiple sclerosis (MS), the number of natalizumab-associated progressive multifocal leukoencephalopathy (PML) cases has reached more than 150, with a mortality rate of 20% [1]. There is clear evidence that delay in making the diagnosis of PML is a critical parameter for prognosis. Despite the development of JC-virus (JCV) testing as a putative surrogate marker, there is still a critical need for better detection of early stages of PML. Here we report an asymptomatic case of PML with an initially negative JCV DNA PCR test in cerebrospinal fluid recognized by frequent MRI scans and describe the further benign disease course. A 28-year-old previously healthy Caucasian female was diagnosed with MS in 1995. She was treated with IFN-b-1a (Rebif 22 l) and experienced no relapses until 2007. In December 2007 the patient suffered from a severe relapse with dysarthria and paraparesis. These symptoms subsided after methylprednisolone therapy; however, a control MRI in February 2008 showed new contrast-enhancing brainstem lesions. Owing to disease progression natalizumab therapy was started in March 2008. Annual MRI controls from 2008 through 2010 revealed no new lesions. An elective control MRI in March 2011 showed a new hyperintense T2 lesion (1.0 9 0.5 cm) in the white matter of the left frontal lobe (Fig. 1b). PML infection was suspected; however, high-sensitivivity JCVPCR (university laboratory) was negative, and treatment was continued. The subsequent MRI in May 2011 revealed slight enlargement of the lesion with a mild increase of signal at the borders after contrast injection, suggesting peripheral enhancement (Fig. 1c). These changes were erroneously interpreted as a new MS lesion, and a possible switch of the therapy was discussed with the patient. Yet a control MRI in July 2011 revealed marked progression of the lesion (5 9 3 cm, Fig. 1d). Therefore, the patient was admitted to our hospital with suspected PML. The patient exhibited no neurological symptoms on admission. Family members did not report any behavioral changes; she continued working and planned traveling for holidays. The only possibly new finding was a slight deterioration of short-term verbal memory in neuropsychological testing. The JCV-PCR revealed 6230 copies/ml in CSF. JCV serology was also positive. The natalizumab therapy (total of 37 infusions) was discontinued, and plasma exchange immediately started. During the last control visit (3 weeks after PLEX) the patient was still asymptomatic, and MRI demonstrated an unchanged white matter lesion in the frontal lobe without contrast enhancement. Our case report illustrates several interesting points. Firstly, the radiological manifestation of PML can be present before clinical deterioration. Depending on the localization of lesions, patients may stay asymptomatic for quite a long period of time. Our patient had no deterioration for at least 4 months after the first changes in MRI had been detected. Secondly, PML can manifest as a monofocal condition and may be difficult to differentiate from a new MS lesion. The observation that PML lesions generally occur in areas not previously affected by multiple sclerosis may be helpful [2]. Thirdly, the first CSF analysis may be I. Ayzenberg (&) N. Trampe R. Gold K. Hellwig Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany e-mail: ilya_ayzenberg@yahoo.com